CIRCULATING TUMOR MARKERS: BASIC CONCEPT-I. CIRCULATING TUMOR MARKERS: BASIC CONCEPT-II.
Your doctor may order blood tests for cancer/tumor markers to detect cancer activity in the body. Proteins and circulating tumor cells are two types of markers that can be measured. A cancer tumor often produces a specific protein in the blood that serves as a marker for the cancer. Circulating tumor cells are cells that break off from the cancer and move into the blood stream. Protein markers and circulating tumor cells can be measured with simple blood tests.
Blood marker tests may be done before treatment, to help diagnose the breast cancer and determine whether it's moved to other parts of the body; during treatment, to assess whether the cancer is responding; and after treatment, to see if the cancer has come back (recurrence).
1. EPIDEMIOLOGY OF CANCER DISEASES
IT IS GENERALLY UNAPPRECIATED HOW BIG A HEALTH PROBLEM CANCER PRESENTS WORLDWIDE - A CHALLENGE THAT IS GROWING.Each year cancer is newly diagnosed in 9 million people worldwide and it causes 5 million deaths. It is second to cardiovascular disease as a cause of death in developed countries, and overall causes 10% of all deaths in the world. It is usually regarded as a problem of the developed world, but more than half of all cancers are seen in the three-quarters of the world’s population who live in developing countries. The answer to this question, “What is cancer?”provides the scientific basis for cancer control. With all of the recent advances in molecular biology which have increased our understanding of the genetic basis of cancer with the description of oncogenes (cancer genes) and the suppressor genes which regulate their expression, the biologic basis of cancer has received most of the attention. But the nature of cancer also has an equally important social aspect which is essential for cancer control.
Neoplasia is a disease process that results in over 100 different malignant diseases that share a common biology and natural history. Any cell in the body that can undergo mitosis or cell division can be affected. Cancer has links to other disease processes. Some infections cause cancer: e.g. schistosomiasis associated with bladder cancer and the liver fluke, Clonorchis sinensis, which causes cancer of the gall bladder. There are also toxic causes: e.g. mesothelioma, a tumor arising in the pleura which lines the thoracic cavity resulting from exposure to asbestos (asbestosis). Despite popular opinion, however, it is unlikely that local trauma is a cause of cancer. As a fundamental disorder of cellular growth and differentiation or development, cancer is essentially a genetic disorder at the cellular level. Most tumors are encapsulated and benign in behavior. Occasionally they may create symptoms from cosmetic or mass effects. In using the generic word “cancer”, however, we are concerned here with malignant tumors that are morphologically abnormal under the microscope. They show uncontrolled growth leading to local invasion with disruption of tissues, and later metastasis or spread to loco-regional lymphatics and later the blood stream. Cancer kills mostly through blood-borne metastasis.
A tumor does not grow freely in its human host as it would in tissue culture. The host puts up a defense, generically called “host resistance”, which resembles defense against infections. There is a homeostatic interaction between the host and tumor cells or microorganisms based on a dynamic balance between them and the host microenvironment in which they grow - an updated version of the seed-and-soil hypothesis. The tumor arises from an abnormality of growth and differentiation based on altered structure, regulation and expression of its genes. The resulting properties of transformation, invasiveness, metastasis, clonality and heterogeneity give rise to its malignant behavior. But the outcome of its growth still depends on its interactions with host defenses for a net result of progression, dormancy or regression. The process is dynamic and chronic with the balance of host resistance changing with the advancing stage of tumor growth.
Cancer has
a characteristic natural history. Healthy cells first become dysplastic showing
subtle morphological abnormalities under the microscope which suggest the
beginning of transformation. The next step is carcinoma in situ where
characteristic abnormalities of both form and proliferation are present but
without invasion of the underlying basement membrane that holds them in place
in the tissue of origin. This earliest phase is highly curable and is detected
with screening programs, such as the PAP smear for cervical cancer. Localized
cancer is stage I disease where the tumor exhibits invasion and disruption of
local tissues to form a primary lesion. Tumor cells then invade local
lymphatics and spread to the regional (stage II) or extended regional (stage
III) draining lymph nodes as secondary tumors. Finally tumor cells invade into
the blood stream where characteristic patterns of blood-borne metastasis herald
the onset of stage IV disease. Particular tumors vary in the extent to which
they follow these phases in sequence: melanoma usually has a distinct
loco-regional phase, while breast cancer is systemic from the beginning.
Staging correlates with survival and provides an essential guide both to
prognosis and to the design of treatment plans.
The “gold standard” for a diagnosis of cancer is a histopathological examination by a pathologist on biopsied tumor tissue. Unfortunately this is not always done and the diagnosis is made from clinical findings or less. Cancer can be mimicked by many other diseases. Moreover, cancer statistics depend on the accuracy of death certificates, where cancer may not be properly noted as the cause of death. Biologic markers are playing an increasingly important role in cancer management. Most of these markers are not unique for cancer cells, but are shared also by normal cells and may also be overexpressed in benign conditions. Thus markers cannot be used to screen populations to detect cancer.
The biology of cancer has important implications for cancer control. At the cellular level the problem is faulty genetic control; cancer is basically a genetic disorder. But hereditary cancers such as retinoblastoma, are uncommon. Instead the disease is usually acquired from external influences which are, therefore, potentially avoidable. With current methods overall one can expect to prevent theoretically 2/3 but in practice more realistically 1/3 of cancer, and to be
able to cure about 1/3 in a developing country, and closer to 1/2 in a developed country.
As a lifestyle disease, cancer arises out of conditions of life which result in exposures to carcinogens. Such exposures result from two situations: * Where people live * Changes people make in the world
Cancer
shows both geographic and temporal variability. There are different patterns of
cancer at different places and different times. These patterns relate both to
habits and to environmental hazards.
Habits: The use of tobacco has resulted in lung cancer in North
America and Europe during the last half of the 20th century. Dietary
habits underlie the high incidence of stomach cancer in Japan, Northern
China, Chile and Eastern Europe. This tumor is associated with
lower socioeconomic status. The incidence falls in second generation Japanese
who have moved to the United States of America. Food preservation methods
are associated with stomach and liver cancers in West Africa and Southeast
Asia. Techniques for pickling as well as contamination with aflatoxins from
mould are responsible. Environmental hazards:
Viruses: Hepatitis B Virus is associated with liver cancer.
Risk factors for cancer which people create by making changes in their world may be thought of as the price for industrialization. Ionizing radiation: In the latter part of the 19th century over half of certain groups of miners working in the Joachimsthal and Schneeburg mines of Central Europe died of lung cancer. High lung cancer rates were also observed in miners digging copper, lead and zinc from the Colorado plateau in the United States during thew first half of the 20th century. In both cases disease was induced by exposure to radioactivity in the mines. Occupational exposure occurs in uranium mines Manufacturing: The manufacture of various substances can lead to cancer. One example is bladder cancer from the dye-stuff, betanaphthylamine which was seen in Europe and North America until exposure was controlled through occupational health and safety initiatives. Now it has reappeared in Southern Asia where industrialization has exported these risks to contexts not appreciated by people who live and work there. Yet another example has been exposure to asbestos in Quebec, Canada, and to asbestiforme erionite in Turkey, both with an association with mesothelioma.
Click here for a summary of each of the key risk factors that are implicated currently in the causation of cancer.
This slide shows the relative importance of the various risks and causes of cancer. It is based on a study of cancer mortality in the United States in 1981. Various adjustments have been attempted since then, but they are minor and the overall pattern remains the same and is important in setting cancer control priorities. It is clear that most of cancer, between 2/3 to 3/4, is potentially preventable. Since comparatively less is known about diet, tobacco control is the major target for cancer prevention programs. In countries like India, 50% of cancer is oral cancer of which 90% is associated with chewing of tobacco in various forms aggravated by smoking. In North America, in contrast, lung cancer makes up 25% of cancer, and 80 to 90% is associated with smoking. Another factor important to prevention initiatives in some countries is HBV infection which leads to primary liver cancer in Sub-Saharan Africa
As a lifestyle disease, cancer arises out of conditions of life which result in exposures to carcinogens. Such exposures result from two situations: * Where people live * Changes people make in the world
Cancer shows both geographic and temporal variability.
There are different patterns of cancer at different places and different times.
These patterns relate both to habits and to environmental hazards.
Habits: The use of tobacco has resulted in lung cancer in North
America and Europe during the last half of the 20th century. Dietary
habits underlie the high incidence of stomach cancer in Japan, Northern China, Chile and Eastern
Europe. This tumor is associated with lower socioeconomic status. The incidence
falls
These social
dimensions of cancer have important implications for the design of cancer
control programming. They stem from behavior patterns that people evolve to
meet their biological, psychological and social needs. These patterns, in turn,
create a lifestyle which influences cancer incidence. They include the
development of addictions to tobacco, drugs and alcohol, the ways in which food
is prepared, stored and eaten, and certain risk patterns of personal
interaction as with sexual mores. With tobacco, for example, oral cancer
predominates where tobacco is chewed, and lung cancer where it is smoked. The
changed cancer patterns that accompany the migration of people provides an
example of the influence of lifestyle on the occurrence of cancer. When Mexicans
migrate to the United States they take on the cancer incidence
patterns of their new country.
There is a very real possibility that lifestyle change can reduce cancer
incidence. But such changes can be very difficult to make, as anyone who has
tried to stop smoking can attest. There is now a major research emphasis on the
application of behavioral science in health promotion and prevention programs
to create lifestyle change at the population level.
Biologic factors in cancer etiology refer largely to the role of four classes of external agents in carcinogenesis: physical, chemical and biological agents, and diet.
Physical Agents: * Ionizing radiation can be
background from cosmic rays and earth sources of radioactivity. More important
are cumulative exposures from medical diagnostic and treatment procedures, and
from commercial and occupational sources. Exposures have also occurred with
warfare, as in the atomic bombs dropped
on Hiroshima andNagasaki in Japan in world war II.
Leukemias and cancers of the breast, lung and thyroid are typical but cancers
of the stomach, colon, bladder, and potentially any human tumor may be seen.
* Nonionizing radiation of solar origin,
especially the ultraviolet (UV)B wavelengths, are associated with basal and
squamous skin cancers and with malignant melanoma. Certain inherited skin types
(Celtic skin) are at greater risk. Commercial sources such as tanning parlors
also provide risk.
* Particles can also be important. The cancer risk
with asbestos relates to fiber length and toughness. The risk from particles in
air pollution is related to their size and propensity to settle in the lung.
Because of the
widespread nature of the tobacco habit, control of carcinogenesis by chemical
agents provides a major basis for cancer control. The process of carcinogenesis
by chemicals is subject to both initiation and promotion steps. These
carcinogens have a particular chemistry as aromatic electrophiles - chemically
very reactive substances often formed as metabolic products.
* Some have medicinal sources, such as the use of diethylstilbestrol
in pregnancy to avert abortion resulting in vaginal cancer in the daughters.
* Others come from habits such as the use of
tobacco (oral and lung cancer, and other tumors) or alcohol (head and neck
cancers).* Industrial
and occupational exposuresare also important:
Viruses are responsible for only about 5% of human cancer. But they are much more common causes of cancer in animals, where their experimental study has played a key role in the identification of oncogenes. Both DNA and RNA viruses are implicated. * Hepatitis B virus (HBV) causes primary liver cancer. Vaccination of the children of susceptible populations is used for prevention.* The Epstein Barr Virus (EBV) is implicated in nasopharyngeal cancer.* The Human Papilloma Virus (HPV), especially certain subtypes like 16, are associated with cervical cancer. These viruses also cause warts, which are benign tumors. Some parasitic infections are associated with cancer.* Infections with Schistosoma haematobium (schistosomiasis) may be associated with bladder cancer. This parasite enters the skin from water infected by snails. * The liver fluke, Clonorchis sinensis, is associated with cancer of the gall bladder and hepatobiliary ducts.
As a lifestyle factor diet has been shown to play a significant
role in the causation of cancer worldwide. But little is known as yet about how
it plays its role as a carcinogen. This is currently a very active area of
cancer research. There are several studies which show that excessive fat in the
diet raises the risk of colorectal and breast cancer, and possibly other
cancers as well, such as prostate cancer.
Methods of food preparation and preservation can also create
risks. There are studies showing that nitrites are associated with stomach
cancer. Other studies are showing that certain broad classes of foods may
contain protective substances against cancer. These include
certain vegetables (the cruciferous group), whole grain products (fiber) and
citrus fruits.
The three major classes of external carcinogens,
and perhaps to some extent diet (although how it plays its role is not yet
understood), exert their effect through multiple steps involving a final common
pathway - the oncogenes.
The final result is malignant transformation and then the development through
further genomic instability the properties of invasiveness and
metastasis.
Lifestyle and the conditions in which people live determine
the prevalence of environmental risk factors. Five groupings of these risk
factors make up the social factors in cancer etiology.
Click here for a summary of each of the key risk factors that are implicated currently in the causation of cancer.
This slide shows the relative importance of the various risks and causes of cancer. It is based on a study of cancer mortality in the United States in 1981. Various adjustments have been attempted since then, but they are minor and the overall pattern remains the same and is important in setting cancer control priorities. It is clear that most of cancer, between 2/3 to 3/4, is potentially preventable. Since comparatively less is known about diet, tobacco control is the major target for cancer prevention programs. In countries like India, 50% of cancer is oral cancer of which 90% is associated with chewing of tobacco in various forms aggravated by smoking. In North America, in contrast, lung cancer makes up 25% of cancer, and 80 to 90% is associated with smoking. Another factor important to prevention initiatives in some countries is HBV infection which leads to primary liver cancer in Sub-Saharan Africa and South East Asia. Contamination of foods by aflatoxins also contributes. Although alcohol contributes to cancer in the West, primary liver cancer is uncommon. These figures show that cancer is a lifestyle disease. The combination of tobacco use, a high fat and low vegetable diet, and no exercise would appear to be the right combination of risk factors for both cardiovascular diseases as well as cancer - especially lung, colorectal and breast cancers!
In developing countries cancer causes about 1 in 20 deaths. The incidence is increasing as living standards improve and life expectancy is prolonged leading to a decline in communicable diseases and an increase in noncommunicable diseases.
In developed countries, cancer is second only to cardiovascular diseases as a cause of mortality and accounts for about 1/4 of all deaths. Three factors contribute to the increase in cancer mortality: *in developed countries deaths from cardiovascular diseases are declining; *the “graying” of the population means that people are living longer and cancer is more frequent in older age groups; and *increasing use of tobacco, mostly as cigarette smoking, during the past few decades has resulted in a greater incidence of related cancers, especially lung cancer. Indeed the increase in smoking in young women is resulting in a rapid rise in the incidence of lung cancer, which in some developed countries is surpassing breast cancer as the commonest cancer in women.
In contrast, perinatal disorders and infections comprise less than 10% of the mortality in developed countries, and it continues to drop.
The basis for the striking contrast in the last two slides between developing and developed countries is the transition phenomenon, which is illustrated here.
The incidence of cancer at various body sites may differ in different countries. Oral cancer is common in India as a consequence of chewing tobacco. Stomach cancer is more frequent in China and Japan, as well as in South and Central America (Mexico, Costa Rica) and also Eastern Europe. Primary cancer of the liver is uncommon except in portions of Africa, east Asia and the western Pacific. Cervical cancer is more common in developing countries especially in situations of low socioeconomic status. Epidemic levels of cigarette smoking have led to the high incidence of lung cancer in developed countries, for example, North America, Europe and Shanghai in China, but it is low in Africa.
Temporal trends in cancer tend to show epidemics that rise to a peak and then recede over very long time periods of decades. The long time periods hide the epidemic nature of the disease. Projections of incidence, prevalence and mortality are important for planning cancer control interventions.
Cancer
impacts not only the patient, but also his or her family and community. In
North America 1 in 3 individuals born during the last decade will
experience cancer at some point in their lifetime. By the year 2000 the figure
will be one in every two. One in four to one in five North Americans will die
of cancer. Thus most individuals in North America have some experience of the
disease, if not personally, then in a family member, friend or acquaintance.
In addition to its pervasive presence in the community, the disease is widely
feared the world over as synonymous with suffering and death. Patients may be
stigmatized and experience social isolation and family tensions as well as
inability to get insurance or even job loss with economic dependence aggravated
by high costs of medical care if there is no health insurance. Progress in
controlling cancer has been frustratingly slow. Critics disagree how resources
should be distributed between treatment and prevention or between research and
putting existing knowledge into practice.
The economic burden of cancer to a country is shown in this example
of a study done in the USA to estimate direct and indirect costs for 1977.
Direct cancer care costs were estimated at US $7 billion with corresponding
indirect costs of US $ 15 billion, for a total in that year of US $22 billion
or nearly $100 per capita. Direct costs for hospitals, health care services and
drugs can be estimated reasonably easily where one has information about what
services and how much of them are provided to cancer patients. Indirect costs
arise from lost productivity following on illness and premature death. They are
more difficult to estimate since they require assumptions about expected future
earnings and a discount rate to convert these back to current dollar value. In
the study cited a discount rate of 10% was used.
Examples of markers your doctor may test for include:
CA 15.3: used to find breast and ovarian cancers
TRU-QUANT and CA 27.29: may mean that breast cancer is present
CA125: may signal ovarian cancer, ovarian cancer recurrence, and breast cancer recurrence
CEA (carcinoembryonic antigen): a marker for the presence of colon, lung, and liver cancers. This marker may be used to determine if the breast cancer has traveled to other areas of the body.
Circulating tumor cells: cells that break off from the cancer and move into the blood stream. High circulating tumor cell counts may indicate that the cancer is growing. The CellSearch test has been approved by the U.S. Food and Drug Administration to monitor circulating tumor cells in women diagnosed with metastatic breast cancer.
Some doctors use marker test results as early indicators of breast cancer progression (the cancer getting worse) or recurrence. They may use this information to make decisions about when to change therapies — if current treatment does not appear to be working — or to start treatment for recurrence. If you have an elevated marker, your doctor may check that marker periodically to assess your response to chemotherapy or other treatments.
While breast cancer blood marker tests are promising, they're not absolutely conclusive. When a breast cancer blood marker test comes back negative, it doesn't necessarily mean you're free and clear of breast cancer. And a positive result doesn't always mean that the cancer is growing. These tests may help with diagnosis, but using cancer marker tests to find metastatic breast cancer hasn't helped improve survival yet.
When deciding if you should get tested for breast cancer blood markers, there are some things you may want to consider:
cost — the tests can be expensive
anxiety — not just from an elevated blood marker, but by all the tests you may need to find out what's causing the marker to go up
Talk to your doctor about the possible benefits and risks of blood marker testing in your unique situation.
Imunoendokrynolohiya a new medical - biological disciplines. As an independent research direction of this area of knowledge emerged in the early 70s of the last century on the basis of numerous accumulated at the time of the actual material that testified to the close reciprocal relationship of the endocrine and immune systems, together with the nervous system performs a regulatory function in body. Formation and development imunoendokrynolohiyi occurred through the joint efforts of researchers, experimenters and clinicians of many specialties: immunologists, endocrinologists, biochemists, physiologists, and other pathophysiologists.
In recent years, several imunoendokrynolohiyi determined the most promising areas:
- Fundamental studies of mechanisms of hormonal regulation of immune;
- Study the role of immunological and immunogenetic factors in the etiology and pathogenesis of endocrine diseases and their complications;
- Immunological monitoring of patients with endocrine disorders and searching informative methods for immunological studies for use in the diagnosis and monitoring of treatment of endocrine diseases;
- Search and development of pathogenesis based prevention of autoimmune endocrine diseases;
- Development of new approaches to the immunotherapy of patients with endocrine diseases in order to improve the treatment and prevention of complications;
- Improvement of methods of transplantation immunological cells of endocrine organs.
Below is a more detailed overview of the most current trends. Some of these problems developed at the Institute of Endocrinology and Metabolism them. VP Komisarenko AMS of Ukraine.
Endocrine regulation of the immune response
Having hormonal control of the immune system is confirmed by numerous experimental and clinical observations and currently there is no doubt. Research in this direction started long ago, but the advent of modern highly specific methodological approaches this research led to a new level, allowing not only complement and flesh out our understanding of the effect of various hormones on the immune system, but also to determine the molecular genetic basis of this effect [22 ].
Found that both systems use similar receptors and ligands for intersystemnoho and intrasystemnoho communication link, which plays an essential role in homeostasis. Effect of hormones occurs in the interaction with specific receptors on cells of the immune system. However, their effect may be direct or indirect. The first option is observed upon binding to receptors of lymphocytes and macrophages. There are more than 20 varieties of these receptors. The second option is realized by the action of hormones on the stromal cells of lymphoid organs, especially the thymus, through its impact on development and functional state of immune cells. The degree of expression of receptors for hormones and cell reactivity vary in different populations and subpopulations of lymphocytes and monocytes, which largely determines the selectivity and intensity and hormonal influences.
Hormonal factors are divided into two alternative groups. The first, which includes cortico-steroids, adrenocorticotropic hormone (ACTH), androgens, estrogens and progestins, in general, have a depressing effect on the immune system. Other: somatotropin hormone (GH), thyroxine, thyroid stimulating hormone (TSH), insulin, prolactin and progesterone - integral stimulate immunological reaction. The essential point is that the effects of many hormones is largely dependent on the dose: some doses they act as suppressors, others - stimulate the immune response. Thus, cortisol and other hormones of the adrenal cortex in physiological concentrations inhibit lymphocyte proliferation, but promote their differentiation, and pharmacological doses induce apoptosis of lymphocytes and their redistribution in the body due to increased emigration of thymocytes thymus cortex. They also inhibit the activation of lymphoid cells in immune response and block cell-cell interactions, reduce the secretion of interleukins and tymichnyh hormones. The effect is similar expressions hypercortisolism, is under stress and administration of glucocorticoids for therapeutic purposes. Chronic stress causes a reduction in stamina to bacterial and viral infections.
Sex hormones also reduce klitynnist lymphoid organs and functional activity of the immune system. Androgens and estrogens contribute to the development of age involution of the thymus. Their effect on the epithelial cells of the stroma of the thymus in early puberty is considered as a starting point involution. Estrogens strongly inhibit the activity of suppressor cells to see why one of the reasons for women's greater susceptibility to autoimmune diseases.
Thyroxine, insulin and insulin-like growth factor directly involved in shaping the immune system and the development of an immune response, enhance processes of proliferation and differentiation of lymphocytes. HGH makes a direct mitogenic effect on T cells.
Extremely important for the normal functioning of the immune system is the level of hormone secretion by epithelial cells of the thymus. It is known that the thymus is the central organ of the immune system that performs tsytokrynnu and endocrine function. That there is a differentiation in the thymus thymocytes from bone marrow precursors in functionally different lymphocyte subpopulations. In addition, the thymus produces tymichni peptides, affecting the activity of peripheral lymphocytes and interleukin production. The main hormone produced by thymic epithelial cells and is present in plasma at physiologically relevant concentrations, is tymulin [10, 22]. Tymulin (second name - tymichnyy serum factor) is a nanopeptyd bound to zinc ions, which are necessary for the implementation of its biological activity. According to modern concepts, tymulinu level in serum is an integral indicator of endocrine function of the thymus is one of the most important characteristics of immune status. The introduction of synthetic tymulinu enhances suppressed (in aging, immunodeficiency, after tymektomiyi) response of T cells to mitogens, allograft rejection, limiting the development of an autoimmune process. Age decrease production tymulinu considered one of the causes of aging of the immune system in general and the weakening of immune protection, especially mediated T-lymphocytes. Tymulinu secretion is controlled by cytokines (interleukin-1α and-1β, IL-2, γ-interferon) and hormones, corticosteroids and sex hormones suppress it, thyroxine, growth hormone and insulin - increase.
Installed changing endocrine function of the thymus in many endocrinopathies. Experiments conducted laboratory staff Endocrine regulation of immune Institute of Endocrinology and Metabolism them. VP Komisarenko Sciences of Ukraine, showed reduction of thymic hormones in mice with chemically-induced (streptozotocin and aloksanom) diabetes and in animals with genetically determined diabetes (BB rat, mouse, db / db) [1, 3]. In clinical trials revealed a significant decrease in the concentration tymulinu in patients with hyperthyroidism and thyroid neoplasms [2] (which deepened after thyroidectomy), and in children with diabetes mellitus (DM) type 1, shows the dependence of these changes on the duration of the disease and the presence of complications.
The relationship between the endocrine and immune systems are not unidirectional. The literature shows evidence of immunological factors regulating influence on the endocrine system. The main mediators of this effect is thymic peptides and cytokines. It is believed that tymichni hormones involved in the regulation of the hypothalamic-gonadal axis pituyitarno-axis by stimulating the secretion of hormones of the pituitary, hypothalamus, thyroid gland. Show their influence on the activity of the adrenal cortex and reproductive organs [22].
Found that IL-2 and IL-6 are potent stimulators of steroid production through effects on corticotropin-releasing hormone. A role, especially in the control of secretory activity of pituitary cells, also play antibodies (including antyidiotypichni) and immune complexes. Noteworthy is the fact that immune cells are able to produce peptide hormones. Proved synthesis of glucocorticoids and all adenohipofizarnyh thymus hormone (TSH, ACTH, LH, FSH, GH and PRL). Feasibility and biological role of this synthesis is actively researched and debated.
The study of the pathogenesis of autoimmune endocrine diseases
Autoimmune pathology of endocrine organs is one of the most studied. In the early 50s E. Witebsky and N. Rose replicated experiment Hashimoto's thyroiditis by immunization with rabbit thyroid extracts. In 1956, British scientists have shown the presence of such antibodies in patients with chronic thyroiditis, was first used the term "autoimmune disease" as a nosological category. Finally, it is proved that all the pathogenesis of autoimmune diseases is the development of an immune response to its own antigens (in cases of autoimmune endokrynopatiy - this antigen glands) [18]. Recent advances in immunology, molecular biology, genetics, experimental and clinical endocrinology much deeper insight into the etiology of autoimmune endocrine organs and key factors of pathogenesis.
The nature of all autoimmune diseases are divided into 2 groups:
- System, where through the wide prevalence antigen in the pathological process involved in almost all tissues of the body (eg, rheumatoid arthritis and systemic lupus erythematosus);
- Organ, when the object of affection is the appropriate body and the pathological process is local.
All autoimmune endocrinopathies, and these include: Hashimoto's thyroiditis (autoimmune thyroiditis, AIT), hyperthyroidism, diabetes mellitus type 1, Addison's disease, and others - are organ.
There are also combined forms of endocrine diseases - autoimmune syndrome polihlandulyarnyy 1st and 2nd types (APS-1 and APS-2). APS-1 develops during the first two decades of life and includes hypoparathyroidism, adrenal insufficiency and candidomycosis (often associated with hypogonadism, pernicious anemia, vitiligo). APS-2 observed in adults and is characterized by the triad: insulin-dependent diabetes mellitus, autoimmune thyroid disease and adrenal insufficiency.
The prevalence of autoimmune endocrine diseases in different countries varies, but all diseases it owns a significant place. The incidence of diabetes mellitus, thyrotoxicosis and autoimmune thyroiditis is increasing annually. Chronic nature of these diseases, frequent development of complications, which in turn is the cause of reduced life expectancy and deterioration of its quality, makes medical and social importance of this issue. Recent years has intensified study of the etiology and pathogenesis of autoimmune endokrynopatiy and to develop effective methods of prevention and treatment.
Today it is generally accepted that autoimmune endocrinopathies are complex diseases caused by the formation of the interaction of three main factors: genetic heredity, the immune system and the environment [4, 7, 8].
Under certain conditions, the action of external factors in the presence of a genetic predisposition leads to disruption of the central and peripheral mechanisms of immune tolerance and immune response to antigens own body. As a result of the activation of lymphocytes and clones autoahresyvnyh hypersecretion of various mediators failure occurs hormonsekretuyuchyh structures endocrine organs, which further manifests clinical signs of hypo-or hyperfunction respective glands.
As mentioned, one of the significant factors considered hereditary autoimmune disease. The existence of familial cases of diseases - a clearly established fact. Evidence of the role of genetic factors in autoimmune diseases is the association of these disorders with specific genes, including the most significance with major histocompatibility complex genes (in humans - HLA-complex). In autoimmune diseases of the endocrine organs are particularly common haplotypes: HLA-B8, DR3 - autoimmune thyroiditis; HLA-DR5, DQw7 - hypertrophic form of thyroiditis; HLA-B8, DR3, DQ2/DQ8 - diabetes type 1; HLA-B1, DR3, DQ8 - Addison's disease; HLA-DR3, DR4, B8 - polihlandulyarnyy syndrome [6, 12]. It is believed that HLA-genes are responsible not only for susceptibility to the disease, but also for the time of occurrence, nature of the flow and are often the result of the pathological process.
In the last decade intensively studied genetic characteristics of diabetes. A large number of publications dedicated to particular genotype in patients with diabetes mellitus type 1 in different ethnic groups, races, countries and continents. Today describes more than two dozen loci and 100 genes that determine the risk of diabetes [4, 24]. However, despite the tremendous efforts of scientists, the role of most of them remains still a mystery. Numerous studies of populations give mixed results on the association of diabetes with genes HLA. Moreover, some genes HLA haplotypes are diabetohennymy in one population, indifferent and even protective in other populations.
The presence of a haplotype that determines the risk of developing autoimmune endocrinopathies relevant, does not mean that this tendency must be implemented. Required triggers that initiate the onset autoimmune process in genetically predisposed individuals. Determined that this action produce environmental factors. First of all, viral and bacterial infections, as well as drugs, food, ionizing radiation, hormones, stress, pregnancy, aging, and probably some other not yet identified factors.
The significance of these factors for a variety of endocrine diseases are not the same. For example, diabetes is a significant Coxsackie B viruses, rubella, cytomegalovirus and retroviruses [16]. According to some precipitating factor of diabetes may be bottle-feeding, cow's milk, over-nutrition, nitrosamines containing nitrates and nitrites. Transient hyperglycemia can cause some chemicals and pharmaceuticals, such as calcium channel blockers, cimetidine, corticosteroids, indomethacin, pentamidine and vincristine.
Autoimmune thyroiditis is more common in people with overweight, which may be due to certain disorders of lipid metabolism and hormonal regulation. In this regard, noteworthy information about the relationship of this disease with elevated levels of estrogen and prolactin. Among the exogenous factors should be noted bacterial and viral infections, excessive iodine, radiation, several immunotherapeutic agents: α-interferon, interleukin-2 and others.
Thus, autoimmune diseases are multifactorial in nature and highly heterogeneous. Their common feature is the development of an immune response to its own antigens. Typically, these conditions are prolonged (chronic) character because of the constant of the antigen in the body (since it is a normal component of cells). Features of the clinical manifestations of autoimmune diseases is largely dependent immune responses that predominate in response to antigen. This may be cell-type reactions associated with the action of cytotoxic cells (eg, diabetes mellitus type 1). These reactions generate T-helper type 1 (Th1). T-helper type 2 (Th2) induce humoral immune responses (antibody synthesis) and dominated in patients with autoimmune thyroiditis.
An important factor in understanding the nature autoagression is that the mechanisms of immune responses in autoimmune diseases are not much different from the immune response to foreign antigen [7]. Only in this case, the target of immune reactions are the body's own cells. Why is this?
According to modern concepts, a two-tier system of immunological tolerance (non-responsiveness of the immune system to its own antigens) - central and peripheral. The purpose of the first level of control is to prevent, if possible, the formation of clones of lymphocytes, aggressive in relation to their own antigens, whereas peripheral tolerance mechanisms provide a suppressor effect on autoreactive cells that were in circulation and peripheral lymphoid organs. Formation of central immunological tolerance occurs in the thymus during maturation of thymocytes at the stage of so-called "negative selection" [5]. Medullary thymic stromal cells, mainly epithelial, to a lesser extent - dendritic cells and macrophages, T lymphocytes are custom peptides in complex with major histocompatibility complex molecules 1st and 2nd grades. Clones of lymphocytes with high affinity receptors that recognize their antigens are culling and elimination. The death of these cells occurs by apoptosis.
It used to be that no thymus tkanynospetsyfichni antigens (TSA), and tolerance mechanisms are provided solely peripheral suppression. In recent years, obtained conclusive evidence of the presence in the thymus almost all known TCA [14]. Moreover, it was found that the synthesis and secretion of TCA is the physiological properties of cells of the thymus [9]. It is shown that the thymus expressed all the genes of the family of insulin: IGF2 (in epithelial cells), IGF1 (in macrophages), INS (in epithelial and dendritic cells) and molecules GAD and IA-2 [11].
With regard to peripheral tolerance, it is provided mainly special population of T cells with the phenotype (CD4 + CD25 +), these regulators, - Treg. This cell type has been described by S. Sakaguchi in 1995 and is currently being studied [15, 21]. The main purpose of these cells - preventing autoimmune processes.
It was believed that this population of cells is generated only in the thymus and in peripheral regions of the immune system just completed their differentiation. Last year, just a few researchers the possibility of de novo appearance of the "naive" predecessors and in the periphery [20, 25]. Regulatory cells provide dominant and recessive immunological tolerance, limit the development of immune responses, including allergic and autoimmune reactions. Treg synthesize a large number of cytokines TGF β (transforming growth factor) and interleukin-10 inhibit the proliferative and secretory activity of effector (CD4 +) and cytotoxic cells (CD8 +). Functional defect of regulatory cells found in many autoimmune diseases in humans and animals. Thus, in NOD-mice (artificially bred strains of mice, which spontaneously develop diabetes type 1) and patients with diabetes mellitus type 1 found a significant reduction in both the number and functional activity of this subpopulation of cells [25].
Suppressor activity of Treg is associated with a molecule Foxp3 - intracellular transcriptional factor encoded by the gene FOXP3, localized on chromosome X. This molecule is of particular interest to researchers, as people and animals who have discovered a genetic defect Foxp3, suffering autoimunniyi pathology [21, 23]. It is shown that the mutation of FOXP3 cause IPEX-syndrome (Immune disregulation, Polyendocrinopathy, Enteropathy X-linked syndrome). This disease begins in early childhood and is characterized by multiorgan autoimmune endocrine lesions (DM 1 - the first type AIT), gastro - intestinal tract, and hematological changes (hemolytic anemia, thrombocytopenia).
Installing the pathogenetic role of Treg in the development of autoimmune diseases has become a basis to develop strategies specific biotherapy. Today it is necessary methodological basis for determining the number and activity of Treg-cells. To study the technology of their isolation and expansion ex vivo, and activation conditions. In experimental studies have shown that the introduction of Treg dose-related decreases the incidence of spontaneous diabetes in NOD-mice. In publications discussed the use of Treg-cells as a means of treating autoimmune diseases in humans [20].
So, are presented in the literature data indicate substantial progress in the study of the etiology and pathogenesis of autoimmune endokrynopatiy.
However, despite intensive research, is still an open question that is primary in the development of autoimmune diseases: congenital and acquired defects of immune dysfunction and / or target organ damage, or both factors.
The earliest recorded evidence of an autoimmune process has begun, is the appearance in the peripheral blood circulating autoantibodies and lymphoid organ infiltration. In autoimmune diseases of the thyroid receptor antibodies determined by thyroid stimulating hormone (TSH), thyroid peroxidase (TPO) and thyroglobulin (TG) in diabetes - to hlutamatdekarboksylazy (GADA), tyrozynfosfatazy (IA-2), insulin (IAA) and cytoplasmic antigens β-cells (ICAs); Addison's disease - to microsomal and mitochondrial antigens of the adrenal glands, and often to the ICA and 21-α-hydroxylase. When poliendokrynnyh syndromes 1st and 2nd type is a wide range of autoantibodies to antigens of peripheral endocrine glands. The appearance of antibodies usually precedes the clinical manifestation of the disease. The latent period of the disease may last from several months to several years (sometimes decades, in AIT), much has individual character and may depend on the etiological factors, heredity and age of patients.
Interestingly, autoantibodies as a base (sometimes only) for diagnosis, rarely directly involved in structural and / or functional disorders of the body of the target.
Pathogenic effect convincingly proven only for TSH receptor [17]. There are 2 types of antibodies: tyreoyidstymulyuyuchi (TCA) and tyreoyidblokuyuchi (TBA), which are associated respectively with thyrotoxicosis and hypothyroidism. TCA detected in 95% of patients with diffuse toxic goiter before treatment. It is shown that these antibodies bind competitively with TSH receptor and produce a series of intracellular reactions leading to stimulate the synthesis and secretion of thyroid hormones. However, there is reasonable doubt that the TSA can stimulate proliferation tyreotsytiv. Assume the existence of patients with goiter (not only toxic) antibodies specific stimulus, interacting with other receptors, such as insulin-like growth factor and fibroblast growth factor, which determine the growth of the parenchyma. In recent years, received evidence that pozatyreoyidni manifestations of Graves' disease (ophthalmopathy and myxedema pretybialna) also have an autoimmune etiology.
The situation with Hashimoto's thyroiditis and its many variants is much more complicated. Among the antibodies determined in sera of patients with AIT, virtually none of those who have showed marked functional activity and were the direct cause atrophy of the gland. Only TPO antibodies to bind complement and theoretically capable of cytolysis tyreotsytiv. In addition, in vitro the possibility of antibodies to TPO and Tg for the formation of thyroid hormones by inhibition of TPO activity and proteolytic action on thyroglobulin. Whether it happens in the body - remains a question. Although AIT is traditionally referred to as autoimmune diseases with predominantly humoral type reactions, in the literature there is growing evidence of participation of cytotoxic T cells in the destruction of thyroid cells [6]. It is also found that the elimination of thyroid cells in destructive forms of thyroiditis is associated with the process of apoptosis, which is initiated by ligands of cell death: FASL, TNF and TRAIL. Currently, a number of drugs that regulate apoptosis, are pre-clinical and clinical testing stage and may be available to clinicians in the coming years.
Autoimmune nature of diabetes type 1 was established relatively recently - in the early 70s. In the serum of patients with diabetes mellitus type 1 G. Bottazo et al in 1974 found antibodies to cytoplasmic antigens β-cells of pancreatic islets of Langerhans. Since in the literature there were hundreds of thousands of publications devoted to the study of the etiology and pathogenesis of this disease. But has not received evidence of participation of antibodies in destroying β-cells. Their appearance in the peripheral blood has pathogenetic significance, and there is only a marker of an autoimmune response. Methods of diabetic autoantibodies in the last decade have significantly improved and standardized. Today work long-term international and national prospective programs of the autoantibodies to antigens of b-cells in children with complicated family history and in the general population. We study the spectrum and dynamics of appearance of antibodies and their titer and affinity. The purpose of this research is to determine the predictability and assessment of risk of diabetes type 1. Found that diabetic autoantibodies appear long (sometimes several years) before the onset of clinical signs of diabetes. Likelihood of developing the disease increases significantly when circulating levels of autoantibodies to several antigens β-cells simultaneously. With a combination of antibodies to insulin, GAD and IA-2 in patients with a genetic predisposition (diabetic haplotypes) risk of developing diabetes type 1 is close to 100%. The specificity and concentration of antibodies depends on the age of the patient (eg, IAA and IA-2 harakternishi for children up to 5 years) and the phase of developing diabetes. In most cases, a first defined antibody specificity. The simultaneous appearance of antibodies to multiple antigens β-cells occurs, usually during the last degradation [19].
Determination of autoantibodies may be also useful for the differential diagnosis of the 1st and 2nd types of diabetes, which is important to select the prompt and adequate treatment.
The mechanism of destruction of β-cells studied in sufficient detail. As mentioned above, with diabetes type 1 develops mainly cellular immune response mediated by Th1. Activated Th1 produce IL-2 and γ-interferon, with the participation of activated macrophages, cytotoxic T lymphocytes and natural killer cells. These cells can exhibit cytotoxic effect on β-cells of the pancreatic islets as specifically - through direct cytolysis and non-specifically - through production of inflammatory mediators that have a toxic effect on β-cells: free radicals, nitric oxide and cytokines (γ-interferon interleukin-1 β, tumor necrosis factor, etc.).
The central issue is the identification avtoantyheniv that trigger the process of destruction of islet β-cells. S. Kent et al. [13] performed drainage of pancreatic lymph nodes in patients with diabetes mellitus type 1 and healthy donors, isolated and cloned specific T cells. In patients with diabetes (as opposed to the control group) showed a high degree of clonal expansion (probably greater proliferative potential). In addition, the receptor of T cells upiznavav piece insulin molecule (epitope 1-15). The authors suggest that insulin may be a target antigen.
Special attention in the mechanism of death of β-cells apoptosis is paid. Various molecular, genetic and biochemical factors affecting the complex process of apoptosis as a result of their action depends on the balance of pro-and antyapoptychnyh incentives. This is a case where "very little" or "very much" leads to development autoagression. Apoptosis play a key role in the elimination of thymocytes in the formation of immunological tolerance in the thymus, and decreased its level in lymphocytes leads to the accumulation autoahresyvnyh clones of cytotoxic cells. On the other hand, increased expression of Fas-and TNFα-receptors on the membrane of pancreatic cells and / or downregulation of genes and mutations antyapoptychnyh (primarily, Bcl-2) causes the death of β-cells.
The list of factors that are directly or indirectly involved in the destruction of β-cells, constantly updated, and their role in the autoimmune process is refined and specified. The focus of research over the years has repeatedly changed.
It is recognized that, despite the enormous advances in understanding the mechanisms of autoimmune reactions and decomposition of β-cells, many questions remain unanswered, such as:
- That environmental factors (or combinations thereof) are critical in the initiation of autoimmune processes?
- What determines the degree of association between certain genes and diabetes, why this relationship is dependent Population?
- Loss of dynamics that β-cells? Is this a continuous process or there are periods of remission? Whether altered β-cell mass in patients with hereditary predisposition to diabetes, which is the birth and the clinical manifestation of the disease?
- Or regenerate β-cells, if so, under what conditions?
- Why autoimmune destruction is so slow (often for years), whereas normal immune response occurs within hours or days?
There are two main points that are an obstacle to scientific interpretation of the results in the study of the etiology and pathogenesis of autoimmune endokrynopatiy:
1. Most of the ideas and concepts of the mechanisms of autoimmune processes formulated on the basis of data obtained in experimental models (although it should be noted quite adequate) and may not be transferred in full to the human body.
2. In clinical studies, all definitions are held in the peripheral blood of patients is far from inflammation (glands).
Achievements and prospects of prevention and treatment of autoimmune endocrine organs
Traditional treatment of patients with autoimmune endocrine disorders is conducted only after the onset of clinical symptoms of hormonal disorders and is based on two main approaches: prescribing hormone replacement therapy in Hashimoto's thyroiditis, diabetes and Addison's disease or suppress excessive hormone secretion in the case of diffuse toxic goiter. This method is often not a full correction of hormonal imbalance, does not prevent the occurrence of complications and, most importantly, can not stop the progression of autoimmune processes.
Impressive achievements in recent years in understanding the causes and nature autoagression offer opportunities not only radically change the treatment strategy of autoimmune diseases, but also to develop approaches for their prevention. Creation of specific pharmacological agents based therapy may identify the most significant in terms of pathogenetic factors for each form of autoimmune endocrinopathies.
In addition, successful prevention requires compliance with conditions:
- Identification of individuals at increased risk of autoimmune diseases;
- Benefit / risk ratio that is used prophylaxis should be less severe side effects than those associated with the same disease.
There are the following levels of preventive measures, each of which has a specific purpose and strategy:
1. Reducing the risk of autoimmune endokrynopatiy.
2. Reduction in the incidence of clinical manifestation of the disease.
3. Preservation of residual function hormonprodukuyuchyh cells and prevent late complications.
As mentioned, the implementation of a genetic predisposition of autoimmune diseases depends on the action of environmental factors. For each disease nosology is launching its own set of factors: certain bacterial and viral infections, nutritional factors, chemicals, drugs, hormonal balance and more. The strategy of this stage - elimination or minimization of trigger factors. Theoretically, primary prevention would be the perfect choice prevent disease but, unfortunately, insufficient knowledge of all environmental factors and very limited opportunities to address them is not enough to allow for effective action.
Clinical phase of autoimmune diseases are often preceded by a long prodromal period, which could theoretically be used for prevention or inhibition of autoimmune protsesiv.Sohodni it is possible using standardized commercial kits to conduct a study to determine antibodies to antigens of the thyroid and pancreas in the blood of patients at risk and high degree of probability to predict the clinical manifestation of the disease.
Advances in knowledge of the subtle mechanisms of pathogenesis of autoimmune diseases and the development of new technologies to change and manipulate the genome of immunological reactions stimulated an enormous amount of work to find new effective treatments and prevention of autoimmune endokrynopatiy.
In recent years there has been a boom of studies on developing ways to prevent diabetes type 1. In this regard, the exponential growth dynamics of the recommendations: in 1994 the number of such methods was about 70, in 1998 - 125, and in 2005 - already numbered 192. The vast majority of studies carried out in experiments on NOD-mice - a model of genetically determined diabetes type 1 [4].
By direction of these methods can be grouped into several major groups:
1. Imunosupresorna therapy (cyclosporine A, imuran).
2. The use of substances that inhibit the action of proinflammatory mediators (nicotinamide-dyhidroksivitamin 1,25-D 3 and its analogs, etc.)..
3. Induction of immunological tolerance by parenteral, oral or intranasal administration avtoantyheniv (eg, insulin or GAD). Antigens used alone or in combination with bacterial adjuvants.
4. Therapy monoclonal antibodies: anti-CD2, anti-CD3, anti-CD8, and others., Causing total or partial destruction of cells involved in autoimmune reactions.
5. Generation of in vivo and ex vivo polyclonal or antyhenspetsyfichnyh regulatory T cells (Treg - Foxp3 + CD25 + CD4 +), which overturned the development avtoahresiyi.
6. Genetic and proteomic technologies.
7. Cellular therapy, including stem cells.
In various research centers have shown that the application of these techniques can significantly slow down and in some cases completely abolish the development of diabetes type 1 in NOD-mice.
Despite reasoned theoretical background and encouraging results obtained in the experiment, clinical testing of some of these developments (including oral and subcutaneous administration of low doses of insulin, the use of nicotinamide) did not meet expectations. Yes, multicenter studies conducted in Western Europe and North America showed no reduction in the risk of diabetes in patients at risk.
The reasons for the low efficiency of attempts preventive treatment of diabetes in humans is analyzed. Obviously, the differences in the mechanisms of the etiology and pathogenesis of autoimmune endokrynopatiy humans and animals far more important than originally thought. Do not devaluing the importance of experimental models should be treated with great caution to extrapolate data from studies with animals, a situation that can occur in humans. Another possible cause of failure may be incorrectly selected target therapeutic effects through a false interpretation, and in some cases, through the role of individual factors in the destruction of endocrine cells.
Recently, high hopes for cell therapy. For example, be possible to regenerate β-cells by their predecessors, and the use of stem cells of different origin (embryonic, bone marrow and liver). Progenitors β-cells identified in adult pancreatic tissue, but no developed technology for cultivation and breeding in quantities sufficient for therapeutic purposes. The past 2-3 years were marked by the appearance of several works on various research centers to obtain insulinprodukuyuchyh cells from bone marrow stem cells.
In summary, it should be noted that the development of fundamental imunoendokrynolohiyi greatly clarified the mechanisms and patterns of mutual influence of the endocrine and immune systems, allowed us to determine the place and role of immunological factors in the pathogenesis of endocrine diseases. Began implementation of research results into clinical practice. Although much remains controversial and unresolved issues, intensive development of new technologies gives reason to hope that in the near future will be a new arsenal of immunomodulating agents that can selectively affect specific subsets of immune cells and simulate their functions. The result of the combined efforts of endocrinologists and immunologists to develop highly efficient methods pathogenesis based treatment and prevention of autoimmune diseases of the endocrine organs.
Tumor marker
Written by dr Muhammad Riduan
Terjadi multiifikasi yang tidak terkontrol, tanpa suatu stimulasi dan tujuan, terdapat mutasi gen seluler, metastase, gangguan apoptosis, angiogenesis, peningkatan ekspresi molekul adhesi permukaan semuanya merupakan ciri dari sel kanker.
Kelemahan marker ini adalah tidak ada satupun yang sensitif dan spesifik.
Manfaat Klinis :
Bukan untuk alat skeerening terkecuali untuk tumor marker α-fetoprotein (AFP) di negara ASIA (insiden ca liver tinggi) dan PSA pada lelaki usia > 50 tahun.
Monitoring treatment, menilai efektifitas pemilihan regimen treatmen untuk setiap kasus secara individual
Prognosis : nilai level tumor marker menunjukkan aggresifitas tumor sehingga dapat memprediksi hasil akhir dari satu pasien.
Tipe tumor marker dapat berupa enzim/isoenzim ; LDH, creatine kinase dan alkaline phosphatase sering meningkat pada kebanyakan kasus kanker. lainnya berupa :
Carsinoembryonik Protein : CEA ( carcinoembryonic antigen) dan AFP.
Monoklonal ; Tabel Immunoassay Tumor Marker Monoklonal Kit Monoklonal Asosiasi dengan Keganasan
CA 125 Karsinoma Ovarium
CA 15-3 Karsinoma Payudara
CA 19-9 Karsinoma Pankreatis
CA 72-4 Karsinoma Gaster
Free PSA Karsinoma Prostat
Nonspesifik tumor marker: dapat terdeteksi pada banyak kanker misal LASA-P (Lipid-asosiated sialic acid in the plasma) : dan
Spesifik tumor marker: SCCA (squamous cell antigen) mareker untuk kanker sel squamous, Cg A (chromogranin A dan NSE (neuron-spesifik enolase) marker karsinoma sel neuroendokrin
Tumor Marker yang sering digunakan :
Tabel Tumor yang Lazim diorderTumor Marker Indikasi Utama Indikasi lainnya Konsentrasi normal Keterangan
AFP Karsinoma Hepatoma Primer 15 ng/mL juga meningkat pada keadaan kehamilan, hepatitis dan sirosis
CA 125 Karsinoma ovarium 35 U/L -
CA 15-3 Kanker Payudara 25 U/L meningkat pada keadaan kronik hepatitis, sirosis, sarkodosis, tuberkulosis dan SLE
CA 19-9 Pankreas paru,lambung, kolorektal 37 U/mL terbatas untuk penderita dengan golongan darah Lewis (Le(a+b-) atau Le(a-b+)
CEA non spesifik tumor marker kanker kolorektal 2,5-5 ng/mL kerusakan hepar, perokok berat, terapi radiasi dan kemoterapi dapat meningkatkan kadar CEA
PSA Karsinoma Prostat BPH, Prostotitis dan infarksion - kombinasi dengan colok dubur merupakan alat skreening y
Immunity is composed of many cell functions that protect people against the effects of injury or microscopic invasion. People interact with many other living organisms in the environment. The size of these organisms varies from large (other humans and animals) to microscopic (bacteria, viruses, molds, spores, pollens, protozoa, and cells from other people or animals). As long as microorganisms do not enter the body's internal environment, they pose no threat to health. The body has some defenses to prevent microorganisms from gaining access to the internal environment. These defenses are not perfect, and invasion of the body's internal environment by microorganisms occurs often. Invasion occurs much more frequently than does an actual disease or illness because of proper immune functioning.
Purpose of Inflammation and Immunity
The purpose of inflammation and immunity is to neutralize, eliminate, or destroy microorganisms that invade the internal environment. To accomplish this purpose without harming the body, immune system cells use defensive actions only against non-self proteins and cells. Therefore immune system cells can distinguish between the body's own healthy self cells and other, non-self proteins and cells.
Self Versus Non-Self
Non-self proteins and cells include infected body cells, cancer cells, and all invading cells and microorganisms. This ability to recognize self versus non-self, which is necessary to prevent healthy body cells from being destroyed along with the invaders, is called self-tolerance. The immune system cells are the only body cells capable of distinguishing self from non-self. The process of self-tolerance is possible because of the different kinds of proteins present on cell membranes.
All organisms are made up of cells. Each cell is surrounded by a plasma membrane. With any cell, many different proteins protrude through the plasma membrane. For example, in liver cells, many different proteins are present on the cell surface (protruding through the membrane). The amino acid sequence of each protein type differs from that of all other protein types. Some of these proteins are found on the liver cells of all animals (including humans) that have livers, because these protein types are specific to the liver and actually serve as a marker for liver tissues.
Other protein types are found only on the liver cells of humans, because these protein types are specific markers for humans. Still other protein types are found only on the liver cells of humans with a specific blood type. In addition, each person's liver cells have surface protein types that are specific to that individual. These proteins are unique to the person and would be identical only to the proteins of an identical twin. These unique proteins, found on the surface of all body cells of that individual, serve as a "universal product code" or a "cellular fingerprint" for that person (Workman, Ellerhorst-Ryan, & Koertge, 1993). The proteins that make up the universal product code for one person are recognized as "foreign," or non-self, by the immune system of another person. Because the cell-surface proteins are non-self to another person's immune system, they areantigens, proteins capable of stimulating an immune response.
This unique universal product code for each person is composed of the human leukocyte antigens (HLAs). "Leukocyte antigen" is actually an incorrect term, becausethese antigens are also present on the surfaces of nearly allbody cells, not just on leukocytes. HLAs are a normal part of the person and act as antigens only if they enter another person's body. These antigens specify the tissue type of a person. Other names for these personal cellular fingerprints are human transplantation antigens, humanhistocompatibility antigens, and class I antigens.
Humans have about 40 major HLAs (known as histocompatibility antigens) that are determined by a series of genes collectively called the major histocompatibility complex(MHC). However, the exact number of minor HLAs that any person has is not known. The specific antigens that any person has (of a large number of possible antigens) are genetically determined by which MHC genes were inherited from his or her parents.
This universal product code (HLA) is a key feature for recognition and self-tolerance. The immune system cells constantly come into contact with other body cells and with any invader that happens to enter the body's internal environment. At each encounter, the immune system cells compare the surface protein universal product codes (HLAs) to determine whether or not the encountered cell belongs in the body's internal environment (Figure 20-2). If the encountered cell's universal product code (HLA) perfectly matches theHLA of the immune system cell, the encountered cell is considered self and is not attacked by the immune system cell. If the encountered cell's universal product code (HLA) does not perfectly match the HLA of the immune system cell, the encountered cell is considered non-self, or foreign. The immune system cell takes action to neutralize, destroy, or eliminate the foreign invader.
Immune function changes during a person's life, according to nutritional status, environmental conditions, medications, the presence of disease, and age. Immune function is most efficient when people are in their 20s and 30s and slowly declines with increasing age. The older adult has decreased immune function, causing greater susceptibility to a variety of pathologic conditions (Chart 20-1).
Nursing Implications
Neutrophil counts may be normal, but activity is reduced or impaired. Clients may have an infection but not show standard changes in white blood cell counts. Not only is there potential loss of protection through inflammation, but minor infections may be overlooked until the client becomes severely infected or septic.
Older adults are less able to make new antibodies in response to the presence of new antigens. Thus they should receive immunizations, such as "flu shots" and the pneu-mococcal vaccination.
Older adults may not have sufficient antibodies present to provide protection when they are re-exposed to microorganisms against which they have already generated antibodies. Thus older clients need to avoid people with viral infections and to receive "booster" shots for old vaccinations and immunizations.
Skin tests for tuberculosis may be falsely negative.
Older clients are more at risk for bacterial and fungal infections, especially on the skin and mucous membranes, in the respiratory tract, and in the genitourinary tract.
Organization of the Immune System
The immune system is not confined to any one organ or area of the body. The cells of the immune system originate in the bone marrow. Some of these cells mature in the bone marrow; others leave the bone marrow and mature in different specific body sites. After maturation, most immune system cells are released into the blood, where they circulate to most areas of the body and exert specific effects.
The bone marrow is the source of all blood cells, including immune system cells. The bone marrow produces an immature, undifferentiated cell called a stem cell (Guyton &Hall, 2000). This immature stem cell is also described as pluripo-tent, multipotent, and totipotent. These terms describe the potential future of the stem cell. When the stem cell is first created in the bone marrow, it is undifferentiated. The cell is not yet committed to maturing into a specific blood cell type. At this stage, the stem cell is flexible and has the potential to become any one of a variety of mature blood cells. Figure 20-3 presents a scheme showing the major possible maturational outcomes for the pluripotent stem cell. The type of mature blood cell the stem cell becomes depends on which maturational pathway it follows.
The maturational pathway of any stem cell depends on body needs at the time, as well as on the presence of specific hormones (cytokines, factors, or poietins) that direct commitment and induce maturation. For example, erythropoietin is made in the kidney. When immature stem cells are exposed to erythropoietin, the immature stem cells commit to following the erythrocyte maturational pathway and become mature red blood cells.
White blood cells (leukocytes) are cells that protect the body from the effects of invasion by foreign microorganisms. These cells are the immune system cells. Table 20-1summarizes the functions of different immune system cells. The leukocytes can provide protection through a variety of defensive actions (Abbas, Lichtman, & Pober, 1997). These actions include the following: Recognition of self versus non-self Phagocytic destruction of foreign invaders, cellular debris, and unhealthy or abnormal self cells Lytic destruction of foreign invaders and unhealthy self cells
Production of antibodies directed against invaders Activation of complement
• Production of hormones that stimulate increased formation of leukocytes in bone marrow Production of hormones that increase specific leukocyte growth and activity.
The three processes necessary for immunity and the cell types involved in these responses can be categorized as inflammation; antibody-mediated immunity (AMI), also known as humoral immunity; and cell-mediated immunity (CMI). These three processes use different defensive actions, and each process influences or requires assistance from the other two processes (Figure 20-4). Therefore full immunity, or immunocompetence, requires the function and interaction of all three processes.
A confusing issue regarding inflammation is that this process occurs in response to tissue injury, as well as to invasion by microorganisms or other foreign proteins. Infection is usually accompanied by inflammation; however, inflammation can occur without invasion by microorganisms. For example, inflammatory responses not associated with infection occur with sprain injuries to joints, myocardial infarction, sterile surgical incisions, thrombophlebitis, and blister formation. Examples of inflammatory responses caused by noninfectious invasion by foreign proteins include allergic rhinitis, contact dermatitis, and other allergic reactions. Inflammatory responses caused by infection with microorganisms include oti-tis media, appendicitis, bacterial peritonitis, viral hepatitis, and bacterial myocarditis, among others. Thus inflammation does not always mean that an infection is present.
MACROPHAGES
Description and Origin
Macrophages arise from the committed myeloid stem cells in the bone marrow and form the mononuclear-phagocyte system. The stem cells first form monocytes and are released into the blood at this stage. Until they mature, monocytes have only limited activity. Most monocytes move from the blood into various tissues, where they complete
ANTIGEN RECOGNITION
To begin to make antibodies against an antigen, the "virgin" or previously unsensitized B-lymphocyte must first recognize the antigen as non-self. Â-lymphocytes cannot carry out this important function alone; they require the actions of macro-phages and helper/inducer T-cells.
This cooperative effort is started by the macrophages. After the membrane of the antigen has been altered somewhat by opsonization (previously discussed under Adherence, p. 314), the macrophage recognizes the invading foreign protein (antigen) as non-self and physically attaches itself to the antigen. This attachment to the antigen does not result inphagocytosis or in immediate destruction of the antigen. Instead, the macrophage presents the attached antigen to the helper/ inducer T-cell. At this time, the helper/inducer T-cell and the macrophage process the antigen in such a way as to expose the antigen's recognition sites (universal product code). After processing the antigen, the helper/inducer T-cell brings the antigen into contact with the B-lymphocyte so that the B-lymphocyte can recognize the antigen as non-self.
virgin B-lymphocyte can undergo sensitization only once. Therefore each B-lymphocyte can be sensitized to only one antigen.
As a result of sensitization, this B-lymphocyte can respond to any substance that carries the same antigens (codes) as the original antigen. Once it is sensitized to a specific antigen, the B-lymphocyte always remains sensitized to that specific antigen. In addition, all daughter cells of that sensitized B-lymphocyte are sensitized to that same specific antigen.
Immediately after it is sensitized, the B-lymphocyte (or B-blast) divides and forms two different types of lymphocytes, each one remaining sensitized to that specific antigen (Figure 20-10). One new cell becomes a plasma cell and immediately starts to produce antibody directed specifically against the antigen that originally sensitized the B-lymphocyte. The other new cell becomes a memory cell. The plasma cell functions immediately and has a short life span. The memory cell remains sensitized but functionally dormant until the next exposure to the same antigen .
LYMPHOCYTE SENSITIZATION
Once the B-lymphocyte recognizes the antigen as non-self, the B-lymphocyte becomes sensitized to this antigen.
SJOGREN'S SYNDROME
OVERVIEW
Sjogren's syndrome (SS) is a group of problems that often appear in association with other autoimmune disorders. Problems include dry eyes (keratoconjunctivitis sicca), dry mucous membranes of the nose and mouth (xerostomia), and vaginal dryness. These problems are thought to be caused by autoimmune destruction of the lacrimal, salivary, and vaginal mucus-producing glands. Most commonly, the client with Sjogren's syndrome also has rheumatoid arthritis. Fibromyalgia also is associated with SS.
Ninety percent of clients with Sjogren's syndrome are women between 35 and 45 years of age. SS is more common among clients with certain tissue types, specifically HLA-DRW52, HLA-DR3, and HLA-B8. Although an exact triggering agent has yet to be identified, viral infection is strongly suspected. The three viruses thought to be possible triggers for the autoimmune changes leading to Sjogren's syndrome are human immunodeficiency virus type 1 (HIV-1), human T-cell lymphotrophic virus type 1 (HTLV-1), and Epstein-BarrVirus (EBV).
Insufficient tears cause inflammation and ulceration of the cornea. Insufficient saliva decreases the digestion of carbohydrates, promotes tooth decay, and increases the incidence of oral/nasal infections. Vaginal dryness increases the incidence of infection and may cause pain during sexual intercourse (dyspareunia).
COLLABORATIVE MANAGEMENT
Assessment
The client with SS usually has blurred vision, burning and itching of the eyes, and thick mattering in the conjunctiva. Difficulty swallowing food is common, and the client often experiences changes in taste sensation. The nurse asks the client about the presence of nosebleeds (epistaxis) and frequent upper respiratory infections.
Physical examination reveals enlarged lymph nodes. If rheumatoid arthritis (RA) accompanies SS, the client has swollen, painful joints and limited joint mobility. Laboratory assessment may show an increased presence of general antinuclear antibodies, anti-SS-A or anti-SS-B antibodies, and elevated levels of IgM rheumatoid factor.
Interventions
IMMUNOMODULATION.
Currently, there is no cure for SS. The intensity and progression of the disorder can be slowed by suppressing immune and inflammatory responses. The agents often used to modulate the immune system in clients with SS include low-dose chemotherapy with methotrexate (Rheumatrex) or cyclophosphamide (Cytoxan). Both agents can have serious long-term detrimental effects, especially on liver and bone marrow function. Other immunosuppressive agents that have shown benefit in managing SS are cortico-steroids, cyclosporine (Neoral, Sandimmune), and hydroxy-chloroquine (Plaquenil).
SYMPTOMATIC THERAPY. A variety of artificial tears and artificial saliva can help reduce symptoms of dry eye and dry mouth. Clients are instructed to use humidifiers in the home to increase the environmental moisture content. The use of water-soluble vaginal lubricants and moisturizers can increase comfort and reduce the incidence of vaginitis. Some clients have obtained significant relief from dry mouth with the use of systemic pilocarpine (Salagen). This agent is acholinergic agonist that mimics the effects of theparasympa-thetic nervous system, including increased salivation.
A nonpharmacologic intervention for dry eyes is to block the tear outflow channel (nasal punctum). The punctum can be blocked temporarily with small plugs or closed surgically. Either method allows the scant amount of tears produced to have longer contact with the eye.
Pain control is an issue for clients who have both SS and either rheumatoid arthritis or fibromyalgia. Nonsteroidal anti-inflammatory drugs (NSAIDs), rather than pure analgesics, are most commonly used to decrease inflammation and reduce the associated pain. Many different types and strengths of NSAIDs are available by prescription and over-the-counter. The mechanism of action and side effects are similar for all NSAIDs, although the duration of action and cost can vary considerably (see the Cost of Care box on p. 404).
GOODPASTURE'S SYNDROME
OVERVIEW
Goodpasture's syndrome is an autoimmune disorder in which autoantibodies are made against the glomerular basement membrane and neutrophils. The two organs sustaining the most damage are the lungs and the kidney. Lung damage is manifested as pulmonary hemorrhage. Kidney damage manifests as glomerulonephritis, which may rapidly progress to complete renal failure (see Chapters 71 and 72). Unlike other autoimmune disorders, Goodpasture's syndrome is more common among males and generally occurs in adolescents or young adults (Cotran, Kumar, & Collins, 1999). The exact cause or triggering agent(s) is unknown.
COLLABORATIVE MANAGEMENT
The client with Goodpasture's syndrome usually is not diagnosed until significant pulmonary and/or kidney problems are evident. Clinical manifestations include shortness of breath, hemoptysis (bloody sputum), decreased urine output, weight gain, generalized nondependent edema, hypertension, and tachycardia. A chest x-ray study reveals multiple areas of consolidation. The most common cause of death is uremia as a result of renal failure.
Spontaneous resolution of Goodpasture's syndrome has been known to occur but is rare. Interventions focus on reducing immune-mediated damage and in performing some type of renal supportive therapy.
Immunomodulation
DRUG THERAPY.
The mainstay of drug therapy for Goodpasture's syndrome is high-dose corticosteroids. Additional drug therapy to suppress the autoimmune response is the same as that forSjogren's syndrome.
OTHER THERAPY.
Additional therapy to modulate the immune responses with this autoimmune disorder involves plasmapheresis (filtration of the plasma to remove some proteins) to remove theautoantibodies. If the lungs and kidneys have not sustained permanent damage, clients undergoing plasmapheresis have shown clinical improvement. Some clients usingplasmapheresis need supplemental administration of IV immunoglobulin (IVIG) to maintain antibody protection against infection.
Renal Support Therapy
Depending on the level of remaining renal function, the client may need ongoing dialysis. Therapy usually begins with hemodialysis. For chronic therapy, peritoneal orhemodialysis may be instituted depending on the client's health status, ability to self-manage the infusion and drainage systems, and lifestyle.
Renal transplantation is an option for some clients with Goodpasture's syndrome. After transplantation, renal function is normal. In rare instances, clients are disease free aftertransplantation. In others, the renal problems are improved but pulmonary destruction continues. Some of the drugs required for immunomodulation for the transplanted kidneyalso suppress the autoimmune response.
The answer to this question, “What is cancer?”provides the scientific basis for cancer control. With all of the recent advances in molecular biology which have increased our understanding of the genetic basis of cancer with the description of oncogenes (cancer genes) and the suppressor genes which regulate their expression, the biologic basis of cancer has received most of the attention. But the nature of cancer also has an equally important social aspect which is essential for cancer control.
Neoplasia is a disease process that results in over 100 different malignant diseases that share a common biology and natural history. Any cell in the body that can undergo mitosis or cell division can be affected. Cancer has links to other disease processes. Some infections cause cancer: e.g. schistosomiasis associated with bladder cancer and the liver fluke, Clonorchis sinensis, which causes cancer of the gall bladder. There are also toxic causes: e.g. mesothelioma, a tumor arising in the pleura which lines the thoracic cavity resulting from exposure to asbestos (asbestosis). Despite popular opinion, however, it is unlikely that local trauma is a cause of cancer. As a fundamental disorder of cellular growth and differentiation or development, cancer is essentially a genetic disorder at the cellular level. Most tumors are encapsulated and benign in behavior. Occasionally they may create symptoms from cosmetic or mass effects. In using the generic word “cancer”, however, we are concerned here with malignant tumors that are morphologically abnormal under the microscope. They show uncontrolled growth leading to local invasion with disruption of tissues, and later metastasis or spread to loco-regional lymphatics and later the blood stream. Cancer kills mostly through blood-borne metastasis.
A tumor does not grow freely in its human host as it would in tissue culture. The host puts up a defense, generically called “host resistance”, which resembles defense against infections. There is a homeostatic interaction between the host and tumor cells or microorganisms based on a dynamic balance between them and the host microenvironment in which they grow - an updated version of the seed-and-soil hypothesis. The tumor arises from an abnormality of growth and differentiation based on altered structure, regulation and expression of its genes. The resulting properties of transformation, invasiveness, metastasis, clonality and heterogeneity give rise to its malignant behavior. But the outcome of its growth still depends on its interactions with host defenses for a net result of progression, dormancy or regression. The process is dynamic and chronic with the balance of host resistance changing with the advancing stage of tumor growth.
Cancer has a characteristic natural history. Healthy cells first become dysplastic showing subtle morphological abnormalities under the microscope which suggest the beginning of transformation. The next step is carcinoma in situ where characteristic abnormalities of both form and proliferation are present but without invasion of the underlying basement membrane that holds them in place in the tissue of origin. This earliest phase is highly curable and is detected with screening programs, such as the PAP smear for cervical cancer. Localized cancer is stage I disease where the tumor exhibits invasion and disruption of local tissues to form a primary lesion. Tumor cells then invade local lymphatics and spread to the regional (stage II) or extended regional (stage III) draining lymph nodes as secondary tumors. Finally tumor cells invade into the blood stream where characteristic patterns of blood-borne metastasis herald the onset of stage IV disease. Particular tumors vary in the extent to which they follow these phases in sequence: melanoma usually has a distinct loco-regional phase, while breast cancer is systemic from the beginning. Staging correlates with survival and provides an essential guide both to prognosis and to the design of treatment plans.
The “gold standard” for a diagnosis of cancer is a histopathological examination by a pathologist on biopsied tumor tissue. Unfortunately this is not always done and the diagnosis is made from clinical findings or less. Cancer can be mimicked by many other diseases. Moreover, cancer statistics depend on the accuracy of death certificates, where cancer may not be properly noted as the cause of death. Biologic markers are playing an increasingly important role in cancer management. Most of these markers are not unique for cancer cells, but are shared also by normal cells and may also be overexpressed in benign conditions. Thus markers cannot be used to screen populations to detect cancer.
The biology of cancer has important implications for cancer control. At the cellular level the problem is faulty genetic control; cancer is basically a genetic disorder. But hereditary cancers such as retinoblastoma, are uncommon. Instead the disease is usually acquired from external influences which are, therefore, potentially avoidable. With current methods overall one can expect to prevent theoretically 2/3 but in practice more realistically 1/3 of cancer, and to be
able to cure about 1/3 in a developing country, and closer to 1/2 in a developed country.
As a lifestyle disease, cancer arises out of conditions of life which result in exposures to carcinogens. Such exposures result from two situations: * Where people live * Changes people make in the world
Cancer shows both geographic and temporal variability. There are
different patterns of cancer at different places and different times. These
patterns relate both to habits and to environmental hazards.
Habits: The use of tobacco has resulted in lung cancer in North
America and Europe during the last half of the 20th century. Dietary
habits underlie the high incidence of stomach cancer in Japan, Northern
China, Chile and Eastern Europe. This tumor is associated with
lower socioeconomic status. The incidence falls in second generation Japanese
who have moved to the United States of America. Food preservation methods
are associated with stomach and liver cancers in West Africa and Southeast
Asia. Techniques for pickling as well as contamination with aflatoxins from mould
are responsible. Environmental hazards:
Viruses: Hepatitis B Virus is associated with liver cancer.
Risk factors for cancer which people create by making changes in their world may be thought of as the price for industrialization. Ionizing radiation: In the latter part of the 19th century over half of certain groups of miners working in the Joachimsthal and Schneeburg mines of Central Europe died of lung cancer. High lung cancer rates were also observed in miners digging copper, lead and zinc from the Colorado plateau in the United States during thew first half of the 20th century. In both cases disease was induced by exposure to radioactivity in the mines. Occupational exposure occurs in uranium mines Manufacturing: The manufacture of various substances can lead to cancer. One example is bladder cancer from the dye-stuff, betanaphthylamine which was seen in Europe and North America until exposure was controlled through occupational health and safety initiatives. Now it has reappeared in Southern Asia where industrialization has exported these risks to contexts not appreciated by people who live and work there. Yet another example has been exposure to asbestos in Quebec, Canada, and to asbestiforme erionite in Turkey, both with an association with mesothelioma.
These social dimensions of cancer have important implications for
the design of cancer control programming. They stem from behavior patterns that
people evolve to meet their biological, psychological and social needs. These
patterns, in turn, create a lifestyle which influences cancer incidence. They
include the development of addictions to tobacco, drugs and alcohol, the ways
in which food is prepared, stored and eaten, and certain risk patterns of
personal interaction as with sexual mores. With tobacco, for example, oral
cancer predominates where tobacco is chewed, and lung cancer where it is
smoked. The changed cancer patterns that accompany the migration of people
provides an example of the influence of lifestyle on the occurrence of cancer.
When Mexicans migrate to the United States they take on the cancer
incidence patterns of their new country.
There is a very real possibility that lifestyle change can reduce cancer
incidence. But such changes can be very difficult to make, as anyone who has
tried to stop smoking can attest. There is now a major research emphasis on the
application of behavioral science in health promotion and prevention programs
to create lifestyle change at the population level.
Biologic factors in cancer etiology refer largely to the role of four classes of external agents in carcinogenesis: physical, chemical and biological agents, and diet.
Physical Agents: * Ionizing radiation can be
background from cosmic rays and earth sources of radioactivity. More important
are cumulative exposures from medical diagnostic and treatment procedures, and
from commercial and occupational sources. Exposures have also occurred with
warfare, as in the atomic bombs dropped
on Hiroshima andNagasaki in Japan in world war II. Leukemias
and cancers of the breast, lung and thyroid are typical but cancers of the
stomach, colon, bladder, and potentially any human tumor may be seen.
* Nonionizing radiation of solar origin,
especially the ultraviolet (UV)B wavelengths, are associated with basal and
squamous skin cancers and with malignant melanoma. Certain inherited skin types
(Celtic skin) are at greater risk. Commercial sources such as tanning parlors
also provide risk.
* Particles can also be important. The cancer risk
with asbestos relates to fiber length and toughness. The risk from particles in
air pollution is related to their size and propensity to settle in the lung.
Because of the
widespread nature of the tobacco habit, control of carcinogenesis by chemical
agents provides a major basis for cancer control. The process of carcinogenesis
by chemicals is subject to both initiation and promotion steps. These
carcinogens have a particular chemistry as aromatic electrophiles - chemically
very reactive substances often formed as metabolic products.
* Some have medicinal sources, such as the use of diethylstilbestrol
in pregnancy to avert abortion resulting in vaginal cancer in the daughters.
* Others come from habits such as the use of
tobacco (oral and lung cancer, and other tumors) or alcohol (head and neck
cancers).* Industrial
and occupational exposuresare also important:
Viruses are responsible for only about 5% of human cancer. But they are much more common causes of cancer in animals, where their experimental study has played a key role in the identification of oncogenes. Both DNA and RNA viruses are implicated. * Hepatitis B virus (HBV) causes primary liver cancer. Vaccination of the children of susceptible populations is used for prevention.* The Epstein Barr Virus (EBV) is implicated in nasopharyngeal cancer.* The Human Papilloma Virus (HPV), especially certain subtypes like 16, are associated with cervical cancer. These viruses also cause warts, which are benign tumors. Some parasitic infections are associated with cancer.* Infections with Schistosoma haematobium (schistosomiasis) may be associated with bladder cancer. This parasite enters the skin from water infected by snails. * The liver fluke, Clonorchis sinensis, is associated with cancer of the gall bladder and hepatobiliary ducts.
As a lifestyle factor diet has been shown to play a significant
role in the causation of cancer worldwide. But little is known as yet about how
it plays its role as a carcinogen. This is currently a very active area of
cancer research. There are several studies which show that excessive fat in the
diet raises the risk of colorectal and breast cancer, and possibly other
cancers as well, such as prostate cancer.
Methods of food preparation and preservation can also create
risks. There are studies showing that nitrites are associated with stomach
cancer. Other studies are showing that certain broad classes of foods may
contain protective substances against cancer. These include
certain vegetables (the cruciferous group), whole grain products (fiber) and
citrus fruits.
The three major classes of external carcinogens, and perhaps to
some extent diet (although how it plays its role is not yet understood), exert
their effect through multiple steps involving a final common pathway - the
oncogenes.
The final result is malignant transformation and then the development through
further genomic instability the properties of invasiveness and
metastasis.
Lifestyle and the conditions in which people live determine
the prevalence of environmental risk factors. Five groupings of these risk
factors make up the social factors in cancer etiology.
Click here for a summary of each of the key risk factors that are implicated currently in the causation of cancer.
This slide shows the relative importance of the various risks and causes of cancer. It is based on a study of cancer mortality in the United States in 1981. Various adjustments have been attempted since then, but they are minor and the overall pattern remains the same and is important in setting cancer control priorities. It is clear that most of cancer, between 2/3 to 3/4, is potentially preventable. Since comparatively less is known about diet, tobacco control is the major target for cancer prevention programs. In countries like India, 50% of cancer is oral cancer of which 90% is associated with chewing of tobacco in various forms aggravated by smoking. In North America, in contrast, lung cancer makes up 25% of cancer, and 80 to 90% is associated with smoking. Another factor important to prevention initiatives in some countries is HBV infection which leads to primary liver cancer in Sub-Saharan Africa and South East Asia. Contamination of foods by aflatoxins also contributes. Although alcohol contributes to cancer in the West, primary liver cancer is uncommon. These figures show that cancer is a lifestyle disease. The combination of tobacco use, a high fat and low vegetable diet, and no exercise would appear to be the right combination of risk factors for both cardiovascular diseases as well as cancer - especially lung, colorectal and breast cancers!
In developing countries cancer causes about 1 in 20 deaths. The incidence is increasing as living standards improve and life expectancy is prolonged leading to a decline in communicable diseases and an increase in noncommunicable diseases.
In developed countries, cancer is second only to cardiovascular diseases as a cause of mortality and accounts for about 1/4 of all deaths. Three factors contribute to the increase in cancer mortality: *in developed countries deaths from cardiovascular diseases are declining; *the “graying” of the population means that people are living longer and cancer is more frequent in older age groups; and *increasing use of tobacco, mostly as cigarette smoking, during the past few decades has resulted in a greater incidence of related cancers, especially lung cancer. Indeed the increase in smoking in young women is resulting in a rapid rise in the incidence of lung cancer, which in some developed countries is surpassing breast cancer as the commonest cancer in women.
In contrast, perinatal disorders and infections comprise less than 10% of the mortality in developed countries, and it continues to drop.
The basis for the striking contrast in the last two slides between developing and developed countries is the transition phenomenon, which is illustrated here.
The incidence of cancer at various body sites may differ in different countries. Oral cancer is common in India as a consequence of chewing tobacco. Stomach cancer is more frequent in China and Japan, as well as in South and Central America (Mexico, Costa Rica) and also Eastern Europe. Primary cancer of the liver is uncommon except in portions of Africa, east Asia and the western Pacific. Cervical cancer is more common in developing countries especially in situations of low socioeconomic status. Epidemic levels of cigarette smoking have led to the high incidence of lung cancer in developed countries, for example, North America, Europe and Shanghai in China, but it is low in Africa.
Temporal trends in cancer tend to show epidemics that rise to a peak and then recede over very long time periods of decades. The long time periods hide the epidemic nature of the disease. Projections of incidence, prevalence and mortality are important for planning cancer control interventions.
Cancer impacts
not only the patient, but also his or her family and community. In North
America 1 in 3 individuals born during the last decade will
experience cancer at some point in their lifetime. By the year 2000 the figure
will be one in every two. One in four to one in five North Americans will die
of cancer. Thus most individuals in North America have some experience of the
disease, if not personally, then in a family member, friend or acquaintance.
In addition to its pervasive presence in the community, the disease is widely
feared the world over as synonymous with suffering and death. Patients may be
stigmatized and experience social isolation and family tensions as well as
inability to get insurance or even job loss with economic dependence aggravated
by high costs of medical care if there is no health insurance. Progress in
controlling cancer has been frustratingly slow. Critics disagree how resources
should be distributed between treatment and prevention or between research and
putting existing knowledge into practice.
The economic burden of cancer to a country is shown in this example of a study done in the USA to estimate direct and indirect costs for 1977. Direct cancer care costs were estimated at US $7 billion with corresponding indirect costs of US $ 15 billion, for a total in that year of US $22 billion or nearly $100 per capita. Direct costs for hospitals, health care services and drugs can be estimated reasonably easily where one has information about what services and how much of them are provided to cancer patients. Indirect costs arise from lost productivity following on illness and premature death. They are more difficult to estimate since they require assumptions about expected future earnings and a discount rate to convert these back to current dollar value. In the study cited a discount rate of 10% was used.
Examples of markers your doctor may test for include:
CA 15.3: used to find breast and ovarian cancers
TRU-QUANT and CA 27.29: may mean that breast cancer is present
CA125: may signal ovarian cancer, ovarian cancer recurrence, and breast cancer recurrence
CEA (carcinoembryonic antigen): a marker for the presence of colon, lung, and liver cancers. This marker may be used to determine if the breast cancer has traveled to other areas of the body.
Circulating tumor cells: cells that break off from the cancer and move into the blood stream. High circulating tumor cell counts may indicate that the cancer is growing. The CellSearch test has been approved by the U.S. Food and Drug Administration to monitor circulating tumor cells in women diagnosed with metastatic breast cancer.
Some doctors use marker test results as early indicators of breast cancer progression (the cancer getting worse) or recurrence. They may use this information to make decisions about when to change therapies — if current treatment does not appear to be working — or to start treatment for recurrence. If you have an elevated marker, your doctor may check that marker periodically to assess your response to chemotherapy or other treatments.
While breast cancer blood marker tests are promising, they're not absolutely conclusive. When a breast cancer blood marker test comes back negative, it doesn't necessarily mean you're free and clear of breast cancer. And a positive result doesn't always mean that the cancer is growing. These tests may help with diagnosis, but using cancer marker tests to find metastatic breast cancer hasn't helped improve survival yet.
When deciding if you should get tested for breast cancer blood markers, there are some things you may want to consider:
cost — the tests can be expensive
anxiety — not just from an elevated blood marker, but by all the tests you may need to find out what's causing the marker to go up
Talk to your doctor about the possible benefits and risks of blood marker testing in your unique situation.
Imunoendokrynolohiya a new medical - biological disciplines. As an independent research direction of this area of knowledge emerged in the early 70s of the last century on the basis of numerous accumulated at the time of the actual material that testified to the close reciprocal relationship of the endocrine and immune systems, together with the nervous system performs a regulatory function in body. Formation and development imunoendokrynolohiyi occurred through the joint efforts of researchers, experimenters and clinicians of many specialties: immunologists, endocrinologists, biochemists, physiologists, and other pathophysiologists.
In recent years, several imunoendokrynolohiyi determined the most promising areas:
- Fundamental studies of mechanisms of hormonal regulation of immune;
- Study the role of immunological and immunogenetic factors in the etiology and pathogenesis of endocrine diseases and their complications;
- Immunological monitoring of patients with endocrine disorders and searching informative methods for immunological studies for use in the diagnosis and monitoring of treatment of endocrine diseases;
- Search and development of pathogenesis based prevention of autoimmune endocrine diseases;
- Development of new approaches to the immunotherapy of patients with endocrine diseases in order to improve the treatment and prevention of complications;
- Improvement of methods of transplantation immunological cells of endocrine organs.
Below is a more detailed overview of the most current trends. Some of these problems developed at the Institute of Endocrinology and Metabolism them. VP Komisarenko AMS of Ukraine.
Endocrine regulation of the immune response
Having hormonal control of the immune system is confirmed by numerous experimental and clinical observations and currently there is no doubt. Research in this direction started long ago, but the advent of modern highly specific methodological approaches this research led to a new level, allowing not only complement and flesh out our understanding of the effect of various hormones on the immune system, but also to determine the molecular genetic basis of this effect [22 ].
Found that both systems use similar receptors and ligands for intersystemnoho and intrasystemnoho communication link, which plays an essential role in homeostasis. Effect of hormones occurs in the interaction with specific receptors on cells of the immune system. However, their effect may be direct or indirect. The first option is observed upon binding to receptors of lymphocytes and macrophages. There are more than 20 varieties of these receptors. The second option is realized by the action of hormones on the stromal cells of lymphoid organs, especially the thymus, through its impact on development and functional state of immune cells. The degree of expression of receptors for hormones and cell reactivity vary in different populations and subpopulations of lymphocytes and monocytes, which largely determines the selectivity and intensity and hormonal influences.
Hormonal factors are divided into two alternative groups. The first, which includes cortico-steroids, adrenocorticotropic hormone (ACTH), androgens, estrogens and progestins, in general, have a depressing effect on the immune system. Other: somatotropin hormone (GH), thyroxine, thyroid stimulating hormone (TSH), insulin, prolactin and progesterone - integral stimulate immunological reaction. The essential point is that the effects of many hormones is largely dependent on the dose: some doses they act as suppressors, others - stimulate the immune response. Thus, cortisol and other hormones of the adrenal cortex in physiological concentrations inhibit lymphocyte proliferation, but promote their differentiation, and pharmacological doses induce apoptosis of lymphocytes and their redistribution in the body due to increased emigration of thymocytes thymus cortex. They also inhibit the activation of lymphoid cells in immune response and block cell-cell interactions, reduce the secretion of interleukins and tymichnyh hormones. The effect is similar expressions hypercortisolism, is under stress and administration of glucocorticoids for therapeutic purposes. Chronic stress causes a reduction in stamina to bacterial and viral infections.
Sex hormones also reduce klitynnist lymphoid organs and functional activity of the immune system. Androgens and estrogens contribute to the development of age involution of the thymus. Their effect on the epithelial cells of the stroma of the thymus in early puberty is considered as a starting point involution. Estrogens strongly inhibit the activity of suppressor cells to see why one of the reasons for women's greater susceptibility to autoimmune diseases.
Thyroxine, insulin and insulin-like growth factor directly involved in shaping the immune system and the development of an immune response, enhance processes of proliferation and differentiation of lymphocytes. HGH makes a direct mitogenic effect on T cells.
Extremely important for the normal functioning of the immune system is the level of hormone secretion by epithelial cells of the thymus. It is known that the thymus is the central organ of the immune system that performs tsytokrynnu and endocrine function. That there is a differentiation in the thymus thymocytes from bone marrow precursors in functionally different lymphocyte subpopulations. In addition, the thymus produces tymichni peptides, affecting the activity of peripheral lymphocytes and interleukin production. The main hormone produced by thymic epithelial cells and is present in plasma at physiologically relevant concentrations, is tymulin [10, 22]. Tymulin (second name - tymichnyy serum factor) is a nanopeptyd bound to zinc ions, which are necessary for the implementation of its biological activity. According to modern concepts, tymulinu level in serum is an integral indicator of endocrine function of the thymus is one of the most important characteristics of immune status. The introduction of synthetic tymulinu enhances suppressed (in aging, immunodeficiency, after tymektomiyi) response of T cells to mitogens, allograft rejection, limiting the development of an autoimmune process. Age decrease production tymulinu considered one of the causes of aging of the immune system in general and the weakening of immune protection, especially mediated T-lymphocytes. Tymulinu secretion is controlled by cytokines (interleukin-1α and-1β, IL-2, γ-interferon) and hormones, corticosteroids and sex hormones suppress it, thyroxine, growth hormone and insulin - increase.
Installed changing endocrine function of the thymus in many endocrinopathies. Experiments conducted laboratory staff Endocrine regulation of immune Institute of Endocrinology and Metabolism them. VP Komisarenko Sciences of Ukraine, showed reduction of thymic hormones in mice with chemically-induced (streptozotocin and aloksanom) diabetes and in animals with genetically determined diabetes (BB rat, mouse, db / db) [1, 3]. In clinical trials revealed a significant decrease in the concentration tymulinu in patients with hyperthyroidism and thyroid neoplasms [2] (which deepened after thyroidectomy), and in children with diabetes mellitus (DM) type 1, shows the dependence of these changes on the duration of the disease and the presence of complications.
The relationship between the endocrine and immune systems are not unidirectional. The literature shows evidence of immunological factors regulating influence on the endocrine system. The main mediators of this effect is thymic peptides and cytokines. It is believed that tymichni hormones involved in the regulation of the hypothalamic-gonadal axis pituyitarno-axis by stimulating the secretion of hormones of the pituitary, hypothalamus, thyroid gland. Show their influence on the activity of the adrenal cortex and reproductive organs [22].
Found that IL-2 and IL-6 are potent stimulators of steroid production through effects on corticotropin-releasing hormone. A role, especially in the control of secretory activity of pituitary cells, also play antibodies (including antyidiotypichni) and immune complexes. Noteworthy is the fact that immune cells are able to produce peptide hormones. Proved synthesis of glucocorticoids and all adenohipofizarnyh thymus hormone (TSH, ACTH, LH, FSH, GH and PRL). Feasibility and biological role of this synthesis is actively researched and debated.
The study of the pathogenesis of autoimmune endocrine diseases
Autoimmune pathology of endocrine organs is one of the most studied. In the early 50s E. Witebsky and N. Rose replicated experiment Hashimoto's thyroiditis by immunization with rabbit thyroid extracts. In 1956, British scientists have shown the presence of such antibodies in patients with chronic thyroiditis, was first used the term "autoimmune disease" as a nosological category. Finally, it is proved that all the pathogenesis of autoimmune diseases is the development of an immune response to its own antigens (in cases of autoimmune endokrynopatiy - this antigen glands) [18]. Recent advances in immunology, molecular biology, genetics, experimental and clinical endocrinology much deeper insight into the etiology of autoimmune endocrine organs and key factors of pathogenesis.
The nature of all autoimmune diseases are divided into 2 groups:
- System, where through the wide prevalence antigen in the pathological process involved in almost all tissues of the body (eg, rheumatoid arthritis and systemic lupus erythematosus);
- Organ, when the object of affection is the appropriate body and the pathological process is local.
All autoimmune endocrinopathies, and these include: Hashimoto's thyroiditis (autoimmune thyroiditis, AIT), hyperthyroidism, diabetes mellitus type 1, Addison's disease, and others - are organ.
There are also combined forms of endocrine diseases - autoimmune syndrome polihlandulyarnyy 1st and 2nd types (APS-1 and APS-2). APS-1 develops during the first two decades of life and includes hypoparathyroidism, adrenal insufficiency and candidomycosis (often associated with hypogonadism, pernicious anemia, vitiligo). APS-2 observed in adults and is characterized by the triad: insulin-dependent diabetes mellitus, autoimmune thyroid disease and adrenal insufficiency.
The prevalence of autoimmune endocrine diseases in different countries varies, but all diseases it owns a significant place. The incidence of diabetes mellitus, thyrotoxicosis and autoimmune thyroiditis is increasing annually. Chronic nature of these diseases, frequent development of complications, which in turn is the cause of reduced life expectancy and deterioration of its quality, makes medical and social importance of this issue. Recent years has intensified study of the etiology and pathogenesis of autoimmune endokrynopatiy and to develop effective methods of prevention and treatment.
Today it is generally accepted that autoimmune endocrinopathies are complex diseases caused by the formation of the interaction of three main factors: genetic heredity, the immune system and the environment [4, 7, 8].
Under certain conditions, the action of external factors in the presence of a genetic predisposition leads to disruption of the central and peripheral mechanisms of immune tolerance and immune response to antigens own body. As a result of the activation of lymphocytes and clones autoahresyvnyh hypersecretion of various mediators failure occurs hormonsekretuyuchyh structures endocrine organs, which further manifests clinical signs of hypo-or hyperfunction respective glands.
As mentioned, one of the significant factors considered hereditary autoimmune disease. The existence of familial cases of diseases - a clearly established fact. Evidence of the role of genetic factors in autoimmune diseases is the association of these disorders with specific genes, including the most significance with major histocompatibility complex genes (in humans - HLA-complex). In autoimmune diseases of the endocrine organs are particularly common haplotypes: HLA-B8, DR3 - autoimmune thyroiditis; HLA-DR5, DQw7 - hypertrophic form of thyroiditis; HLA-B8, DR3, DQ2/DQ8 - diabetes type 1; HLA-B1, DR3, DQ8 - Addison's disease; HLA-DR3, DR4, B8 - polihlandulyarnyy syndrome [6, 12]. It is believed that HLA-genes are responsible not only for susceptibility to the disease, but also for the time of occurrence, nature of the flow and are often the result of the pathological process.
In the last decade intensively studied genetic characteristics of diabetes. A large number of publications dedicated to particular genotype in patients with diabetes mellitus type 1 in different ethnic groups, races, countries and continents. Today describes more than two dozen loci and 100 genes that determine the risk of diabetes [4, 24]. However, despite the tremendous efforts of scientists, the role of most of them remains still a mystery. Numerous studies of populations give mixed results on the association of diabetes with genes HLA. Moreover, some genes HLA haplotypes are diabetohennymy in one population, indifferent and even protective in other populations.
The presence of a haplotype that determines the risk of developing autoimmune endocrinopathies relevant, does not mean that this tendency must be implemented. Required triggers that initiate the onset autoimmune process in genetically predisposed individuals. Determined that this action produce environmental factors. First of all, viral and bacterial infections, as well as drugs, food, ionizing radiation, hormones, stress, pregnancy, aging, and probably some other not yet identified factors.
The significance of these factors for a variety of endocrine diseases are not the same. For example, diabetes is a significant Coxsackie B viruses, rubella, cytomegalovirus and retroviruses [16]. According to some precipitating factor of diabetes may be bottle-feeding, cow's milk, over-nutrition, nitrosamines containing nitrates and nitrites. Transient hyperglycemia can cause some chemicals and pharmaceuticals, such as calcium channel blockers, cimetidine, corticosteroids, indomethacin, pentamidine and vincristine.
Autoimmune thyroiditis is more common in people with overweight, which may be due to certain disorders of lipid metabolism and hormonal regulation. In this regard, noteworthy information about the relationship of this disease with elevated levels of estrogen and prolactin. Among the exogenous factors should be noted bacterial and viral infections, excessive iodine, radiation, several immunotherapeutic agents: α-interferon, interleukin-2 and others.
Thus, autoimmune diseases are multifactorial in nature and highly heterogeneous. Their common feature is the development of an immune response to its own antigens. Typically, these conditions are prolonged (chronic) character because of the constant of the antigen in the body (since it is a normal component of cells). Features of the clinical manifestations of autoimmune diseases is largely dependent immune responses that predominate in response to antigen. This may be cell-type reactions associated with the action of cytotoxic cells (eg, diabetes mellitus type 1). These reactions generate T-helper type 1 (Th1). T-helper type 2 (Th2) induce humoral immune responses (antibody synthesis) and dominated in patients with autoimmune thyroiditis.
An important factor in understanding the nature autoagression is that the mechanisms of immune responses in autoimmune diseases are not much different from the immune response to foreign antigen [7]. Only in this case, the target of immune reactions are the body's own cells. Why is this?
According to modern concepts, a two-tier system of immunological tolerance (non-responsiveness of the immune system to its own antigens) - central and peripheral. The purpose of the first level of control is to prevent, if possible, the formation of clones of lymphocytes, aggressive in relation to their own antigens, whereas peripheral tolerance mechanisms provide a suppressor effect on autoreactive cells that were in circulation and peripheral lymphoid organs. Formation of central immunological tolerance occurs in the thymus during maturation of thymocytes at the stage of so-called "negative selection" [5]. Medullary thymic stromal cells, mainly epithelial, to a lesser extent - dendritic cells and macrophages, T lymphocytes are custom peptides in complex with major histocompatibility complex molecules 1st and 2nd grades. Clones of lymphocytes with high affinity receptors that recognize their antigens are culling and elimination. The death of these cells occurs by apoptosis.
It used to be that no thymus tkanynospetsyfichni antigens (TSA), and tolerance mechanisms are provided solely peripheral suppression. In recent years, obtained conclusive evidence of the presence in the thymus almost all known TCA [14]. Moreover, it was found that the synthesis and secretion of TCA is the physiological properties of cells of the thymus [9]. It is shown that the thymus expressed all the genes of the family of insulin: IGF2 (in epithelial cells), IGF1 (in macrophages), INS (in epithelial and dendritic cells) and molecules GAD and IA-2 [11].
With regard to peripheral tolerance, it is provided mainly special population of T cells with the phenotype (CD4 + CD25 +), these regulators, - Treg. This cell type has been described by S. Sakaguchi in 1995 and is currently being studied [15, 21]. The main purpose of these cells - preventing autoimmune processes.
It was believed that this population of cells is generated only in the thymus and in peripheral regions of the immune system just completed their differentiation. Last year, just a few researchers the possibility of de novo appearance of the "naive" predecessors and in the periphery [20, 25]. Regulatory cells provide dominant and recessive immunological tolerance, limit the development of immune responses, including allergic and autoimmune reactions. Treg synthesize a large number of cytokines TGF β (transforming growth factor) and interleukin-10 inhibit the proliferative and secretory activity of effector (CD4 +) and cytotoxic cells (CD8 +). Functional defect of regulatory cells found in many autoimmune diseases in humans and animals. Thus, in NOD-mice (artificially bred strains of mice, which spontaneously develop diabetes type 1) and patients with diabetes mellitus type 1 found a significant reduction in both the number and functional activity of this subpopulation of cells [25].
Suppressor activity of Treg is associated with a molecule Foxp3 - intracellular transcriptional factor encoded by the gene FOXP3, localized on chromosome X. This molecule is of particular interest to researchers, as people and animals who have discovered a genetic defect Foxp3, suffering autoimunniyi pathology [21, 23]. It is shown that the mutation of FOXP3 cause IPEX-syndrome (Immune disregulation, Polyendocrinopathy, Enteropathy X-linked syndrome). This disease begins in early childhood and is characterized by multiorgan autoimmune endocrine lesions (DM 1 - the first type AIT), gastro - intestinal tract, and hematological changes (hemolytic anemia, thrombocytopenia).
Installing the pathogenetic role of Treg in the development of autoimmune diseases has become a basis to develop strategies specific biotherapy. Today it is necessary methodological basis for determining the number and activity of Treg-cells. To study the technology of their isolation and expansion ex vivo, and activation conditions. In experimental studies have shown that the introduction of Treg dose-related decreases the incidence of spontaneous diabetes in NOD-mice. In publications discussed the use of Treg-cells as a means of treating autoimmune diseases in humans [20].
So, are presented in the literature data indicate substantial progress in the study of the etiology and pathogenesis of autoimmune endokrynopatiy.
However, despite intensive research, is still an open question that is primary in the development of autoimmune diseases: congenital and acquired defects of immune dysfunction and / or target organ damage, or both factors.
The earliest recorded evidence of an autoimmune process has begun, is the appearance in the peripheral blood circulating autoantibodies and lymphoid organ infiltration. In autoimmune diseases of the thyroid receptor antibodies determined by thyroid stimulating hormone (TSH), thyroid peroxidase (TPO) and thyroglobulin (TG) in diabetes - to hlutamatdekarboksylazy (GADA), tyrozynfosfatazy (IA-2), insulin (IAA) and cytoplasmic antigens β-cells (ICAs); Addison's disease - to microsomal and mitochondrial antigens of the adrenal glands, and often to the ICA and 21-α-hydroxylase. When poliendokrynnyh syndromes 1st and 2nd type is a wide range of autoantibodies to antigens of peripheral endocrine glands. The appearance of antibodies usually precedes the clinical manifestation of the disease. The latent period of the disease may last from several months to several years (sometimes decades, in AIT), much has individual character and may depend on the etiological factors, heredity and age of patients.
Interestingly, autoantibodies as a base (sometimes only) for diagnosis, rarely directly involved in structural and / or functional disorders of the body of the target.
Pathogenic effect convincingly proven only for TSH receptor [17]. There are 2 types of antibodies: tyreoyidstymulyuyuchi (TCA) and tyreoyidblokuyuchi (TBA), which are associated respectively with thyrotoxicosis and hypothyroidism. TCA detected in 95% of patients with diffuse toxic goiter before treatment. It is shown that these antibodies bind competitively with TSH receptor and produce a series of intracellular reactions leading to stimulate the synthesis and secretion of thyroid hormones. However, there is reasonable doubt that the TSA can stimulate proliferation tyreotsytiv. Assume the existence of patients with goiter (not only toxic) antibodies specific stimulus, interacting with other receptors, such as insulin-like growth factor and fibroblast growth factor, which determine the growth of the parenchyma. In recent years, received evidence that pozatyreoyidni manifestations of Graves' disease (ophthalmopathy and myxedema pretybialna) also have an autoimmune etiology.
The situation with Hashimoto's thyroiditis and its many variants is much more complicated. Among the antibodies determined in sera of patients with AIT, virtually none of those who have showed marked functional activity and were the direct cause atrophy of the gland. Only TPO antibodies to bind complement and theoretically capable of cytolysis tyreotsytiv. In addition, in vitro the possibility of antibodies to TPO and Tg for the formation of thyroid hormones by inhibition of TPO activity and proteolytic action on thyroglobulin. Whether it happens in the body - remains a question. Although AIT is traditionally referred to as autoimmune diseases with predominantly humoral type reactions, in the literature there is growing evidence of participation of cytotoxic T cells in the destruction of thyroid cells [6]. It is also found that the elimination of thyroid cells in destructive forms of thyroiditis is associated with the process of apoptosis, which is initiated by ligands of cell death: FASL, TNF and TRAIL. Currently, a number of drugs that regulate apoptosis, are