INFLUENCE OF CENTRAL NERVOUS SYSTEM VIOLATIONS ON ORGANISM REACTIVITY.

INFLUENCE OF EXTERNAL FACTORS ON ORGANISM REACTIVITY.

 PROTECTIVE MECHANISMS OF REACTIVITY. MONONUCLEAR PHAGOCYTES SYSTEM. 

ROLE OF PHAGOCYTES IN PATHOLOGY. PHAGOCYTOSIS DISTURBANCES

 

INFLUENCE OF CENTRAL NERVOUS SYSTEM VIOLATIONS ON ORGANISM REACTIVITY

Reactivity is ability of the organism to alter functional activity of the systems and organs for the adaptation of organism to new conditions of the environment  for the survival. The concept “reactivity” is connected with the   concept “resistance”.

Resistance is a state of insusceptibility of an organism to the influence of pathogenic factors. There are such types of resistance: active and passive, primary and secondary, specific and unspecific. Active resistance is a result of the organism adaptation to the long time pathological factor influences. Passive resistance is a result of anatomical and physiological peculiarities of each organism. Primary (congenital) resistance is a result of the inherited peculiarities of an organism and it manifest itself after birth of the person. Secondary (acquired) resistance is a result of organism functional reactions changes, which occur during the whole life. Unspecific resistance is the opposition to the influence of many pathological agents. Specific resistance is the opposition to the defined agent influence, for example, microorganisms; its result is activation of the immune system.

 

Types of reactivity

There are biological reactivity and individual reactivity.

Biological reactivity is a result of the morphological and physiological peculiarities of all individuals, which are of the same biological species. For example: some species of birds, fishes, and animal change the vital activity according to the changes of the seasons. The lowering of temperature of air promotes seasonal migration of birds to the places with higher temperature of air. During the period of reproduction many species of fishes move to the defined places for reproduction. Some animals can fall into a state of anabiosis, which is accompanied by lowering of their vital activity.

Individual reactivity is the reactivity of every individual. Individual reactivity is determined by age, sex, heredity, constitution, and functional conditions of organism’s regulatory systems, external environmental influences. For example: some diseases arise only in infant organism (measles, roseola, small pox, rachitis, scarlet-fever) but not in adult’s one. Children are less adapted to sharp changes of air temperature, but infant organism is more resistant to the hypoxia (oxygen deficiency), than adults. Resistance of the old organism to the infection reduces, but the number of cancer-ill adults and atherosclerotic-ill increases. Old people have very slowly developing inflammatory reaction. The dependence of the reactivity on sex can be explained by the morphological and physiological peculiarities of men and women. Reactivity of a female organism varies during the menstrual cycle time, pregnancy, climax. Resistance of a women to the hypoxia, hunger, and bleeding is better, than men’s. Women live longer, than men. But men are physically stronger.

 Individual reactivity of an organism is realized by specific and unspecific mechanisms.

 

 

The older adult population is typically defined in chronologic terms and includes individuals 65 years of age and older. This age was chosen somewhat arbitrarily, and historically it is linked to the Social Security Act of 1935. With this Act, the first national pension system in the United States, which designated 65 years as the pensionable age, was developed. Since then, the expression old age has been understood to apply to anyone older than 65 years. Because there is considerable heterogeneity among this group, older adults often are subgrouped into young-old (65 to 74 years), middle-old (75 to 84 years), and old-old (85+ years) to reflect more accurately the changes in function that occur. Age parameters, however, are somewhat irrelevant because chronologic age is a poor predictor of biologic function. However, chronologic age does help to quantify the number of individuals in a group and allows predictions to be made for the future.

In the year 2000, 12.4% of the total United States population (34.4 million) was 65 years of age or older. The proportion of older adults declined for the first time in the 1990s, due partly to the relatively low number of births in the late 1920s and early 1930s. This trend is not expected to continue, however, as the “baby boomers” (born from 1946 to 1964) reach age 65, beginning in the year 2011. During the 1990s, the most rapid growth of the elderly population occurred in the oldest age groups. Those 85 years and older increased by 38%, whereas the 75- to 84-year-olds increased by 23% and the 65- to 74-year-old group increased by less than 2%. The entire population of older adults is expected to grow to over a million by the year 2030. Average life expectancy has increased as a result of overall advances in health care technology, improved nutrition, and improved sanitation. Women who are now 65 years of age can expect to live an additional 19.2 years (84.2 years of age), and men an additional 16 years (81 years old). Aging can be thought of somewhat as a women’s issue because women tend to outlive men. In the year 2000, there was a sex ratio of 143 women for every 100 men older than 65 years in the United States. This ratio increases to as high as 243 women for every 100 men in the 85 years and older age group. Marital status also changes with advancing age. In 2000, almost half of all older women living in the community were widows, and there were four times as many widows as there were widowers.1,2 Although about 4 million older adults were in the workforce in 2000 (i.e., working or actively seeking work), most were retired.1 Retirement represents a significant role change for older adults. Attitudes and adjustment to retirement are influenced by preretirement lifestyles and values. Individuals with leisure pursuits during their work life seem to adjust better to retirement than those whose lives were dominated by work. For many of today’s cohort of older adults, the work ethic of the Great Depression remains profoundly ingrained as the central purpose in life. When work is gone, a significant loss is felt, and something must be substituted in its place. Because leisure has not always been a highly valued activity, older adults may have difficulty learning to engage in meaningful leisure pursuits. Loss of productive work is just one of many losses that can accompany the aging process. Loss of a spouse is a highly significant life event that commonly has negative implications for the survivor. Experts cite an increased mortality among recently bereaved older adults (especially men), an increased incidence of depression, psychological distress, loneliness, and higher rates of chronic illness. Loss of physical health and loss of independence are other  changes that can affect the psychosocial aspects of aging, as can relocation, loss of friends and relatives, and changes in the family structure. Poverty is common among the elderly population. In 2001, 10% of those 65 years of age and older lived below the poverty line, and another 6.5% were classified as “near poor” (income between the poverty level and 125% of this level). Poverty rates vary among elderly subgroups, with 21.9% of elderly African Americans at poverty level in 1999, 20.4% of elderly Hispanics, and 8.9% of elderly Caucasians. The main sources of income for older persons in 1998 were Social Security (90% of older persons), income from assets (59%), public and private pensions (41.6%), and earnings (22%). Contrary to popular belief, most older adults live in community settings. Most live in some type of family setting, with a spouse, their children, or other relatives, and  approximately 30% live alone. Only 4.5% of all individuals 65 years of age and older reside in long-term care facilities or nursing homes. However, this number increases to 18.2% for persons 85 years of age or older. Older adults are the largest consumers of health care. In 1997, more than half of the population (54.5%) reported having one or more disabilities. One third had at least one severe disability, and approximately one sixth (14%) had difficulties with activities of daily living (ADL). Almost half of all adult hospital beds are filled with patients 65 years of age and older.

The lifestyle changes that occur with aging have been described in various developmental theories. Probably the most widely known is Erikson’s eight stages of development. According to this theory, the first seven developmental stages span the period from childbirth through middle adulthood. The eighth stage, in older adulthood, focuses on “ego integrity versus despair.” Ego integrity is the acceptance of one’s life in relation to humanity and one’s place in history. Lack of ego integrity leads to despair, signified by nonacceptance of one’s lifestyle and a fear of death. Despair may be manifested as apathy, depression, or decreased life satisfaction. The stages of physical change that occur as part of the aging process are less well articulated. Several theories attempt to explain the biology of aging through a variety of scientific observations at the molecular, cellular, organ, and system levels. No one theory explains all of the aging processes, but each holds some clues. In reality, it is reasonable to suppose that there are multiple influences that affect the aging process. The various theories of aging can be categorized as either programmed change theories or stochastic theories. Developmental-genetic theories propose that the changes that occur with aging are genetically programmed, whereas stochastic theories maintain that the changes result from an accumulation of random events or damage from environmental agents or influences.It is accepted now that the process of aging and longevity is multifaceted, with both genetics and environmental factors playing a role. In animal studies, genetics accounted for less that 35% of the effects of aging, whereas environmental influences accounted for more than 65% of the effects. The developmental-genetic theory resides with genetic influences that determine physical condition, occurrence of disease, age of death, cause of death, and other factors contributing to longevity. At the cellular level, Hayflick and Moorhead observed more than 35 years ago that cultured human fibroblasts have a limited ability to replicate (approximately 50 population doublings) and then die. Before achieving this maximum, they slow their rate of division and manifest identifiable and predictable morphologic changes characteristic of senescent cells. Another explanation of cellular aging resides with an enzyme called telomerase that is believed to govern chromosomal aging through its action on telomeres, the outermost extremities of the chromosome arms. With each cell division, a small segment of telomeric deoxyribonucleic acid (DNA) is lost, unless a cell has a constant supply of telomerase. In the absence of telomerase, the telomeres shorten, resulting in senescence-associated gene expression and inhibition of cell replication. It is thought that in certain cells, such as cancer cells, telomerase maintains telomere length, thereby enhancing cell replication. Currently, there is interest in developing telomerase therapy that could be used to initiate cell death in selected targets such as cancer cells and preventing cell senescence in other cell types, such as the chondrocytes in joints, the retinal epithelial cells in the eye, and the lymphocytes in the immune system. The stochastic theories propose that aging is caused by random damage to vital cell molecules. The damage eventually accumulates to a level sufficient to result in the physiologic decline associated with aging. The most prominent example of the stochastic theory is the somatic mutation theory of aging, which states that the longevity and function of cells in various tissues of the body are determined by the double-stranded DNA molecule and its specific repair enzymes. DNA undergoes continuous change in response both to exogenous agents and intrinsic processes. It has been suggested that aging results from conditions that produce mutations in DNA or deficits in DNA repair mechanisms. The oxidative free radical theory is a stochastic idea in which aging is thought to result partially from oxidative metabolism and the effects of free radical damage. The major byproducts of oxidative metabolism include superoxides that react with DNA, ribonucleic acid, proteins, and lipids, leading to cellular damage and aging. Another damage theory, the wear and tear theory, proposes that accumulated damage to vital parts of the cell leads to aging and death. Cellular DNA is cited as an example. If repair to damaged DNA is incomplete or defective, as is thought to occur with aging, declines in cellular function might occur. Although these theories help to explain some of the  biologic phenomena of aging, many questions remain. It seems likely that the human genome project will begin to explain some of the questions regarding the genetics of aging, but many questions need to be answered regarding the effects of environmental influences on aging.

Progeria is an extremely rare genetic disease of childhood characterized by dramatic, premature aging. The condition, which derives its name from “geras,” the Greek word for old age, is estimated to affect one in 4 millioewborns worldwide.

The most severe form of the disease is Hutchinson-Gilford progeria syndrome, recognizing the efforts of Dr. Jonathan Hutchinson, who first described the disease in 1886, and Dr. Hastings Gilford who did the same in 1904.

As newborns, children with progeria usually appear normal. However, within a year, their growth rate slows and they soon are much shorter and weigh much less than others their age. While possessing normal intelligence, affected children develop a distinctive appearance characterized by baldness, aged-looking skin, a pinched nose, and a small face and jaw relative to head size. They also often suffer from symptoms typically seen in much older people: stiffness of joints, hip dislocations and severe, progressive cardiovascular disease. However, various other features associated with the normal aging process, such as cataracts and osteoarthritis, are not seen in children with progeria.

Some children with progeria have undergone coronary artery bypass surgery and/or angioplasty in attempts to ease the life-threatening cardiovascular complications caused by progressive atherosclerosis. However, there currently is no treatment or cure for the underlying condition. Death occurs on average at age 13, usually from heart attack or stroke. In 2003, NHGRI researchers, together with colleagues at the Progeria Research Foundation, the New York State Institute for Basic Research in Developmental Disabilities, and the University of Michigan, discovered that Hutchinson-Gilford progeria is caused by a tiny, point mutation in a single gene, known as lamin A (LMNA). Parents and siblings of children with progeria are virtually never affected by the disease. In accordance with this clinical observation, the genetic mutation appears iearly all instances to occur in the sperm prior to conception. It is remarkable that nearly all cases are found to arise from the substitution of just one base pair among the approximately 25,000 DNA base pairs that make up the LMNA gene.

The LMNA gene codes for two proteins, lamin A and lamin C, that are known to play a key role in stabilizing the inner membrane of the cell’s nucleus. In laboratory tests involving cells taken from progeria patients, researchers have found that the mutation responsible for Hutchinson-Gilford progeria causes the LMNA gene to produce an abnormal form of the lamin A protein. That abnormal protein appears to destabilize the cell’s nuclear membrane in a way that may be particularly harmful to tissues routinely subjected to intense physical force, such as the cardiovascular and musculoskeletal systems.

Interestingly, different mutations in the same LMNA gene have been shown to be responsible for at least a half-dozen other genetic disorders, including two rare forms of muscular dystrophy.

In addition to its implications for diagnosis and possible treatment of progeria, the discovery of the underlying genetics of this model of premature aging may help to shed new light on humans’ normal aging process.

 

Progeria (rapid ageing)

 

Hutchinson-Gilford progeria syndrome is a genetic condition characterized by the dramatic, rapid appearance of aging beginning in childhood. Affected children typically look normal at birth and in early infancy, but then grow more slowly than other children and do not gain weight at the expected rate (failure to thrive). They develop a characteristic facial appearance including prominent eyes, a thiose with a beaked tip, thin lips, a small chin, and protruding ears. Hutchinson-Gilford progeria syndrome also causes hair loss (alopecia), aged-looking skin, joint abnormalities, and a loss of fat under the skin (subcutaneous fat). This condition does not disrupt intellectual development or the development of motor skills such as sitting, standing, and walking.

People with Hutchinson-Gilford progeria syndrome experience severe hardening of the arteries (arteriosclerosis) beginning in childhood. This condition greatly increases the chances having a heart attack or stroke at a young age. These serious complications can worsen over time and are life-threatening for affected individuals.

 

Syndromes of Gatchinson–Gilford

 

Syndromes of Werner – types of progeria

 

The specific mechanisms are formed by immune system. There are physiological specific mechanisms and pathological ones. The specific physiological mechanisms of the individual reactivity are the immune reactions, which form the specific resistance to some antigens (bacteries, viruses, fungus, tumours cells). The pathological specific mechanisms of the individual reactivity can cause development of the immunodeficiency or immunodepressive conditions of an organism or the allergic reactions and diseases.

The unspecific mechanisms of the reactivity are physiological and pathological. Physiological unspecific reactivity is the vital reactions complex of the healthy organism iormal life conditions. Pathological unspecific reactivity is the complex of an organism’s reactions in abnormal life conditions as a result of the decrease of the adaptive potential of an organism (for example: shock, collapse, narcosis).

Mechanisms of the unspecific reactivity are realized by means of nervous system reactions (central nervous system, vegetative nervous system), endocrine system reactions; barrier systems; cell’s reactions; humoral reactions.

The nervous and endocrine system are the main systems, which form the organism’s reactions on the various factors. The nervous system changes activity of receptors, neurons, nervous fibres, spinal cord and brain in the new vital conditions. The alteration of the nervous system activity changes the organism resistance. For example, the extreme stimulation of the central nervous system by coffeine reduces the resistance of an organism to hypoxia. The psychic trauma complicates the disease course. Reactivity of an organism depends on the vegetative nervous system conditions. Changes of adrenergic and cholinergic link of the vegetative nervous system activity, which always is counterbalanced iormal conditions, characterize the organism’s adaptation to some influences of environment. The stimulation of the sympathoadrenal system on the first stages of adaptation is a protective reaction. In pathological conditions (for example, continuous hypoxia) the cholinergic link of the vegetative nervous system activation increases of an organism resistance to hypoxia.

Endocrine system takes the certain part in forming of the individual reactive mechanisms, so its alteration can complicate life of the human. The suprarenal gland function lessening reduces the resistance to hypoxia, hypofunction of the thyroid gland increases the resistance of an organism to hypoxia too, and the decrease of insulin excretion by pancreas elongates maim incarnation. The role of endocrine system and nervous systems, that operate synergically, is possible to explain on the example of stress-reaction. Canadian pathologist Selye was the first who has worked out the concept about stress. Stress is the unspecific reaction of an organism to different influences. Hypothalamus-hypophisis-suprarenal system plays the main role. This system carries out a general adaptive syndrome.

 

The barrier systems preserve an organism against the pathological factors of the external environment.

There are external and internal barriers.

The external barriers are skin, mucous membranes, liver, spleen, lymphatic nodes and other organs, which have the cells of the system of mononuclear phagocytes.. The skin is covered with multilayer epithelium. It is a barrier for the majority of microorganisms. Peeling of a surface layer promotes the deleting of bacteria. The clean skin has bactericidal activity, which depends on the рН of the sweat, on the structure of a secret of grease glands, on the excretion of antiseptic products. The mucous membranes, which cover conjunctiva, throat, respiratory, digestive and urogeninal tracts, prevent the penetration of microorganisms, due to the insignificant permeability. The secret of the mucous coat glands and active function of glimmer epithelium promotes the mechanical deleting of dust, microorganisms. The bactericidal substance lysocim, which destroys some microorganism’s species, and the immunoglobulines are in the mucous coats secret. Protective reflexes, such as cough, sternutation, and delay of breath have the large value too. The gastric juice has bactericidal activity too, for example, kills of the cholera vibrion. Vomiting reflex also has protective function.

 

There are internal barriers in the organism, which are named histohematic barriers. Wall of a capillary has the function of a barrier. The wall of a capillary lets in only the nutritious substances and does not let in the toxins, medicines. Examples of internal barriers: hematoencephalic (blood-brain), hematoophtalmic (blood-eye tissue), hematolabirintic (blood-lymph of a labyrinth), hematoovarial (blood-ovarium tissue), hematotestical (blood-testicular tissue), placenta (mother’s blood-foetus blood).

 

Scheme of the structure of hematoencephalic barrier.

1 – endothelium of hemokapilar

2 – basement membrane,

 3 – astrocytes,

4 – contact processes of astrocytes on astrocytes hemokapilyari

5 – the body of the neuron,

6 – the part of the neuron

7 – olihodendrohlioсyt.

 

 

Connective tissue, which surrounds the vessels and penetrates into a tissue, executes the protective function too. The most powerful and complex barrier surrounds the nervous system and organs of reproduction. The nervous cells are the most sensitive to the internal environment changes. The hematoencephalic barrier permeability is various in different sites of the central nervous system. For example, hematoencephalic barrier in the area of hypothalamus lets pass all substances, which are in the blood. The information about the chemical structure of blood is necessary for the hypothalamus functions correction. The delay of the information can be dangerous for life. Hematoencephalic barrier includes the endotelium of the brain capillaries, their basal membrane, the glia and the brain coats. Hematoencephalic barrier structure: slots between endothelial cells of the capillaries are absent; glial cells cover all surface of the capillary; basal membrane is very dense. The peculiarity of the hematoencephalic barrier structure promotes protection of the brain against the influence of toxic substances. But in some cases this property complicates the treatment of some diseases of the nervous system. The permeability of barrier amplifies when the temperature of body increases. Doctors use this property for the treatment of infectious diseases of the nervous system. The protective function of barriers is dependend oervous and humoral influences, on a state of the external and internal environment. The alcohol has specific influence up hematoencephalic barrier. The permeability of this barrier increases during initial stage of alcoholism, so various toxic substances influence up the brain. Then permeability of the barrier decreases, that provokes violation of nutrition of the brain. Alcoholic psychoses, degradation of the person, premature aging develop in such patients. The alcohol easily damages reproductive system, poisons a foetus.

 

Structural features of a lymph node

 

Cellular mechanisms of reactivity are manifested by the change of a functional state of a separate cell. The main effect of various cells reactions is adaptation to the conditions of the life, which permanently change. There are 2 types of adaptive cells reactions: immediate and continuous. The immediate mechanisms of cellular adaptation arise at once after the influence of stimulator and are realized due to present mechanisms. The continuous mechanisms of cellular adaptation arise gradually after durablis or multiplis influences of stimulator. The durablis influence of any factor promotes accumulation of the defined information in a cell and inclusion of mechanisms of selfregulation. In a cell there is an interrelation of their function with the genetic apparatus. The increasing of influence functional load of cell strengthens activity of the genetic apparatus and promotes accumulation of some proteins, which must promote increasing of the function. The example of durablis adaptation is hypertrophy of a body, hyperplasia of a body.

 

Humoral mechanisms of the reactivity are very important for the organism too. The system of the plasma blood proteins, which is named system of complement, has the protective function. The system of complement and system of phagocytes have functional connection with immune system. Humoral factors are start mechanisms of the reactivity due to their operation on organs-effectors. The strongest substances are mediators and hormones. For example, the stress-reaction occurs due to the amplified excretion of norepinephrine (mediator), epinephrine (neurohormone), adrenotropic (hormon), glucocorticoids (hormones) and other substances. Individual reactivity can be changed as a result of influence of the factors of the external environment. Reactivity of an organism depends on ecology. Some changes of an ecological situation can prevent development of disease; others on the contrary provoke development of disease. For example: the small doze of a ultra-violet irradiation increases resistance of an organism to the infectious diseases, promotes synthesis of vitamin D in the organism, and the large doze promotes development of skin burn. The durablis operation of ionizing rays lowers resistance of an organism to infection. The intensive physical load is accompanied by significant psychoemotional overload and can provoke development of cardiovascular pathologies. The nonrational nutrition, hypovitaminosis lower resistance of an organism to an infection, promotes development of various violations of metabolism. Reactivity of the person can be changed as the result of the influence of alcohol, nicotine, automobile gases, which contain CO, Hg, Pb, industrial wastes. Sharp changes of weather, season of year and climate influence on reactivity and resistance too. Low temperature of air influences on organism variously. The overcooling lowers resistance to the infection, so in such conditions influenza and pneumonia may occur. The short-term contact of a human body with the cold environment, which periodically repeats, increases resistance of an organism to the infection. Low temperature (hypothermia) is used in medicine during complex continual operations on the heart and brain.

 

Role of constitution in pathology

Constitution is a complex of functional and morphological peculiarities of an organism, which were derivated by the heredity, and which forms during all life as a result of influences of the environmental factors, it determines reactivity of every individual. All people belong to some constitutional type. Hyppocrate (firstly) had determined some types of the constitution. The physicians, who lived `in Hyppocrate’s times, knew, that the individual peculiarities of the person determined his reaction on the external environment and caused disease course peculiarities.

 

 

Hyppocrate had divided all people on four types: choleric (1), phlegmatic (2), melancholic (3) and sanguinic(4).

 

Sigo had divided all people into 4 morphological types. This classification is based on the peculiarities of the anatomic structure of the person.

Constitution types by Sigo are:

 respiratory type (A), digestive type (B), muscular type (C), and brain type (D).

 

Krechmer has offered the classification, based on the functional peculiarities of an organism.

Constitution types by Krechmer are: asthenic(A), athletic(B), digestive(C).

 

Constitutional types by Chornoruzkiy. He determined due to the size of costal arcs angle of a person

1)    Asthenic (less than 90 degree)

2)    Normosthenic (90 degree)

3)    Hypersthenic (more than 90 degree)

 

А.А.Bogomoletz has offered the classification, which characterizes  the connective tissue peculiarities. Constitution types by Bogomoletz are: asthenic type, fibrosis type, pastosis type, and lipomatosis type. Constitutional type of an organism plays important  role in the development of the pathological process.

 

 

DIATHESIS

Diathesis is the manifestation of the abnormal constitution, which is characterised by the abnormal reaction of an organism to the physiological and pathological influences

 

Diathesis appears the most frequently during the childhood, because the homeostatic regulation mechanisms are imperfect. There are 4 types of the diathesis: exudative-cataral, lymphohypoplastic, nervous-arthritic, asthenic.  Very intensive exudative processes, allergy reactions and long disease course characterize the development of the inflammation in such patients, who are suffering from the exudative-cataral diathesis. Allergic reactions are the result of the high level of immunoglobulines in the patient’s blood, so bronchial asthma, and anaphylactic shock саn develop very often. The patients, who are suffering from the lymphohypoplastic diathesis, are usually pale, theirs muscular tissue is developed deficiently, the lymphatic nodes size is increased. The aytoallergic diseases arise in these patients very often. Nervous-arthritic diathesis cause the obesity intensification, nervous system irritability, diseases of joints, skin diseases, psychological disorders in some patients. Astenic diathesis is characterized by adynamia; lability of vascular reactions and gastroptosis. Diathesis is not a fatal condition of the patient. The environment can promote or inhibit its manifestation. The causes of many forms of diathesis, probably, are hereditary pathology of different enzymes.

 

Types of diathesis:

1. EXUDATIVE-CATARAL (very intensive exudative processes, allergy reactions and long disease course)

2. LYMPHOHYPOPLASTIC (muscular tissue is developed deficiently, the lymphatic nodes size is increased aytoallergic diseases arise in these patients very often)

3. NERVOUS-ARTHRITIC (obesity intensification, nervous system irritability, diseases of joints, skin diseases, psychological disorders in some patients)

4. ASTHENIC (adynamia; lability of vascular reactions and gastroptosis

 

 

INFLUENCE OF EXTERNAL FACTORS ON ORGANISM REACTIVITY

PROTECTIVE MECHANISMS OF REACTIVITY.

 

Characteristic of stress and general adaptation syndrome 

 The term “stress” means an unspecific reaction, which arises on action of any irritant. For the first time a stress conception was represented by H.Selye. Stress is the part of our daily life, however in medicine it associates with action of diverse causal factors, such, as surgical trauma, burns, emotional excitation, mental or physical efforts, tiring, pain, fear, necessity to concentrate, disappointment or humiliation, blood loss, intoxication by medicines or due to contamination of environment ivy, unexpected success. Stress occurs to businessman, which lies under permanent life circumstances pressure, to sportsman, aspiring to win, to aircraft moving traffic-controller, which carries permanent responsibility after lives hundreds, in running horse, it’s horseman and in onlookers. Medical researches show, that, in spite of problems distinction, standing up in front of these organisms, all of they reciprocate with stereotype form of biochemical, functional and structural changes, which are drawn in reaction in order to overcoming of any raised it needs to vital functions, adaptation to new situations in particular.

All of endogenic and exogenic agent creating such a requirements, are called stressors. Selye turned mind to the fact, that, in spite of variety stressors (trauma, infection, super cooling, intoxication, narcosis, muscle loading, strong emotions and others), all of then lead to the same type changes in thymus, adrenal glands, in lymphatic tissue, blood composition and metabolism. In experiments on rats he observed a typical triad, which includes  hypertrophy of cortical matter of adrenal glands, involution of thymico-lymphatic system an hemorrhagic ulcers on mucous membrane of stomach and duodenum.

Stress displays as general adaptation syndrome totality of unspecific changes, which arise in animal or human organism attached to action of any pathogenic irritant. It consist of three successive stages: alarm reactions, stage of resisttance  and exhaustion stages.  Alarm reaction signifies immediate mobilization of protective organism forces.  It consists of shock and antishoke phases. During shock phase muscle and arterial hypotension are observed, hypothermia, hypoglycemia, condensing of blood, eosinopenia, increasing of permeability of capillary vessels, dominance of catabolism processes. Simultaneously resistibility decreases and if stressor is sufficiently strong (large burns, extreme temperatures), it can tread death. If an organism survives, an elementary reaction goes in stage of steadiness or resistance. The displays of this second phase are perfectly different, sometimes even opposed to alarm reaction displays.  A phase of untishock is described by rise of arterial pressure, muscular tone, maintenance of glucose in blood. In second phase of this stage takes place renewal of broken equilibrium and transition in resistance stage, when an organism becomes more steady not only to action of this irritant, but and on relation to other pathogenic factors (cross resistance). During resistance stage hypertrophy of a cortical adrenal matter occurs and big number of hormones, is recreated anabolic processes, are activated glycogenesis increases. This stage is observed in that case, if action of stressor is commensurable with adaptation. The signs, typical for alarm reaction, already disappear and resistibility is above norm. Selye named protective reactions, which provide the vital processes attached to stress, as syntotaxic reactions.

During protracted action of damaging agent adaptation disturbs.  Exhaustion of functional reserves, atrophy of cortical adrenal matter, lowering of arterial pressure, disintegration of proteins occur and organism goes from stage of resistance to exhaustion stage. Signs of alarm reaction appear again, but now they are irreversible, and organism dies. This testifies, that adaptation ability of organism and its adaptation energy are not boundless, in conditions of protracted stress inevitably treads exhaustion. Engine of human organism early or later falls as victim of continuous use. Three stress stages resemble life periods:  childhood (with it’s typical low resistibility and high reactivity on any irritation), maturity (in time of which an organism fits in majority of agents and his resistibility rises) and old age (is described by loss of adaptation ability and final exhaustion). Thus, a tie between stress and aging exist.

The stress end depends on force and action duration of stressor and potential possibilities of protective organism forces.  Circumstance that one certain stressor can be followed with diverse damages in different individual, is accounted for by influence of stipulating factors. They can electorally reinforce or weaken certain effect of stress. The stipulating factors can be endogenous (genetic predisposition, age or sex) or exogenous (treatment by some hormones, medicines, diet). Under their influence a stress reaction can became pathological and to be followed with adaptation illnesses.  In this situation a stress reaction can transform from adaptation link, in link of pathogenesis and in appearance of numerous stress diseases.

A biological significance of general adaptation syndrome consists not only in rise of an organism resistance on relation to factor, which caused stress, but also in fact, that during not very strong and protracted stress an unspecific organism resistance to various other factors increases. It is displayed in raised survival after influence of lethal agents or in affection of heart, kidneys or other organs, which appears under influence of pathogenic factors.  Systematic influence on organism of weak and moderate irritants (cold shower, physical exercises) backs up adaptation reactions.

Selye considers general adaptation syndrome as obligatory manifestation of illness.  Therefore the same type picture of general adaptation syndrome is by general component attached to the very various diseases, unconnected with action specific character of pathogenic factor.

 

Stress reaction mechanisms

 Irrespective of irritant nature is a decisive significance in effectors realization of stress reaction belongs to activation of higher vegetative centers and related to them systems of hypothalamus pituitary adrenal cortex and excitation of sympathetic nervous system. As result of the following processes  a big significance develops.

1. Activation of hypothalamus system causes releasing of ACTH somatotropin’s thyreotrophy hormones, which accordingly stimulate a secretion of glucocorticoids, somatomedins, thyroid hormones.

2. Activation of vegetative nervous system (sympathetic and parasympathetic) is attended with receipt of catecholamines, insulin, glucogone in blood.

3. Activation of aldosterone-vasopressine system displays by increase of blood concentration of angiotensines, aldosterone, vasopressin (antidiuretic hormone).

Hormones, released during stress, according to contemporary conceptions, determine development of three successive phases of this reaction.

Acute phase. Hormones, released in this phase provide defense from decrease of arterial pressure and volume of circulatory blood. This is provided by increasing of general peripheral resistance and preservation of water in organism. These reactions are related to increasing  of release of  catecholamines, glucocorticoids, angiotensin II,vasopressin in blood.

Sub acute phase. It is described by resources mobilization for power and plastic guaranteeing of systems, realizing adaptation. This is provided by means of redistribution of mentioned resources among actively functioning organs (heart, brain) and structures, abiding at relative rest (skeletal muscles, digestive canal, lymphoid and fatty tissues). The metabolic changes in this phase are caused by increasing  of secretion of catecholamines, glucocorticoids, glucagons and by diminution of insulin release. These hormones, reinforcing, glycogenesis, gluconeogenesis, lypolysis and proteolysis are cause augmentation of concentration of glucose, amino acids, free fat acids in blood.

Phase lasting adaptation.  It is described by structural changes (hypertrophy, hyperplastic) of organs and tissues, providing adaptation and including hyper functioning organs. In its realization insulin taking part, STH, somatomedines, thyroid hormones, growth   factors – true and tissue hormones, activating the anabolic processes and adaptations.

Many researchers show, that reaction of front pituitary gland part and adrenal cortices arises double-quickly (minutes and even seconds) and its depends on hypothalamic, where the special substances are   produced realising-factors, which stimulate a secretion of front pituitary gland part (liberines). Starting mechanisms of this system include release of adrenalin and, noradrenalines significance of which was shown by W.Cannon.

In experiments and in clinic it is firmly established, that attached to functional adrenal cortex insufficiency organism resistance sharply decreases. Introduction of steroid hormones (glycocorticoids) organism resistance, can be restored, therefore Selye considers them adaptation hormones. This group include, ACTH, STH,  adrenalines and noradrenalines, because their action isrelated to adrenals gland and adaptation.

Adaptation іnsufficiency can cause adaptation illnesses development. Basic cause of their development, according to Selye is or irregular correlation of hormones, when the hormones prevail, which heighten inflammation reaction (Pituitary gland STH) and adrenal cortex mineralocortycoids, and there is deficiency anti-inflammatory hormones (Pituitary gland ACTH and adrenal cortex glycocorticoid), or special reactivity of organism, caused by inauspicious influences (surplus loading by salt, application of corticosteroids, etc.). This creates predisposition (diathesis) to development of pathological processes.

In experiment conditions it was succeed to reproduce whole number of diseases like collagenous, nodules epiarteritis, nephrosclerosis, high blood pressure, myocardium necrosis, sclerodermia, metaplasia of muscular tissue and others. Confirmation of this regulation is beginnings of hypertension, nephrosclerosis, organs hyalinosis, reinforcement of inflammatory reactions after introduction of big doses desoxycorticosterone, which has anti-inflammatory properties. Introduction of animal glucocorticoids (anti-inflamator hormones) brakes inflammation, but simultaneously represses the immune reactions causes ulcerous stomach and duodenum, defeating and, creates the conditions for beginnings of myocardium necrosis.

As a rule, surplus of sodium chloride in diet provides pathogenic dominance in of endogen corticosteroids. Surplus of sodium chloride in combination with action of mineralocorticoids conduces development of electrolyte-steroidal cardiomyopathy with hyalinosis. This pathology form is observed attached to myocarditis, nodules periarteriitis and is attended with development of nephrosclerosis and hypertension. Electrolyte-steroidal cardiomyopathy with necrosis can be easy reproduced in rats by means of injections of synthetic glucocorticoid and introduction Na₂HPO₄, Na₂SO₄ or NaClO₄. The experiments showed, that in similar conditions a simultaneous introduction of MgCl₂ or КСl protects myocardium from beginnings of necroses.

Thus, one factors (corticosteroids, sodium salts) sensibilizate organism, other (magnesium salts, potassium) desensabilizate it.

Stress affects immune organism system.  The experimental animals, exposed to various stress influences, become more sensible to viruses herpes simplex, poliomyelitis, polyoma, and also to exciters of other infections. Also resistance to tumor growth diminishes.  Duration and degree of immune depression depend on force and duration of stress action.  Immune depression attached to stress is related with increase of concentrations of glucocorticoids in blood serum,  redistribution of lymphocytes, disbalance of cells in immune reaction and Т-lymphocytes  activation (suppressors).

 

Adaptation   diseases

They are the diseases, in development of which a leading role belongs to excessive stress and to so called stressor mechanisms of damage.

Stress of big intensity and duration can turn from adaptation mechanism can turn into mechanism of pathogenesis. Illnesses of adaptations include:

а) psychosomatic diseases (ischemic heart disease, hypertensive and duodenum illness, ulcerous stomach illness);

b) metabolic diseases (diabetes mellitus);   

c) allergic and inflammatory diseases (bronchial asthma, rheumatism).

Attached to typical adaptation illnesses, the base of disorder is insufficiency, surplus depravity of reaction on stressors (for example, inadequate primary or hormonal reactions). However, circumstance that one certain stressor can cause various damages in different individuals, is accounted by ‘stipulating factors’ influence. They can electoral increase or weaken certain effect of stress. The stipulating factors can be endogenous (genetic predisposition, age or sex) or exogenous (treatment with some hormones, medicines, diet). Under their influence well bearable iorm stress reaction can begin pathologic and cause adaptation illnesses.  Stressor electorally acts on those parts of body, which are peculiarly sensebilisated as by these stipulating factors, and by specific dominances of primary agent. Consequently, adaptation illnesses cannot be ascribed to some one certain pathogen, and they are conditioned by action of a few potentially pathogenic factors, among which there is no one able to cause disease independently. This “multifactor” or “pluricausal” illness. Attached to any disease a general adaptation syndrome influence clinical illness displays. 

Nature of pathologic processes attached to adaptation illnesses can be various depending on:

1) amount and changed correlation of hormones of front pituitary gland part ACTH/STH and adrenal cortex glucocorticoids/mineralocorticoids; 

2) abnormal metabolism of hormones and their abnormal them fixing in tissues; 

3) change of tissue sensitiveness to hormones;

4) violation of function of other systems and organs (for example, nervous system, liver and kidneys);

5) various stipulating factors (diet, heredity, dominance of other stressors).

Under conditions of auspiciously course of illness hormonal reaction is optimum. Usually it is performed due to secretion activating of ACTH and glucocorticoids, but in some circumstances the effects of STH and mineralocorticoids prevail the latter can be promoted by such stipulating factors, as diet, rich in chlorous sodium or too overlade by proteins (to 60 % of proteins), one-side nephroectomy, chronic action of dampness and cold.

An organism has ability to maintain homeostasis. In order for preserve helth neither index in body must not out of norm. In case of such deviation or even death are possible. There are much complicated biochemical mechanisms, which provide constancy and homeostasis stability.

The biochemical stress-syndrome analysis showed, that a homeostasis depends on two reactions types:  syntaxic and catatoxic. In order to resist to various stressors, organism must regulate its own reactions by means of chemical mediators and nervous impulses, which calm, or stimulate an organism to counteraction. Syntoxic impulses operate as tissue calmer, creating conditions of passive tolerance, which allows coexisting with damaging factors. Catatoxic agents are followed with chemical changes (in the main by the way of development of hepatic microsomal enzymes), which conduct active offensive on pathogen usually by means of acceleration of its metabolic destruction. The most active syntoxic hormones are glucocorticoids.  A stress reaction has the definite peculiarities during extremal condition. If during to action of stressors of moderate force on organism violation of the homeostasis disappear on adaptation forming measure, under condition of extreme influences, when adaptation processes and compensation find oneself insufficiently effective, displacements of basic homeostatic parameters protractedly exist and even progress.

Thus, intensity, duration and seriousness of stress manifestations during extreme states are conditioned by dominance of stimulant and potentiating influences on hypothalamus-pituitary-adrenal system, that leads to it’s hyper activation.

A stress-reaction role during to action of extreme factors to a great extent is determined by effects of corticosteroids and catecholamines. Basic action of these hormones displays in urgent mobilization of power and functional reserves of organism, by their redistribution in favor of primary systemss upplying, functioning with maximum loading.

Thus, one can be thought firmly established, that a stress-reaction plays a major role in adaptation processes and compensation attached to extreme states. Preliminary weakening of hypothalamus-pituitary-adrenal system functions cause sharp worsening of course and end of process, where as introduction of corticosteroids gives a positive prophylactic and therapeutic result.

However excessive intensity and duration of stress attached to extreme influences causes display of biologically negative sides of this reaction. A surplus amount of catecholamines can cause centralization of the blood circulation, dangerous for parenchyma organs, violation of microcirculation, hypoxia, metabolic acidosis, activation of peroxide oxidation of lipids of cellular membranes.  High concentration of glucocorticoids attached to heavy stresses sharply stimulates catabolic processes, peculiarly in proteins metabolism, disturbs activity of immune system, causes disintegration and migration of lymphoid cells. Phenomenon of hypercompensation in the development of stress-reaction attached to action of extreme factors can transform this reaction from adaptation link in link of pathogenesis, playing an important role in progressing of homeostasis violations.

Typical stress peculiarity attached to extreme fortunes is forming of corticosteroid insufficiency and lowering of organism resistibility.

 

Methods of lowering damaging  stress action

There are many methods, significance of which was established empirically. Among methods, used for defense against damaging effects of distress, some of them are used by people as distraction means from everyday routine, and other are more formal therapeutic. Most important among them are rest and entertainments, psychotherapy, weakening, acupuncture, balneotherapy, physiotherapy, physical procedures and activities.

For prophylaxy and therapy of central and vegetative violations attached to stress make  the main three group of officinal remedies are used:

1) preparations, affecting transformation processes of afferent impulsation and raising activity of antinociceptive or brake systems of brain;

2) medications, impedimental to realization of raised activity of sympatthic-adrenal and peptidergic systems by means of blockade of specific receptors through which toxic action and of catecholamines and endorphins is mediated;

3) medications, affecting neurochemical processes in central nervous system and peripheral organs, preserving violations of energy and chemical homeostasis.

Substances, rendering antistressoraction on level of cell metabolism, include also group of adaptogenes of vegetable origin (ginseng, eleuterococcus and ets.).

However there is no medicine, which rendered reliable unspecific antistress action irrespective of pathogenic stressor agent.

It is incorrect to use narcotics, alcohol, smoking, which can  cause considerable damages in organism. The search of effective antistress remedies is pursued in different directions, however we still distant from final aim.

 

 

MONONUCLEAR PHAGOCYTES SYSTEM. 

ROLE OF PHAGOCYTES IN PATHOLOGY.  PHAGOCYTOSIS DISTURBANCES

 

Many organs have barrier activity due to special cells, which form the system of mononuclear phagocytes (SМP).

SMP is the system of cells, which are united due to 3 features:

1) mutual function (all these cells are capable to phagocytes);

2) mutual derivation (all these cells derive from the stem cell of red bone marrow);

3) mutual structure (all these cells have one nucleus).

 

 

All cells of the SМP occur from the stem cell of red bone marrow and develop according to such scheme: stem cell  → promonocyte → monocyte. Monocytes enter into the blood and are divided into two groups: circulating and pre-wall. The pre-wall monocytes penetrate through the vessel wall and enter the tissues. Monocytes differentiation occurs in tissue and these cells transform into the  macrophages of this organ. Tissue macrophages were found in various organs (table).

 

 

The functions of cells of SМP are deleting of various particles from blood, lymph and tissues, due to absorption and enzymatic destruction of alien agent. Highly specific phagocytosis is the result of the specific structure of cellular membrane of macrophage: receptors to the immunoglobuline G, complement fractions and lymphokines are placed on the membrane of macrophage and metabolic processes of the SМPcells are very active. The pathology of SМPcells can be hereditary and can occur during life. The hereditary defects of the enzymes myeloperoxidase, glucose-6-phosphatdehydrogenase, enzymes of glutation system, lysosomal hydrolases  provoke the violation of macrophages protective functions. Primary metabolism violations of an organism (diabetes mellitus, obesity, atherosclerosis, uremia), malignant tumours, intoxication can cause the defects of macrophages too.

 

 

IMMUNOLOGICAL REACTIVITY.

IMMUNODEFICIENCY STATES

Organization and development of immune system

The organs of the immune system can be thought of as central or peripheral. The primary function of the central organs is the generation of new lymphocytes to populate and repopulate the peripheral organs, in which immune responses actually take place. Here the immune system is intimately connected with the mononuclear system. By birth the main central lymphocyte-producing organs are the bone marrow and the thymus as part of the blood system they derive from a pluripotential hematopoietic stem cell, and it in turn gives rise to two types of precursors, pre-B- and pre-T-cells.

T–lymphocytes and cell immunity

Pre-T-cells also arise within the bone marrow but must travel to the thymus to their complete maturation. Whether the thymus stroma elaborates maturation hormones thymosin, thymopoietin, thymulin and other.

The selected cells that are exported from the thymus home to particular areas of the peripheral lymphoid tissues. They are deployed so that interaction are optimized between the antigen-trapping macrophages and reticular cells on the one hand and T- and B-cells on the other. They travel in the blood until they reach a lymphatic node.

The central cell in antigen response is the helper T-cell (Th). The helper T-cell role in the immune response is to help other lymphocytes get activated by antigen. It does so by secreting a variety of growth and differentiation factor (lymphokines) to which they respond.

The Th-cell seems to need two signals to become activated; binding antigen plus MHC provides the first signal , and the antigen-presenting cell provides the second in the form of a soluble or membrane-associated growth factor called interleukin1 (IL-1). Together these activate the helper cell, which begins to produce other growth factors, including interleukin 2 (IL-2). Help, in the form of growth and differentiation factors like IL-2,is nearly obligatory for most immune responses, and an individual with deficient Th will be severely impaired, even if the other components of the immune system are intact (the situation in AIDS). Among the lymphokines are factors that attract and activate macrophages. Such phagocytes will ingest and destroy the antigen.

The other important class of effector T-lymphocyte is the “killer” or cytotoxic T-cell (Tc). Cells of this type are selected for seeing antigen in the context of class I MHC product. They are specialized for killing the body’s own cells. There are at least two circumstance under which this would be desirable: when the cell in question has undergone a change, possibly malignant ; and when the cell is infected by a virus. Viruses are not really living, so they are hard to “kill”; the tactic of the immune system is to destroy the infected cell before the viruses can multiply. They need to be in physical contact with their target cell for about 5 minutes, after which the target is programed to die and the killer can go on another cell. The killer may deposit some toxic molecule or structure on the target cell surface, it signal the target to self-destruct by activating a “death program”.

Less is known about the last subpopulation of T-lymphocytes, the suppressor T-cells (Ts). These cell can be shown to oppose the activation or expression of all the other cells of immune system. It is assumed that they are a part of the normal regulation of immunity.

B–lymphocytes and humoral immunity

B-lymphocytes (B-cells) have receptors or antigens as do T-cells, but the structure is different: B-cells use a membrane-bound version of the antibody they will later secrete. This receptor antibody is of the IgM and IgD classes. As with T-cells, each B-cell has many copies of one particular receptor. B-cell receptors see antigen alone and do not require the joint recognition of self markers so characteristic of T-cells. There are some antigens that can activate a B-cell that has appropriate receptors directly. The B-cells begins to grow and divide, and its daughters eventually differentiate into highrate, antibody-secreting cells (plasma cells). Antibodies are immunoglobulins (Ig), and occur in five structurally and functionally distinct classes: IgG, IgM, IgD, IgA and IgE. Any particular specificity will occures in more than one class.

 

Natural killer cells

Cytotoxic T-cells appear in the tissues in response to an appropriate antigen. There is another class of killer that do not seem to depend upon prior immunization and so are called natural killer (NK) cells. They kill certain types of tumor cells, primarily of the hematopoietic system. Their activity is significantly increased by interferon. NK-cells look line large, granular lymphocytes but, for the most part, are distinct from mature T- or B-cells.

Pathology of immune system

 

Immunity means protection or security from diseases or poisons. Immunopathology is the study of diseases caused by immune mechanisms. The word immunopathology illustrates the paradox of immune reactions. On one hand, immune reactions provide efficient organisms protection against infections; on other hand, they may destroy the host’s own tissues and cause disease.

Specific immune protection is mediated by products generated as a result of an immune response, which involve proliferation and differentiation of cell in the lymphoid system. This specific protection depends on previous exposure of the individual to the particular noxious agent or organisms (antigen). As a result of this primary exposure to antigen, there develop serum proteins (antibodies) or altered cells (specifically sensitized cells) that have the capacity to recognize, react with and neutralize the noxious agent or infecting organism.

Essential to an immune response is the capacity of the individual’s immune system to recognize an antigen. Most natural antigen are other organisms (bacteria, viruses, fung). Experimental of therapeutic procedures provide contact with other potential antigens, such as exogenous macromolecules (drugs), serum proteins, blood cells, or tissues (grafts) from individuals of the same or other species. An antigen that can induce an immune response is termed as immunogen. The capacity of an individual to respond to a given immunogen depends on several factors, such as dose, route, form, degree of foreignness, and number of previous exposure to the immunogen. The products of the immune response are humoral (immunoglobin) antibody and cellular (specifically sensitized cells).

 

Immune deficiencies

Immune deficiency diseases may be classified as primary or secondary. Primary immune deficiencies result from genetic or development abnormalities in the acquisition of immune maturity. Secondary deficiencies result from diseases or drugs that interfere with the expression of a mature immune system.

Multiple levels of defensive reactions must be considered in the evaluation of resistance to infection. Infections may occur with increased frequency in elderly individuals, in debilitated patients, or wheatural nonimmune barriers are affected. The depression of pulmonary clearing mechanisms because of the loss of ciliary activity of bronchial lining cells found associated with exposure to cigarette smoke is an example. In addition there is a genetic disorder resulting in a microtubule defect that affects the mobility of cilia, the immobile ciliar syndrome. Affected patient also have immobile sperm and chronic respiratory infections, frequent homophilus influenzae infection and abundant mucus secretions. Because of the complexity of immune deficiencies and the diverse clinical presentation of deficiency states, a careful systematic diagnostic work up must be carried out in order to select appropriate therapy.

 

Primary immune deficiencies

Primary immune deficiencies may be understood as defects in the development of the immune system and classified into the following four general groups depending on the stage in development of which the defect occurs:

1.       Combined (T- and B-cell) deficiencies

2.       B-cell deficiencies

3.       T-cell deficiencies

4.       Deficiency of stem cells.

The type infection observed is determined by the kind of immune abnormality present. Deficiencies in T-cell immunity usually result in fatal viral, fungal, or mycobacterial infections. Defects in B-cell immunity (humoral antibody) are associated with fatal bacterial infections. Defects in production of inflammatory cells, particularly polymorphonuclear leukocytes (agranulocytosis) are also associated with bacterial infections.

Defects in purine metabolism are responsible for a small number of immune deficiencies. Such deficiencies may result in a loss of T-cell (purine nucleoside phosphorylase deficiencies) or T- and B-cell (adenosine deaminase, ADP deficiency) function because of accumulation of toxic metabolites. Other purine metabolizing enzyme deficiencies are hypoxanthine-guanine phosphoribosyl transferase (Lesch-Nyhan syndrome) and ceto-5′-nucleotidase, which may be associated with a B-cell deficiency.

 

Secondary immune deficiencies

 Secondary immune deficiencies occur after full development of the immune system. Some of these are secondary to immunosuppressive therapy or infections (such as AIDS). Secondary immune deficiencies are associated with debilitating diseases, such as cancer.

The most common immune deficiencies are those that are secondary to immune suppressive therapy, as in graft recipients or cancer patients. Less common are immune deficiencies secondary to infections, such as AIDS or infection with virus. Many chemotherapeutic agents for cancer are antimetabolites also suppress the immune system. Frequently cancer patients die from infections that are treatment related. Particularly important are steroids, which are used for therapy of diseases variety of. High doses of steroids are particularly dangerous because they are directly toxic for lymphocytes and suppress phagocytosis.

Defect may also occur in the accessory inflammatory systems activated by immune effector mechanisms.

There are very rare but may be associated with particular infections. Also rare, but more severe, are disorders in phagocytosis.

 

Іmmune deficiency associated with predominanty T-cell

Di George’s syndrome. This appears to be one of series of similar multiorgan developmental defect reflecting abnormal embryogenesis at 4-6 weeks of gestation. There are probably a variety of causes for these anomalies. The characteristic manifestations include multiple anomalies of the third and fourth bronchial arch derivabires, type 1 truncus arteriosus, dysmorphic facies with micrognathia low-set ears, a shortened filtrum of the upper lip, thymic and parathyroid hypoplasia or aplasia. Neonatal tetany is observed in most affected infants. About 20 % of those involved have decreased number and function of T-lymphocytes. The lymph nodes and spleen show poorly developed T-cell-dependent zones and usually expanded B-cell-depended areas.

Immune deficiency T-cell associated with puriucleoside phosphorylase (PNP) deficiency. This autosomal recessive disease results from defects in the gene located on chromosome 9. In the absence of PNP, toxic metabolites, in this case d-GTP, accumulate within the cell and impair proliferation. T-lymphocytes are particularly sensitive to the accumulation of d-GTP, and they are affected to a greater degree than B-lymphocytes. There are such immunologic differences between ADP and PNP deficiency.

Immune deficiency associated with predominanty B-cell

Bruton’s X-linked agammaglobulinemia. This is the prototypic antibody deficiency. Affected males present in infancy or early childhood with recurrent pyogenic infections. Criteria for diagnosis include profound in ability to make antibody and resultant extremely low concentrations of all immunoglobulin isotypes. There is a profound decrease in circulating B-lymphocytes (usually less than 5/1000 lymphocytes); plasma cells are absent from lymph nodes and bone marrow. The number and function of T-lymphocytes (including cell-mediated immunity) are unaffected. Pre-B-cell are found in the bone marrow. The gene defect has been localized to the long arm of the X chromosome. In female carriers the defective chromosome is preferentially lionized during B-lymphocyte proliferation, permitting carrier defection.

Selective IgA deficiency. IgA deficiency is more frequent in patients with chronic lung disease than in a normal agematched population.

In complete IgA deficiency. The defect is presumed to result from maturational failure of IgA-producing lymphocytes. Autosomal recessive in heritance has been shown in some families. A fixed haptotype of MHC genes is frequently associated with IgA deficiency.

IgA is the characteristic antibody class in the secretion associated with mucous membranes. The helper T-cells found in the lymphoid tissues of the gastrointestinal and respiratory tracts seem to be specialized for driving B-cells to switch from IgM to IgA secretion. The B-cells also make a joining chain that allows two IgA subunits to from a dimer. In passing through epithelial cells on their way to the lumen, the IgA molecules acquire another polypeptide chain called secretory component, which is necessary for secretion and may provide some resistance to proteolytic digestion. Thus the IgA class of antibodies function primarily on the interface between the body and outside world and forms the first line of defense against invaders at the mucous membranes.

Selective IgG deficiencies with IgA deficiency. Criteria for diagnosis should include normal total serum IgG levels are frequently, but not invariably decreased.

IgG is the predominant antibody class in blood. It is useful in the defense against bacterial invaders: when it binds antigen it becomes able to activate a series of precursor proteins in blood collectively called complement. Activated complement components are chemotaxic for polymorphonuclear neutrophils, and so an inflamatory process is set up that helps get rid of the pathogens. Certain activated complement components are lytic and can destroy some bacteria directly. Other complement components adhere to the bacterial surface, and this is desirable since phagocytes have receptors for one of them (C3b), as indeed they do for IgG, which has bound antigen. This results in the bacterium being coated with “handles” for the phagocytes to seize (opsonized) and increases the effeciency of phagocytosis several numdred fold.

Immunoglobulin deficiency with increased IgM. This syndrome apparently represents a group of distinct entities with similar clinical expression. Some of the families reported have been clearly X-linked in inheritance; others have been autosomal recessive. Diagnostic criteria include impacted antibody formation. Thus, serum M, levels are elevated while IgG (and IgA) levels are diminished of irculating B-lymphocytes. Most patients have reccurent of persistent neutropenia; it is not clear whether this caused by IgM autoantibodies to granulocytes or by myeloid maturation arrest.

 

Severe combined immune deficiency diseases

Swiss type of agammaglobulinemia. This group of diseases is characterized clinically and immunologically by defects in both T- and B-lymphocytes. Criterie for diagnosis generally include presentation in infancy with severe, potentially lethal infections, profound abnormalities of T-cell-mediated immunologic reactivity and antibody deficiency, and lymphopenia, particularly of T-lymphocytes. The clinical presentation usually includes failure to thrive and unusually persistent infections with low-virulence opportunistic organisms. These findings require differentiation from infants with AIDS.

Immune deficiency with ataxia and telangiectasia (Louis-Bare’s syndrome). This autosomal recessive syndrome is characterized by combination of progressive cerebellar ataxia and fine telangiectases, especially on the earlobes and conjunctival selera. Raised levels of serum a-fetoprotein and immunodeficiency are regularly present. Serum immunoglobulins are frequently low or absent. Antibody responses are decreased. Circulating numbers of T-lymphocytes are often decreased, and T-cell-mediated immunologic reactivity is diminished. Cells from patients with ataxia telangiectasia have defective DNA repair-processing mechanisms and express hypersensitivity to ionizing radiation. Lymphocytes show frequent chromosomal breaks, inversions, and translocations involving sites of the T-cell receptor genes in T-cells and immunoglobulin gene complexes in B-cells. Death usually occurs in early adult life after years of increasing disability, often from lymphoreticular malignancy.

The disease has many genetic variants, and at least five complementation groups have been identified. The chromosome locus of the defective gene for the complementation group A, C, and D.

Immunodeficiency with thrombocytopenia eczema (Wiskott-Aldrich’s syndrome). The Wiskott-Aldrich’s syndrome (WAS) is an X-linked monogenic disease. Affected males have small platelets and severe thrombocytopenia, eczema, and undue susceptibility to both pyogenic and opportunistic infections. Their T-cell function declines with age.

Obligate female heterozygotes who bear the WAS gene are immunologically normal. However, all their peripheral white blood cells exhibit nonrandom inactivation of the X chromosome, and this implies that all the nucleated blood cells as well as platelets are affected by the defect. The basic defect in WAS is not known. The platelets are invariably small. Platelets related sialoglycoprotein of the T-cells, CD43, is also defective. However, the genes of neither othese sialoglycoprotein map to the X chromosome and the defects appear to be secondary to some unknown cytosceletal abnormality in the blood cells of these males. The characteritic eczematous dermatitis is clinically and histologically identical to that of ordinary atopic dermatitis.

 

Phagocytosis and it disorders

 

Many cells possess the ability to ingest material by engulfment. The ingested matter is usually particulate, such as bacteria, protozoal parasites or other microorganisms, tissue cells (usually necrotic), dust, pigment and other foreign material. When engulfment involves such particulate matter, the process is termed phagocytosis.

Phagocytes comprise two main classes of cell: those that are capable of migrating to the site where their phagocytic ability is required (such as neutrophilic and eosinophilic leycocytes and circulating mononuclear phagocytes) and those that are fixed in tissues during all or most of their life and therefore depend on chance encounter with foreign materials (such as Kupffer cell in liver and liking sinusoid of lymphatic node). In the act of phagocytosis, small particle such as a grain of charcoal may be ingested in an instant. Larger objects such as tissue cell, clumps of bacteria, or a single large bacterium are ingested by the more active response. This process is similar for neutrophils (microphages), monocytes and tissue macrophages.

The process of phagocytosis involves four stages:

 1. The approach stage or chemotaxis.

2. The attachment stage, in which the particle becomes found to the surface of the phagocyte.

3. The ingestion stage, involving invagination of the surface membrane and the surrounding of the particle.

4. The digestion stage.

 

Сhemotaxis – the phenomenon being defined as a response in which the direction of locomotion of a cell is determined by a substance in its environment. Chemotaxis ensures that, rather than wandering at random the leukocytes move toward the site of injury or foreing material and therefore concentrate in the infected or injured tissues tissues. Factor chemotic for monocytes overlap with those for neutrophils and include cleavage products of C3 and C5 and soluble bacterial products. Lymphocytes stimulate with antigen. Mononuclear phagocytes able to play a key role in various types of immunologic injury. Many examples are known in which the leukocytes contribute to the breakdown of the host’s own tissue.

The fate of ingested particulate matter is closely related to the process of degranulation and the discharge of granule contents into the newly formed digestive pouch or phagosome. The nature of the surface of the object to be ingested (whether bacterium, cell, or foreign body) determines whether there can be firm fixation to the neutrophils surface as the necessary prelude to phagocytosis. Since both bacteria and neutrophils usually have a net surface charge that is negative and therefore repellent, some form of physical or chemical bond must be established between particle and cell membrane. Opsonins (such as plasma fibronectin) are factors that act on the surface of many bacteria, presumably by absorption and render them susceptible to phagocytosis.

In the absence of opsonins (as in serum), ingestion of most microorganisms by neutrophils proceeds slowly or not all. (film 1), (film 2).

 

The physical nature of the environmental influence upon phagocytosis by neutrophils. Phagocytosis is accompanied by degranulation of the macrophags, resulting in the liberation of digestive enzymes and antibacterial substances. The degranulation stees to result from contact of the membranes of the cytoplasmic granules with the membranes of the “phagocytic pouch” surrounding the ingested particle. The hydrolases released by the granules are discharged into the pouch, and so the cell cytoplasm is protected from its own ferments. The antibacterial substances released include lysosome, hydrogen peroxide, basic peptides (leukins), and a basic protein (phagocytin) that kills a wide range of organisms without lyzing them.

 

Chediak-Higashi syndrome. The Chediak-Higashi syndrome is inherited as an autosomal recessive trait. Precise mapping of the gene has not yet been accomplished. The disease is characterized by abnormally large granules in the cytoplasm of several cell types. Affected children have recurrent bacterial infections, particularly with the staphylococcus aurens. This has been attributed to their abnormal granulocyte function. Partial oculocutaneous albinism and a variety of central and peripheral neuropathies are observed in the Chediak-Higashi syndrome. The diagnosis is established by the presence of giant peroxidase-positive granules in peripheral blood granulocytes or, more reliably, in bone marrow myelocytes . The abnormality of the bone marrow myelocytes also leads to ineffective myelopoiesis so that many patiets are neutropenic. Chemotaxis and degranulation are abnormal. The monocytes, lymphocytes and natural killer cells are also abnormal in morphology and function, and all contain abnormally large granules in their cytoplasm. Although thrombocytopenic does not occur in Chediak-Higashi syndrome, the platelets contain large granules also and do not aggregate normally. The outcome is usually fatal. The pathological hallmark of Chediak-Higashi syndrome is the presence of large memrane-bound intracellular inclusious. Although these structures are most easily demonstrated in leukocytes, they are also present in renal tubular epithelial cells, gastric mucose, pancreas, thyroid , neural tissue, and melanocytes. The leukocytes inclusions are 2 to 4 µm in diameter and stain violet to blue with routine Romanowsky agents.

Chronic granulomatous disease. Chronic granulomatous disease (CGD) is an inherited defect in phagocytic cells so that they are unable to produce superoxide and related toxic metobolites. CGD results from an abnormality in phagocyte-specific cytochrome b. This enzymatic activity has many component parts, one of which is encoded on the X chromosome and the others on outosomes. Consequently CGD may be inherited as an X-linked or as an autosomal recessive trait. The phagocytes in CGD have normal chemotaxis, ingestion, and degranulation , but the intracellular killing of microbial pathogens is abnormal. Patients with CGD have chronic and recurrent bacterial infections. The most common sites of infection are the lung, skin, lymphatic nodes, liver, and bone. Abscess formation occurs most frequently at these sites because of intracellular persistence of catalase-producing microorganisms. The most common of these encountered in CGD are staphilococcus aureus, Aspergillus and Nocardia species. Hystologically the abscesses contain poorly formed granulomas with necrosis and many neurophils. A distinctive feature of these inflammatory lesions is the presence of macrophages containing a light yellow-brown pigment.

 

ALLERGY. PATHOPHYSIOLOGY OF AUTOIMMUNE AND IMMUNOPROLIFERATIVE DISEASES.

Allergy is an immune response, which is followed by damage of own tissues. If damage is followed by such changes in organism, that are typical for a disease, than allergic diseases arise. Allergic diseases – is a group of diseases, in development base of which damage lies, caused by an immune reaction on allergens. Allergic diseases are widely spread among people. It is considered that they cover about 10 % of earth population. In different countries these sizes vacillate from 1 to 50 % and more.

 

General etiology of allergic diseases

The cause of allergic diseases is the allergen, the conditions of their appearing are the specific peculiarities of the environment and state of organism reactivity.

Allergen – is a substance that causes development of an allergic reaction.

Allergens have all properties of antigens (macromolecularity, mainly proteiature, foreign for a particular organism). However allergic reactions can be caused by substances of not only antigen nature, but also substances, not possessing these properties. To this group belong many officinal preparations, bacterial products, polysaccharides, simple chemical substances (bromine, iodine, chrome, nickel). These substances are called haptens. While entering the organism they become antigens (allergens) only after binding with tissues proteins. Herewith complex antigens, which sensitize the organism are formed.

All allergens are divided into two groups – exogenous and endogenous allergens (autoallergens). Exogenous allergens come into the organism from outside, endoallergens are formed in the organism. There are few allergens classifications. According to the origin exogenous allergens are divided into following groups: a) allergens of noninfectious origin: home, epidermal, pollen, food, industrial and officinal; b) allergens of infectious origin: bacterial, fungous, viral.

 

Domestic allergens. Main role among them domestic dust plays, which includes particles, bed-clothes, furniture, bacteria.

Epidermal allergens. To this group refer: scurf, wool, birds, fur, fish, scales. Professional sensitization by epidermal allergen is observed in sheepmen, horsemen, poultry farms workers, hairdressers.

Officinal allergens. Any officinal preparation with a little exception causes the development of an officinal allergy. Medicines or their metabolites are, as usual, haptens. In case of sensitization of the organism to one preparation, allergic reactions to other medicines, having alike chemical structure can arise.

Pollen allergens. Allergic diseases are caused by shallow plants, pollen. It is called pollinosis. The diverse types of pollen can have the general allergens, therefore in people, sensitive to one type of pollen, a reaction on its other kinds is possible.

Food allergens. Many food products can be by allergens. They are usually fish, wheat, beans, tomatoes, milk, eggs. Chemical substances added to food products (dye-stuffs, antioxidants, aromatic and other substances) may also be allergens.

Industrial allergens. The industrial allergens for the most are haptens. In each industrial production a particular admission of chemical matters is used. These are: resin, glue and covering materials, plastics, dye-stuffs, metals and their salts, wood products, latex, perfumer substances, washing means, synthetic cloths and others.

Allergens of infectious origin. All the different causative agents of infectious diseases and products of their life activity cause the development of allergic processes. Those infectious diseases, in pathogenesis of which allergy plays a leading role, were named infectiously allergic. These are all the chronic infections (tuberculosis, lepra, brucellosis, syphilis, rheumatism, chronic candidosis etc.). The widespread allergens are the fungi. Many nonpathogenic fungi while entering the organism cause sensitization and development of diverse allergic diseases (bronchial asthma). Such fungi are contained in atmospheric air, dwellings, domestic dust, food products. With biotechnological development a possibility of sensitization on enterprises on production of stern squire, vitamins, antibiotics, enzymes arises.

 

Pathogenesis of allergic reactions

There are different classifications of allergic reactions. R.A.Cook picked out allergic reactions of immediate type and allergic reactions of delayed-type or hypersensitization of delayed-type. In the base of classification the time of appearing of reaction after contact with allergen has been placed. The reactions of immediate type developed during 15-20 minutes, delayed-type – after 1-2 days. However it does not envelop all the variety of allergy displays. For example, some reactions develop over 4-6 or 12-18 hours. Therefore the distinctions between allergic reactions were interconnected with different mechanisms of their development and the classifications based on pathogenic principle were put together.

The classification by P.Gell, R.Coombs is widely spread in the world. It is based on pathogenic principle. The peculiarities of immune mechanisms lay in its base. In accordance to this classification there are 4 types of allergic reactions: anaphylaxic, cytotoxic, immune-complex, delayed hypersensitivity.

Allergy development stages. Entering into the organism antigen causes its sensitization. Sensitization is an immunological rising of organism sensitiveness to antigens (allergens) of exogenous or endogenous origin. According to method of receiving there are active and passive sensitizations. Active sensitization develops in artificial introduction or natural penetration of the allergen into the organism. Passive sensitization is reproduced in the experiment by introduction of blood plasma or lymphoid cells of an actively sensitized donor to an intact recipient. In the development of allergic reaction there are three stages:

1. Immunological stage. It covers all the changes in immune system during the penetration of an allergen into the organism, formation of antibodies or sensitized lymphocytes and their binding with the repeatedly entering allergen.

2. Pathochemical stage. Its sense is in formation of biological active substances. The stimulus to their formation is the binding of allergen to antibodies or sensitized lymphocytes at the end of immunological stage.

3. Pathophysiological stage. It is described by pathogenic action of formed mediators onto cells, organs and tissues of the organism with a clinical display.

In this way the immunological mechanisms lay in development base of allergic processes. Central cell of immune system is a lymphocyte. Lymphocytes are heterogenic according to their functions, markers, receptors. They develop from a stem cell. A lymphoid stem cell will form from it, from which T- and B-lymphocytes develop. The T-lymphocytes acquire the specific antigen receptors, with the help of which they identify an antigen and other markers. There are 3 types of T-cells: T-helpers, T-suppressors, T-effectors. The last ones form sensitized lymphocytes or killers, which participate in realization of allergic reaction of delayed-type and realize cytotoxic action on cell-target. The B-lymphocytes produce 5 classes of immunoglobulins IgG, IgM, IgA, IgE, IgD. These cells during ripening acquire the receptors for antigen on their membranes. During binding of such B-cells with proper allergens and after the signal, received from T-helper, they become activated, and proliferation and differentiation into antibody producing cells starts.

  The correlation between two groups of subpopulations of T-helpers (T_h-1 and T_h-2) plays an important role in the development of immune reaction. They are both formed of T_h-0 and differ form each other by the set of secreted lymphokines and quantity of Fc-receptors for immune globulins on their surface. On T_h-2 there are many receptors for immune globulins A, M, E, and on T_h-1 there are a few of them or they are absent. During the activation of T_h-1 the formation of IL-2 increases, it stimulates the secretion of immune globulins A, M and G by B-cells and turns on cellular mechanism of immunity. Activation of T_h-2 leads though IL-4 to changing of synthesis of IgE by B-cells to proliferation of fat cells and through IL-5 to increasing and proliferation of eosinophiles. There are antagonistic relationship between these two ways. The choice of way of activation depends on character of allergen. Besides that the form of allergen, conditions on introduction into organism and its quantity play role.

Anaphylactic type of allergic reactions

According to anaphylactic type a group of atopic diseases (atopic bronchial (film 4) asthma, pollinosis, atopic dermatitis, nettle-rash, food and officinal allergy, Quinke’s edema(pic.)

 

Immunological stage. IgE and IgG₄ are formed as an answer to penetrating of allergen into the organism. They get fixed on the mast cells and basophiles of blood. These cells have on their surface Fc receptors for immune globulin. The state of sensitization of the organism appears. If the same allergen again gets into the organism or it still stays in the organism after the first penetration, connection of antigen with IgE-antibodies occurs. The same thing is observed with IgG₄. they bind with their receptors on basophiles, macrophages, eosinophiles, trombocytes. Depending on the quantity of molecules of IgE-antibodies connected to antigen, quantity of antigen we can observe either inhibition of activity of the cell or its activation and transfer of the process to the next, pathochemical stage.

 

Pathochemical stage. Activation of the most and basophile cells leads to releasing of different mediators. The process of secretion of mediators need energy, that’s why blocking of energy-formation blocks also releasing of mediators. A certain role in this process play cyclic nucleotides of the cells – cAMP and cGMP. Secretion of one of the main mediators – histamine depends on their correlation. Many different mediators have been excluded from the most cells and basophile leucocytes. Some mediators are in the cell in ready form and are easily secreted (histamine, serotonin, eosinophiles chemotaxic factors). Some mediators are formed after stimulation of the cell (leukotriens, trombocyte activating factors). This mediators act on vessels and target-cells, including in the development of allergic reaction eosinophiles, trombocytes and other cells. As a result eosinophiles, neutrophiles, which start also to release mediators – phosrholipase D, histaminase, leukotriens and others come to the place of activation of the most cells.

  Histamine is localized in ready form in granules of the most cells and basophile leucocytes. In the blood of healthy people histamine almost totally stays in basophile leucocytes. Histamine acts on the tissues cells through the receptors of two types – H₁ and H₂. Their correlation and spreading on the cells of different cells is different. Stimulation of H₁ promotes to contraction of smooth muscles, endothelial cells and postcapillary part of microcirculation. This leads to increasing of permeability of vessels, development of edema and inflammation. Stimulation of H₂ causes the opposite effects. Besides this releasing of histamine from basophile leucocytes and from the lungs is diminished through them, the function of the lymphocytes modulates, formation of migration ingibitory factor (MIF) by T-lymphocytes gets oppressed, releasing of lysosome enzymes by neutrophile leucocytes diminishes as well. In many cases the increasing of quantity of histamine in blood is observed in the intensive stage of bronchial asthma, nettle-rash, officinal allergy.

  Heparin is activated after releasing out of the most cells. It possesses an antitrombine and anticomplementar activity. Trombocyte activating factor (TAF) is secreted by basophiles, lymphocytes, trombocytes and endothelial cells. TAF acts on target-cells through corresponding receptors: 1) it causes the aggregation of trombocytes and releasing of histamine and serotonin out of them; 2) it helps to chemotaxis and secretion of granular content of eosinophiles and neutrophiles; 3) it causes spasm of smooth muscles; 4) it increases permeability of vessels.

  Metabolites of arachidone acid. It is metabolized in two different ways: cyclooxygenic and lipooxygenic. Under the influence of cyclooxygenase prostaglandins, tromboxans and prostacycline are formed from arachidone acid. Under the influence of lipooxygenase leukotriens are formed from it. In allergy prostaglandins of F group possess the ability to cause contraction of smooth muscles, including bronchi, and prostaglandins of E group provide the relaxing action. Leukotriens cause the spasm of smooth muscles, increase secretion of mucous, decrease coronary blood flow and power of heart contractions, increase chemotaxis of polymorphic-nuclear leukocytes, lead to development of prolonged bronchial spasm.

Pathophysiological stage. Under the influence of mediators the permeability of vessels and chemotaxis of neutrophiles and eosinophiles increase, which leads to development of inflammatory reaction. The increasing of permeability of vessels promotes the exit of fluid, immunoglobulins and complement into tissues. With the help of mediators and also through the IgE-antibodies, the cytotoxic effect of macrophages is activated, secretion of enzymes, prostaglandins and leukotriens, trombocyte activating factor is stimulated. The released mediators cause also a damaging action onto cells and connective tissue structures. Bronchospasm develops in respiratory organs. These effects are clinically manifested by attacks of bronchial asthma , rhinitis, conjunctivitis, nettle-rash, skin itch, diarrhea. Anaphylactic shock develops in severe complication. Spasm of smooth muscles of internal organs with clinical manifestation of bronchospasm (cough, expiratory breathlessness), spasm of gastro-intestinal tract muscles (spastic pain in the whole abdomen, nausea, vomiting, diarrhea), spasm of uterus in women (pain below abdomen) are observed. Spastic phenomena are worsened by edemas of mucous covers of internal organs, during the edema of larynx the picture of asphyxia may develop. The arterial pressure is sharply decreased, the heart insufficiency, ischemia of brain, seizes paralysis develop, danger for the life of the patient appears.

Cytotoxic type of allergic reactions

Immunological stage. It is called cytotoxic because the antibodies that developed to antigen of the cell bind to cells and cause their damage or even lysis (cytolytic action). For turning on of this mechanism cells of tissues have to acquire autiallergen properties. Than the formation of autoantibodies starts. In this process action of chemical substances, usually medicines, viruses, microbes onto the cell plays a big role. They may change the antigen structure of cell membranes. The formed autoantibodies belong to IgG and IgM. They connect to corresponding antigens of the cells by their Fab-fragments.

Pathochemical stage. The main mediator of cytotoxicity is the activated enzymes of complement. Phagocytes release some lyzosome enzymes and generate superoxide anion-radical.

Pathophysiological stage. The damage of the cell with the antigen properties may be caused by three reasons: due to activation of complement, the components of which damage the cell membrane; due to activation of phagocytosis of the cells covered with antibodies; due to activation of T-lymphocytes, natural killers, K-lymphocytes.

Cytotoxic type of the allergy can be a manifestation of officinal allergy with the development of leucocytopenia, trombocytopenia, hemolytic anemia etc. This may also happen in blood transfusion and also in rhesus incompatibility of mother and fetus.

Immune complex type

Immunological stage. Many exogenous and endogenous antigens participate in formation of immune complexes. Among them there are officinal preparations (penicillin, sulfanilamides,), antitoxic vaccines, allogen gamma-globulins, food product (milk, egg white), inhalation allergen (home dust, fungi). In case of penetration of soluble antigen into the organism IgG and IgM antibodies are formed. These antibodies can cause the formation of precipitate and connection to antigen. Immune complex can be formed in tissues or in blood flow.

Patochemical stage. Under the influence of immune complexes the following mediators are formed: fragments C3a, C5a, C4a of the complement, lyzosomal enzymes of phagocytes, kinines, superoxyde anion-radical.

Pathophysiological stage. Usually immune complexes are placed on vessels of cannalicular apparatus of kidneys, inflammation with alteration, exudation and proliferation (glomerulonephritis) develops, in case if the complexes are placed in the lungs alveolitis appears, in skin – dermatitis. The inflammation may lead to formation of ulcers, hemorrhages, thrombosis is possible in the vessels. This type of allergic reactions is the prominent one in development of serum , some cases of officinal and food allergy, some autoallergic diseases (rheumatoid arthritis, systemic red lupus erythematosus). In case of massive activation of complement anaphylactic shock, bronchial asthma may develop.

 

 

Allergic reactions of delayed type

Immunological stage. The cellular mechanism of immunity is usually activated in cases of insufficiency of effectiveness of humoral mechanisms, for example, in case of intracellular localization of the antigen (mycobacterium, brucella, histoplasma etc.) or when cells are antigen themselves. They may microbes, fungi and their spores, which get into the organism from the outside. The cells of own tissues also may acquire the auto allergen properties. This mechanism may turn on as a response to formation of complex allergens, in case of including haptens into proteins, for example, in case of contact dermatitis, which appears during the contact of the skin with different medicinal, industrious and other allergens. The foreign antigen is phagocyted by macrophages and get to T-helpers. At the same time macrophages secrete IL-1, which stimulates T-helpers. The latest excrete the growth factor pro-T-lymphocytes – IL-2, which activates and supports proliferation of antigen stimulated T-cells. This process leads to formation of sensitized lymphocytes. They belong to T-lymphocytes and in the cell membrane they have receptors of the antibody type, which are able to connect with the antigen. In case of repeated penetration of the allergen into the organism it binds with the sensitized lymphocytes.

Pathochemical stage. This leads to morphological, biochemical and functional change in lymphocytes. They are presented by blast transformation and proliferation, increasing of synthesis of DNA, RNA and proteins and secretion of different mediators, which are called lymphokines. With the help of lymphokines (MIF, interleukines, chemotaxic factors, factor of transfer) mobilization of different cells (macrophages, polymorph-nuclear), increasing of chemotaxic activity and placing in the site of allergen occur.

MIF promotes accumulation of macrophages in the site of allergic damage, increases their activity and phagocytosis. It takes part in formation of granulems during infectious-allergic diseases, increase the ability of macrophages to destroy certain kinds of bacteria.

There are several kinds of chemotaxic factors, each of which is called chemotaxis of leukocytes – macrophages, neutrophiles, eosinophiles and basophiles. Lymphotoxins cause damage and destroying of all different target-cells.

Interferon is secreted by lymphocytes and under the influence of α-interferon and nonspecific mitogens. It acts a modulating influence on cellular and humoral mechanisms of immune reaction.

Besides lymphokines, lizosome enzymes also provide a damaging activity. They are released during phagocytosis and destroying of cells. Kallikreine-kinine system is also activated. Histamine doesn’t play a big role in this type of allergic reactions.

Pathophysiological stage. A particular form of lymphokines (lymphotoxin, interferon) shows a cytotoxic action and decreases activity of cell. In allergic reaction of delayed type damaging action may develop in several ways: 1) direct cytotoxic action of sensitized T-lymphocytes on target-cells, which acquired autoallergen properties; 2) cytotoxic activity of T-lymphocytes, mediated by lymphotoxin; 3) releasing of lysosome enzyme, which damage tissue structures during phagocytosis.

Inflammation that is associated to immune reaction by action of mediators is a component of allergic reaction of delayed-type. Nevertheless inflammation is at the same time a factor of damage of function of the organs. Allergic reactions of delayed type make the base of development of infectious-allergic diseases (tuberculosis, lepra, brucellosis, syphilis), rejection of transplant, and autoallergic diseases (disturbance of nervous system, endocrine glands etc.).

 

Pseudoallergic reactions

Pseudoallergy is a pathological process, which is clinically similar to allergy but doesn’t have an immune stage of its development. Pseudoallergy differs from a simple one by the absence of first (immune) stage. The rest two stages – releasing of mediators (pathochemical) and pathophysiological (stage of clinical manifestations) are the same both in pseudoallergy and a real one. To pseudoallergic reactions refer only processes in the development of which the leading role play mediators, which are formed also in pathochemical stage of true allergic reactions.

The reason of pseudoallergy is any substance that acts directly on effector cells (fat cells, basophiles etc.) or biological fluids and cause releasing of mediators from the cells or production of them in the fluids. Practically most of the allergens can lead to development of both allergic and pseudoallergic reactions. This depends oature of the substance, its phase, frequency of introduction into the organism and reactivity of the organism. Pseudoallergic reactions usually occur in officinal and food intolerance. Many remedies more usually lead to development of pseudoallergy than true allergy.

Clinical picture of pseudoallergic diseases is close to one of allergic diseases. Development of such pathological processes as increasing of permeability of vessels, edema, inflammation , spasm of smooth muscles, destroying of blood cells lay in the base of this clinical picture. These processes may be local, organic and systemic. They are presented by rhinitis, nettle-rash, Kvinke’s edema, periodical headaches, disturbance of gastro-intestinal tract, bronchial asthma, vaccine disease, anaphylactic shock and also damaging of certain organs.

 

Preventing of allergy. Hyposensitization

Prophylaxis of an allergic disease depends on its character and group of the allergens. It consists of measures of preventing of penetration of given allergen into the organism and preventing of the influence of different irritating factors on the organism. If sensitization has already occurred and allergic diseases has already started, the following measures are appropriate.

1. Suppression of antibodies and sensitized lymphocytes production with the help of immune depressants, ionizing radiation, cytostatics, specific lymphocyte vaccines and monoclonal antibodies.

2. Specific desensitization by Bezredka. (film 5) Desensitization is provided by little doses of the antigen, which do not cause severe reactions. The doses are introduced repeatedly after certain intervals of time, during which produced mediators get inactivated in the organism. The main dose of the antigen is introduced after antibodies binding. This method is effective in introduction of foreign medical vaccines.

3. Inactivation of biological active substances. For this purpose antihistamine preparations, inhibitors of proteolytic enzymes etc. are introduced.

4. Protection of the cells from the influence of biological active substance and also normalizing of functional disorders in organs and systems (narcotic, spasmolytic substances, receptor blockers etc.).