Immune system in infancy and in toddler. Physiologic anatomical peculiarities of the blood system in children of different age.
Associated Proff. Nykytyuk S
The thymus is the central organ For differentiation of T (thymus- dependent) lymphocytes. Stem cells migrating to the thymus in early foetal lift are influenced by humoral factors, such as thymosin and thymopuetin Oil leaving the thymus, these T cells migrate throughout the body and preferentially seed specific T celt areas within the lymph nodes, spleen,. appendix, and intestinal Peyer’s patches- The thymus is a rather mature organ after birth Its maturation continues 111! 12-15 years. After 15 years the thymus function decreases; this is called physiological involution. If involution takes place early due to action of pathological factors (stress and severe diseases), this is called accidental (convertible) involution.
Immune cells of another main type (B cells) are produced and differentiated in bone marrow (in people) and in bursa of Fabrieius (in birds). In the beginning, bursa of Fabrieius was described as the source of B lymphocytes and these cells were mined from ;’bursa” Bone marrow, which is the major site of maturation of B cells, monocytes-macrophages and granulocytes, contains pluripotent stem cells. The latter, under the influence of various colony-stimulating factors, arc capable of giving rias to x\\ haematopoietic cell types.
The structure of lymph nodes resembles that of the thymus. It consists of a capsule, paraconieal (T-dcpcndent) areas and germinal (thymus-not-dependent) centres. This is a place for synthesis ol antibodies, A delay of antigens and lumour cells and destruction of erythrocytes occur hcrt.
The spleen is formed in the 5th week of the intrauterine development, but its maturation is over some years after birth The function of ihe spleen in immunity resembles that of lym^h nodes ^
The intestinal lymphoid tissue is formed from the $ till the 20 week of gestation. The lymphoid tissue of the intestines takes part in ihe formation of tolerance to food allergens.
The tonsils arc laid in the 22** week of gestation, but develop Lilt the period of sexual maturity. The lymphoid tissue of (he intestines and respiratory tract is or great value for local defence, synthesis of antibodies and differentiation oflymphocytes.
Immunity may be divided into two types: innate {non-adaptive, non-specific) and adaptive.
Innate (non-adaptive, non-specific} immunity is formed earlier in ontogenesis and provides the function of protection before final maturation of more perfect mcchanisms (the adaptive immune system). Thai is why innate immune is of yreat value for foetuses and children of early age.
The innate immune system consists of the following parts.
Natural barriers:
anatomical barriers (the skin and mucous membranes);
mechanical removal (cough, diarrhoea, vomiling, the discharging of urine, sweat, saliva., tears),
-biochemical barriers (lysozyme, acidity of stpmach juice, Fatty acids of sebaceous glands, biochemical changes due to high temperature, the hormonal status, etc )
Cells of the innate immune system:
macrophages phagocytic and kill hacteria; they produce antimicrobial peptides and inflammatory cytokines;
natural killer (NK) cells kill foreign and host-afTccted cells;
-neutrophils phagocytic and kill bacteria; they produce
antimicrobial peptides,
-eosinophils kill invadingparasites;
-mast cells and basophils release inflammatory cytokines in response to antigens;
epitheM cells produce ant i-microbial peptides; tissue-specific epilhclia produce mediator of local innate immunity, e.g. lung Cpitheli&l cells produce surfactant proteins that bind and promote c I earance o f I ung- ivadi ng mic rob e s,
Humoral (plasma) factors;
complement system;
blood coagulation system (plasma factors);
properdin;
acute phase proteins (C-teadive protein);
interferon.
Lysozyme is a termostable factor, present in lymphocytes, blood plasma, tear, saliva, mucous secretions of the respiratory and intestinal tracts, it plays an important part in lot at immunity. It causes Lysis of Gram-positive microbes. The quantity of Lysozyme m
newborns versus adults is higher.
Phagocytosis is the main function of cells of the innate immune
system.
Phagocytosis consists of several stages: activation, chemotaxis, adhesion, absorption of antigen into eytoplasma-fbrming vacuoles, lysis All phagocytes may be divided into two groups: macrophages (monocytes, NK) and microphages (neutrophils, eosinophils, basophils) Phagocytosis iewborns is not perfect. The function of absorption is advanced, but lysis is underdeveloped The function of digestion (maturation of cation protein in phagocytes) is formed only to 6 months. Except for that, some microbcs (Haemophilus influenzae, Klebsiella pneumoniae) cannot be destroyed by phagocytosis in early childhood. This is the causc of a high frequency of pneumonia and its severe course with complications and serious prognosis in this age period. Other microbes (Staphylococci, Conococci) keep an ability lo multiply in the protoplasm or phagocytes and cause destruction of phagocytes
The complement system is a series of plasma enzymes, regulatory proteins atid proteins thai are activated in a cascading fashion, ^suiting in cell lysis. There are two arms of the complement system activation- by classic and alternative complement pathways. Both lead to C^avage and activation of C3. The latter is a protein whose activation fragments, when bound to target surfaces such as bacteria and other foreign antigens, are critical Tor opsonization (coating by antibody and complement) in preparation for phagocytosis. The classic complement pathway is activated by interaction of antigen and antibody to form immune complexes The classic pathway is a rapid and efficient manner lo activation of terminal complement components. In contrast, activation of the alternative complemenl pathway is slower and less efficient. In addition to the role ol” complement in opsonization of bacteria and cell tysis, several complement fragments are potent mediators of immune cell activation, C3a and C5a bird to receptors on mast cells and basophils, resulting in release of histamine and other mediators of anaphylaxis. C5a is also a potent chemoattractant for neutrophils and monocytes-macrophages. The complement system activity iewborns is Eow [50% versus in adults), but it increases very fast during the first month and at tbs aye of 1 month it is equal to the level of adults.
The level of properdin (a protein for activation of the alternative way of the complement system) is low at once aRer delivery, hut it increases very fast during the first week and its level during all periods of childhood is high.
Interferon (IFN) is produced by leukocytcs (macrophages, lymphocytes), dcndritic and epithelium cells in response to viral infections. IFN in tum activates NK cells to kill virally infccted cells and activates monocytes-macrophages to recruit antigen-specific T and B cells to respond to viral infections. There are 3 types of INF: INF-tt is synthesized by B lymphocytes; INF-/3 is synthesized by fibroblasts; INF-y is synthesized by O and T lymphwytes. The newborn is characterized by a high ability to synthesize INF, but then this ability decreases till 1 year. After L year it increases and reaches its max i mum level by the age o fl 2 ■ 18 years.
The adaptive immune system is characterized by antigen-specific responds to antigen and, compared to innate immunity which occurs immediately (1 to 2 days), generally takes several days or longer to materialize A key feature of adaptive immunity consists in memory for the antigen, so that subsequent antigen exposures lead TO’ more rapid and often more vigorous immune responses. The adaptive immune system consists of dual limbs: cellular and humoral immunity.
Adaptive immunity is found only in the vertebrates and is based on (he generation or antigen receptor T and B lymphocytes by germ- tme gene rearrangements that occur during the development of each person By a complex series of molecular mechanisms of gene rearrangement, individual T or B cells express unique antigen receptors on their surface, so that taken together the pools of adult human T and B lymphocytes contain ceils capable of specifically recognizing the diverse antigens of myriads of infectious agents in the environment, Coupled with finely tuned specific recognition mechanisms that maintain tofcrance to self antigen, T and B lymphocytes of the adaptive immune system with their postnatally rearranged collotypes antigen receptors bring both specificity and immune memory to vertebrate host defenses.
Mature T lymphocytes constitute 70 to 80 % of normal peripheral hlood lymphocytes. T cells are the primary effectors of cell-mediated immunity, with subsets of T cells maturing into CDH cytotoxic T cells capable for lysis of virus-infected or foreign cells wd CD4+ helper T cells, which are regulatory cells for immunity by the production of cytokines. In addition, T cells regulate erylhroid cell maturation in bone marrow, and through ceil contact play an important pari m activation Of B cclls and induction of Ig isotypv;
SW11 Mature B cells comprise 10 to 15 % of human peripheral blood Ivmphocytes. On their surface, B cells express intramembranous immunoglobulin (lg> molecules that ftinction a? B cell receptors tor antigen in a complex of lg-associated. The primary junction of B cells consists m production of antibodies. B cells also arc highly efficient at antigen processing. Their antigen-prcsentmg function is enhanced by a variety of cytokines. B-lymphocyte development can be divided into antigen-independent and antigen-dependent phases. Antigen-independent B ccll development occurs in the primary lymphoid organs, including ihc foetal liver and bone marrow. Antigen-dependent B cell maturation is driven by the interaction of antigen with the mature B cell, leading to memory B cell induction, Jo class switching, and plasma cell formal ion. Antigen-dependant si ages of B cell maturation occur in the secondary lymphoid organs, including lymph nodes, spleen, and gut Peyer’s patches.
Immunoglobulins arc products of differentiated B cells and mediate the humoral immune response The primary functions of antibodies are to bind specifically to antigen and bring about the maciivalion or removal of the offending tovin, microbe, parasite, or another foreign substance from die body. All immunoglobulins have the basic structure of two heavy and two light chains. Immunoglobulin isotype (G, M, A, D. R) is determined by the type of
!g heavy chasn present. IgG and IgA isotypes can be divided further into subclasses (Gl, G2, G3, G4, and Al, A2)t based on specific antigenic determinants on 1g heavy chains.
IgG comprises approximately 75 to 85 % of the total serum immunoglobulin- IgG antibodies are frequently predominant antibodies made after challenge of the host with antigen (the secondary antibody response). The ability to synthesize antibodies arises in the intrauterine period. LgG msy be synthesiw:d from 5 months orgestation, Rut the foetus is in sterile conditions, that is why the levels of all its own Igs are not high. They may increase only after antigen stimulation due to some intrauterine infection. But maternal IgG is actively transported across Ibe placenta and found in the foetal intravascular and extrava&cular spaces. Maternal IgG provides passive immunity against generalized infections. Blood group antibodies are also in the IgG class and therefore can freely cross the placenta to cause haemolytic disease of the newborn.
IgM is the firsi immunoglobulin io appear in the immune response (the primary antibody response). It is the initial type of antibodies made by neonates, IgM may be synthesized from S months of gestation. The IgM molecule is the largest of all immunoglobulins, therefore it cannot cross the placenta. If IgM is fount! in the foetus or neonate it must be or a foetal origin and prove the existence of a congenital infection.
IgA comprises only 7 to 15 % of the total semm immunoglobulin hut is the predominant class of immunoglobulins in secretions <tears, saliva* nasal secretions, gastrointestinal tract fluid and human milk) and plays an important part in local immunity. IgA may be synthesized from 1 months of gestation. IgA is the second largest group of immunoglobulins and it cannot cross the placenta. Its presence in human breast milk lowers the incidence of enteric infections in breastfed infants. IgA can be found in saliva of neonates after several days of life.
IgD is found in small quantities in serum. It is & marker for mature B cells.
IgE, which is present in serum in very low concentrations, involves mast cells and basophils in activation. Antigen cross-linking of IgE molecules on basophil and masi celt surfaces results in release of mediators of the immediate hypersensitivity response (aliergy,
antiparasite responses) –
At once after birth a newborn has a high IgG (maternal) level but low levels of IgM and IgA- It explains high susceptibility of newborns to bacteria! infections. During the first 3-6 months the maternal IgG is destroved, but the own Ig level is not high enough: this if physiological hypoimmun-e condition. Iben synthesis ot Igs increases and IgM reaches the level of adults till 4-5 years, JgG till 56 years and IgA only till 10-12 years.
Cytokines are soluble proteins produced by a wtde variety oi haematopoietic and nonhaematopoietic cells. They arc critical for both normal innate and adaptive immune responses. Cytokines exert their effects hv influencing gene activation that results in cellular activation growth, differentiator, functional cell-surface molecule expression “and cellular effector function. In this regard, cytokines can have dramatic effects on the regulation of immune responses »n4 pathogenesis of a variety oi” diseases. Indeed, T cells have been categonzed on the basis of the pattern of cytokines, that they secrete, and it results in either humoral immune response (Tfi2) or a cell-mediated immune response (Th1>
Several responses by the host’s innate and adaptive immune svstems to foreign microbes culminate in rapid and efficient elimination of microbes. In these scenarios, the classic weapons of the adaptive immune system <T cells, B cdls) interface with ceMs [macrophages, dendritic cells, NK cells, neutrophils, eosinophils, basophils) and soluble products (microbial peptides, pentraxms, complement and coagulation systems) of the innate immune system.
There are five general phases of host defences:
migration of leukocytes to sites of antigen localization;
anlTgen nonspecific recognition or pathogens by macrophages and other cells of the innate immune system;specific recognition of foretgn antigens mediated by T and B lymphocytes;
amplification of the inflammatory response with recruitment of specific and nonspecific effector cells by complement components, cytokines, kinins, arachidonic acid metabolites and mast cell-basophil products; macrophage, neutrophil, and lymphocyte participation in destruction of antigen with ultimate removal of antigen particles by phagocytosis or direct cytotoxic mechanisms.
Under normal circumstances, orderly progression of host defences through these phases results in a well-controlled immune and inflammatory response that protects the host from the offending antigen.
The clinical examination of patients sufTering from immune disorder includes’ questioning (complaints, case history, family history, side effects of vaccination, scrum and blood transfusion);physical examination:-visual examination (assessment of physical development, condition of the skin, mucous metnhrancs and skeleton, presence of ataxia, etc.) to revcat si^ns of immunological insufficiency (described in part “Semiology of the immune system diseases”); palpation (the spleen, liver a^d lymph nodes,);-auscultation (to reveal infections from the respiratory and cardiovascular systems, which can be clinical manifestations of the immune sysleiit disorders).
Paracl ii cal me [hod s o f investigation
Clinical assessment of immunity requires investigation of the four major components of the immune system that participate in host dcfence and in the pathogenesis of autoimmune diseases: (I) humoral immunity (B celts); (2) cell-mediated immunity (T celts, monocytes); (3) phagocytic cells of the reticuloendothelial system (macrophages), as well as polymorphonuclear leukocytes, and (4) complement, flic table .presents a resume of widely available laboratory investigations.
Laboratory evaluationoTHosUI^pce Stains
Initial Screening Assays Complete blood count with differentia) smear Serum immunoglobulin Levels: IgM, IgG, IgA, IgB Other Readily Available Assays
Quantification of cell populations by immunofluorescence assays
employing monoclonal antibody markers
B cells: CD19, CD20, CD21, Ig (A. M, G, E, D)
NK cells: CD16/CD56
Monocytes: CD 15
T cell functional evaluation
1 Delayed hypersensitivity skin tests
Proliferative response to mitogens (phytohacmag&luimin, concanavalin A)
Cytokine production
B ceil functional evaluation
Natural or commonly acquired antibodies: antibodies to common viruses (influenza, rubella) and bacterial toxins (diphtheria, tetanus)
Response to immunization with protein (tetanus) and carbohydrate (pneumococcal vaccine. // influenzae B vaccine) antigens
3. Quantitative IgG subclass determinations Complement and its components Phagocyte function
Reduction of nitroblue tetrazolium
Chemotaxis assays
Bactericidal activity.
*Toaethcr with a historv and physical examination, these tests will identify more _ than’ 95% of patients with primary immunodeficiencies .
Semiology of the immune system diseases Clinical problems that require an evaluation of immunity include chronic infections, recuiTenl infection, unusual infecting agents and certain autoimmune syndromes. Immunodeficiency disorders may he primary and secondary
Primary immunodeficiencies may be either congenital or manifested later in Hfe and arc currently classified according to the mode of inheritance and whether the genetic defect affccts T cells, B cells or both
Secondary immunodeficiencies are those, which arc not caused by intrinsic abnormalities in development or function of T and B ceils. Their examples arc: AIDS, immune deficiency associated with malnutrition, protein-losing enteropathy, intestinal lymphangiectasia, hypercatabolic states such as occur in myotonic dystrophy, lymphorcticular malignancy. Secondary immunodeficiencies may be permanent or transient,
Defects in cellular immunity generally result in viral, mycobacterial and fungal infections Abnormalities of cell-mediated immunity predispose to disseminated vims infections, particularly with latent viruses such as herpes simplex, van cell a zoster and cytomegalovirus, In addition, patienls so affected almost invariably develop mucocutaneous candidiasis and frequently acquire systemic fungal infections, Pneumonia, caused by Pneumocystis carinii, is also common Severe enteritis, caused by Cryptosporidium infection, may extend to the biliary tract with resultant sclerosing cholangitis. Severe complications (systemic illnesses) after vaccination by alive viruses and BCG, a high frequency oT malignant diseases in the family arc typical for abnormalities of cell-mcdiatcd immunity. T cell deficiency is always accompanied by some abnormality of antibody responses, although this may not be reflected by hypogammagiobulinaemia. This explains in part why patients with primary T cell defects are also subject to overwhelming bacterial infections.
Examples of T-oell immunity deficiency;
Pi-George’s syndrome is probably caused by an embryo logic field defect that ofieri results in thymic abnormalities (immune defects), heart malformations, facial anomalies, parathyroid deficiency (convulsion) and urinary tract abnormalities.
Nezeloffs syndrome, a carlilage-hair hypoplasia, a bone dysjjhis!^ is associated with short-limbed dwarfism and immune deficiencies similar to Di-Ceorgevs syndrome.
Antibody deficiencies result in recurrent or chronic bacterial infections (sinopulmonary infection, otitis media, meningitis and bacteremia), frequently with organisms such as S, pneumonia and Haemophilus influenza* and Staphylococci; and nodular lymphoid hyperplasia. Infestation with the intestinal parasite Giardia lambUa is a frequent cause of diarrhoea in antibody-deficient patients. Examples of B-ccll immunity deficiency:
X-Hnked Bniton’s agammaglobulinaemia includes all classes of immunoglobulin deficiency. Typical for agammaglobuhnactma arc recurrent bacterial infections. There may be growth failure but usually there is no lymphadenopathy or splenomegaly. Skm disorders and later pulmonary dysfunction ate frequent,
Selective deficiencies of immunoglobulins (IgA, IgM, IgG) Selective deficiency of immunoglobulin A is characterized by recurrent respiratory infections and diarrhoea. Autoimmune diseases are associated, but many children are asymptomatic Senim and secretory IgA disorders may be distinguished, but they are usually not isolated defects.
Selective deficiency of immunoglobulin M. These patients have a high risk of rapid haematogenous spread of bacterid infections.
Combined immunodeficiency disease (T and B cell associated deficiency).
The most severe form of immune deficiency occurs in infants,
who lack both cell-mediated and humoral immune functions.
Individuals with severe combined immunodeficiency are susceptible
to the whole range of infectious agents including organisms not
ordinarily considered pathogenic. Multiple infections with viruses
bacteria and fungi occur, often simultaneously. Combined
immunodeficiency disease may be a mild or severe disorder leading to death within several years of birth. The type of infections that occur depends on the combination and degree of T and B cell detect.
Common are gastroenteritis, hepatitis and skin manifestations.
Wiscott- Aid rich syndrome, an X-linked recessive disorder, is
characterized by thrombocytopenia, otitis, pneumonia and eczema
and during the first 6 months of life. Hepatosplenomegaly lymphadcnopathy are common. Serum IgG and IgE arc markedly elevated. Ataxia-telangiectasia is characterized by ataxia, ocular and cutaneous telangiectases, chronic sinopulmonary disease, endocrine abnormalities and neurological disorders.
Disorders of phagocyte function are frequently manifested by recurrent skin infections, often due to Staphylococcus aureus, abscesses of the subcutaneous tissue and lungs, purulent arthritis and osteomyelitis-
Deficiencies of early and late complement components are associated with autoimmune phenomena and recurrent Neisseria infections
Acquired immune deficiency syndrome, or acquired immunodeficiency syndrome (AIDS), is a disease of the human immune system caused by the human immunodeficiency vims (HIV), This condition progressively reduces the effectiveness of the immune system and leaves individuals susceptible to opportunistic infections and tumours. FHV is transmitted through direct contact of a mucous membrane or the bloodstream with a HIV-containing bodily fluid, such as blood, semen, vaginal fluid, and breast milk. This transmission can be due to anal, vaginal or oral sex, blood transfusion, contaminated hypodcrmic needles, exchange between mother and baby during pregnancy, childbirth, breast-feeding or other exposure to one of the above bodily fluids. AIDS is now a pandemic.
HIV is a retrovirus with cytopathic effects. The most prominent effect of HIV virus is T helper cell suppression and lysis. Oncc HIV has killed so many CD4+ T cells that there arc fewer than 200 of these cells per microlitre ( iL) of blood, cellular immunity is lost. Except for CD4+- T helper cells, the virus acts prim an ly on the following cells: lympitoreticular system (macrophages, monocytes, B lymphocytes), certain endothelial cells, the central nervous system (microglia, astrocytes, oligodendrocytes, neurones). Acute HIV infection progresses over time to clinically latent HIV infection, iheti lo early symptomatic HIV infection and later to AIDS. In the absence of antiretioviral therapy, the average time of progression from HIV infection to AfDS is 9-10 years, and the average survival time after developing AIDS is only 9.2 months. However, the rate of clinical disease progression varies widely between individuals, from two
weeks up to 20 years.
The scmciology of AIDS includes infections caused by bacteria, viruses fungi and parasites that are normally controlled by the elements of the immune system that HIV damages (opportunistic infections). HIV affects almost every system in the organism. Pneumocvslie pneumonia is common among HIV-infected individuals. Toxoplasmosis usually infects the bram, causing toxoplasmic encephalitis, but it can also infect and cause disease in the eyes and lungs. Cryptococcal meningitis is typical for AIDS too. Infection of the cells of the central nervous system causes acute aseptic meningitis, subacute encephalitis, vacuolar myelopathy and peripheral neuropathy. l ater it leads even to the AIDS dementia complex. Unexplained chronic diarrhoea in HIV infection is due to many possible causes, including common bacterial (Salmonella, Shigella, Listeria or Campylobacter) and parasitic infections; and uncommon opportunistic infections such as crypto spondiosis, microspondiosis, Mycobacterium and viruses, such as astro vims, adenovirus, rotavirus and cytomegalovirus. People with AIDS also have an increased risk of developing various cancers such as Kaposi’s sarcoma, cervical cancer and cancers of the immune system known as lymphotnala. Additionally, people with AIDS often have systemic symptoms of infection like fevers, sweats (particularly at night), swollen glands, chills, weakness, and weight loss.
” There are two main definitions fcr AIDS, both produced by the Centres for Disease Control and Prevention (CDC). The older definition is to refemng to AIDS using the diseases (hat were associated with it, for example, lynphoma. In 1993, the CDC expanded their definition of AIDS to include all HIV-positive people with a CE>4+ T cell count beW 200 per \iL of blood or 14 % of all lymphocytes. The AIDS diagnosis still siandseven if, after treatment, the CD4~ T cell count rises to above 200 per nL of blood or other A IDS-defining illnesses are cured.
In 1990 the World Health Organization (WHO) grouped these opportunistic infections and conditions together by introducing a staging system for patients infected with HLV-1. An update took place in September 2005.
Stage 1; HIV infection is asymptomatic and not categorized as
AIDS. <JF ,
Stage II includes minor mucocutaneous manifestations and
recurrent infections of the upper respiratory tract.
Stage III includes unexplained chronic diarrhoea for longer than a month, severe bacterial infections and pulmonary tuberculosis
Stage IV includes toxoplasmosis of the brain, candidiasis of the oesophagus, trachca. bronchi or lungs and Kaposi’s sarcoma; these diseases are indicators of AIDS-
Peculiarities of HIV infection in children
Every day about 1,000 children under the age of 15 become infected with HIV, and in 2007 UNISEh estimated that there were 2 million children with Hl\\ about 90 % of them living in Africa.
The vast majority of these children either acquire 111V before they arc bom, during pregnancy or during delivery, or when they are breast-fed (if their mother is HIV-positive). The transmission of the virus from the mother to the child can occur in utcro during the last weeks of pregnancy and at childbirth. In the absence of treatment, the transmission rate between a mother and her child during pregnancy, labour and delivery is 25 %. However, when the mother takes anliretro viral therapy and gives birth by caesarean section, the rate of transmission is just’! %. The risk of infection is influenced by the viral load of the mother at birth, with the higher the viral load, the higher the risk. Breast-fading also increases the risk of transmission by about 4%. Current recommendations state that HIV-infected mothers should avoid breast-feeding their infant.
The course of HIV and AIDS is particularly aggressive m children. About 50 per cent of children who acquire HIV from their mothers die before their second hirthday. in 2007, 270,000 children under 15 years died of HIV-related illnesses.
Antirctroviral therapy is extremely effective in children. Survival rate* of over 80 % have been reporied from scientific studies as well as programmes. The World Health Organization (WHO) guidelines currently recommend cotrimoxazole prophylaxis for all infants bom by HIV-infected mothers from 6 weeks of age until infection is ascertained. Cotrimoxrcole, given to HIV-exposcd children, can reduce mortality from opportunistic and other common childhood infections, including malaria.
Other risk group for HIV infection consists of adolescents. Many adolescents are engaged in multiple risk behaviour such as unprotected sex with an infectcd paitner or using non-sterile injecting equipment. More effective primary prevention for this age group consists in teaching adolescents and young people risk-reduction skills, sueh as to make informed decisions, solve problems,think critically, cope with emotions and stress, and negotiate, all this can endow them with the ability to manage challenging siiuaiions, lo adopt healthy behaviour, and give power to act on their own decisions.
engulfing anthrax bacteria (orange).
The immune system is a system of biological structures and processes within an organism that protects against disease. To function properly, an immune system must detect a wide variety of agents, from viruses to parasitic worms, and distinguish them from the organism’s own healthy tissue.
Pathogens can rapidly evolve and adapt to avoid detection and neutralization by the immune system. As a result, multiple defense mechanisms have also evolved to recognize and neutralize pathogens. Even simple unicellular organisms such as bacteria possess a rudimentary immune system, in the form of enzymes that protect against bacteriophage infections. Other basic immune mechanisms evolved in ancient eukaryotes and remain in their modern descendants, such as plants and insects. These mechanisms include phagocytosis, antimicrobial peptides called defensins, and the complement system. Jawed vertebrates, including humans, have even more sophisticated defense mechanisms,[1] including the ability to adapt over time to recognize specific pathogens more efficiently. Adaptive (or acquired) immunity creates immunological memory after an initial response to a specific pathogen, leading to an enhanced response to subsequent encounters with that same pathogen. This process of acquired immunity is the basis of vaccination.
Disorders of the immune system can result in autoimmune diseases, inflammatory diseases and cancer.[2][3] Immunodeficiency occurs when the immune system is less active thaormal, resulting in recurring and life-threatening infections. In humans, immunodeficiency can either be the result of a genetic disease such as severe combined immunodeficiency, acquired conditions such as HIV/AIDS, or the use of immunosuppressive medication. In contrast, autoimmunity results from a hyperactive immune system attacking normal tissues as if they were foreign organisms. Common autoimmune diseases include Hashimoto’s thyroiditis, rheumatoid arthritis, diabetes mellitus type 1, and systemic lupus erythematosus. Immunology covers the study of all aspects of the immune system.
[edit] History of immunology
For more details on this topic, see History of immunology.
Immunology is a science that examines the structure and function of the immune system. It originates from medicine and early studies on the causes of immunity to disease. The earliest known reference to immunity was during the plague of Athens in 430 BC. Thucydides noted that people who had recovered from a previous bout of the disease could nurse the sick without contracting the illness a second time.[4] In the 18th century, Pierre-Louis Moreau de Maupertuis made experiments with scorpion venom and observed that certain dogs and mice were immune to this venom.[5] This and other observations of acquired immunity were later exploited by Louis Pasteur in his development of vaccination and his proposed germ theory of disease.[6] Pasteur’s theory was in direct opposition to contemporary theories of disease, such as the miasma theory. It was not until Robert Koch‘s 1891 proofs, for which he was awarded a Nobel Prize in 1905, that microorganisms were confirmed as the cause of infectious disease.[7] Viruses were confirmed as human pathogens in 1901, with the discovery of the yellow fever virus by Walter Reed.[8]
Immunology made a great advance towards the end of the 19th century, through rapid developments, in the study of humoral immunity and cellular immunity.[9] Particularly important was the work of Paul Ehrlich, who proposed the side-chain theory to explain the specificity of the antigen-antibody reaction; his contributions to the understanding of humoral immunity were recognized by the award of a Nobel Prize in 1908, which was jointly awarded to the founder of cellular immunology, Elie Metchnikoff.[10]
[edit] Layered defense
The immune system protects organisms from infection with layered defenses of increasing specificity. In simple terms, physical barriers prevent pathogens such as bacteria and viruses from entering the organism. If a pathogen breaches these barriers, the innate immune system provides an immediate, but non-specific response. Innate immune systems are found in all plants and animals.[11] If pathogens successfully evade the innate response, vertebrates possess a second layer of protection, the adaptive immune system, which is activated by the innate response. Here, the immune system adapts its response during an infection to improve its recognition of the pathogen. This improved response is then retained after the pathogen has been eliminated, in the form of an immunological memory, and allows the adaptive immune system to mount faster and stronger attacks each time this pathogen is encountered.[12]
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Components of the immune system |
|
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Response is non-specific |
Pathogen and antigen specific response |
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Exposure leads to immediate maximal response |
Lag time between exposure and maximal response |
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Cell-mediated and humoral components |
Cell-mediated and humoral components |
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Exposure leads to immunological memory |
|
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Found iearly all forms of life |
Found only in jawed vertebrates |
Both innate and adaptive immunity depend on the ability of the immune system to distinguish between self and non-self molecules. In immunology, self molecules are those components of an organism’s body that can be distinguished from foreign substances by the immune system.[13] Conversely, non-self molecules are those recognized as foreign molecules. One class of non-self molecules are called antigens (short for antibody generators) and are defined as substances that bind to specific immune receptors and elicit an immune response.[14]
[edit] Surface barriers
Several barriers protect organisms from infection, including mechanical, chemical, and biological barriers. The waxy cuticle of many leaves, the exoskeleton of insects, the shells and membranes of externally deposited eggs, and skin are examples of mechanical barriers that are the first line of defense against infection.[14] However, as organisms cannot be completely sealed against their environments, other systems act to protect body openings such as the lungs, intestines, and the genitourinary tract. In the lungs, coughing and sneezing mechanically eject pathogens and other irritants from the respiratory tract. The flushing action of tears and urine also mechanically expels pathogens, while mucus secreted by the respiratory and gastrointestinal tract serves to trap and entangle microorganisms.[15]
Chemical barriers also protect against infection. The skin and respiratory tract secrete antimicrobial peptides such as the β-defensins.[16] Enzymes such as lysozyme and phospholipase A2 in saliva, tears, and breast milk are also antibacterials.[17][18] Vaginal secretions serve as a chemical barrier following menarche, when they become slightly acidic, while semen contains defensins and zinc to kill pathogens.[19][20] In the stomach, gastric acid and proteases serve as powerful chemical defenses against ingested pathogens.
Within the genitourinary and gastrointestinal tracts, commensal flora serve as biological barriers by competing with pathogenic bacteria for food and space and, in some cases, by changing the conditions in their environment, such as pH or available iron.[21] This reduces the probability that pathogens will reach sufficient numbers to cause illness. However, since most antibiotics non-specifically target bacteria and do not affect fungi, oral antibiotics can lead to an “overgrowth” of fungi and cause conditions such as a vaginal candidiasis (a yeast infection).[22] There is good evidence that re-introduction of probiotic flora, such as pure cultures of the lactobacilli normally found in unpasteurized yogurt, helps restore a healthy balance of microbial populations in intestinal infections in children and encouraging preliminary data in studies on bacterial gastroenteritis, inflammatory bowel diseases, urinary tract infection and post-surgical infections.[23][24][25]
[edit] Innate immune system
For more details on this topic, see Innate immune system.
Microorganisms or toxins that successfully enter an organism encounter the cells and mechanisms of the innate immune system. The innate response is usually triggered when microbes are identified by pattern recognition receptors, which recognize components that are conserved among broad groups of microorganisms,[26] or when damaged, injured or stressed cells send out alarm signals, many of which (but not all) are recognized by the same receptors as those that recognize pathogens.[27] Innate immune defenses are non-specific, meaning these systems respond to pathogens in a generic way.[14] This system does not confer long-lasting immunity against a pathogen. The innate immune system is the dominant system of host defense in most organisms.[11]
[edit] Humoral and chemical barriers
For more details on this topic, see Humoral immunity.
[edit] Inflammation
For more details on this topic, see Inflammation.
Inflammation is one of the first responses of the immune system to infection.[28] The symptoms of inflammation are redness, swelling, heat, and pain, which are caused by increased blood flow into tissue. Inflammation is produced by eicosanoids and cytokines, which are released by injured or infected cells. Eicosanoids include prostaglandins that produce fever and the dilation of blood vessels associated with inflammation, and leukotrienes that attract certain white blood cells (leukocytes).[29][30] Common cytokines include interleukins that are responsible for communication between white blood cells; chemokines that promote chemotaxis; and interferons that have anti-viral effects, such as shutting down protein synthesis in the host cell.[31] Growth factors and cytotoxic factors may also be released. These cytokines and other chemicals recruit immune cells to the site of infection and promote healing of any damaged tissue following the removal of pathogens.[32]
[edit] Complement system
For more details on this topic, see Complement system.
The complement system is a biochemical cascade that attacks the surfaces of foreign cells. It contains over 20 different proteins and is named for its ability to “complement” the killing of pathogens by antibodies. Complement is the major humoral component of the innate immune response.[33][34] Many species have complement systems, including non-mammals like plants, fish, and some invertebrates.[35]
In humans, this response is activated by complement binding to antibodies that have attached to these microbes or the binding of complement proteins to carbohydrates on the surfaces of microbes. This recognition signal triggers a rapid killing response.[36] The speed of the response is a result of signal amplification that occurs following sequential proteolytic activation of complement molecules, which are also proteases. After complement proteins initially bind to the microbe, they activate their protease activity, which in turn activates other complement proteases, and so on. This produces a catalytic cascade that amplifies the initial signal by controlled positive feedback.[37] The cascade results in the production of peptides that attract immune cells, increase vascular permeability, and opsonize (coat) the surface of a pathogen, marking it for destruction. This deposition of complement can also kill cells directly by disrupting their plasma membrane.[33]
[edit] Cellular barriers
A scanning electron microscope image of normal circulating human blood. One can see red blood cells, several knobby white blood cells including lymphocytes, a monocyte, a neutrophil, and many small disc-shaped platelets.
Leukocytes (white blood cells) act like independent, single-celled organisms and are the second arm of the innate immune system.[14] The innate leukocytes include the phagocytes (macrophages, neutrophils, and dendritic cells), mast cells, eosinophils, basophils, and natural killer cells. These cells identify and eliminate pathogens, either by attacking larger pathogens through contact or by engulfing and then killing microorganisms.[35] Innate cells are also important mediators in the activation of the adaptive immune system.[12]
Phagocytosis is an important feature of cellular innate immunity performed by cells called ‘phagocytes‘ that engulf, or eat, pathogens or particles. Phagocytes generally patrol the body searching for pathogens, but can be called to specific locations by cytokines.[14] Once a pathogen has been engulfed by a phagocyte, it becomes trapped in an intracellular vesicle called a phagosome, which subsequently fuses with another vesicle called a lysosome to form a phagolysosome. The pathogen is killed by the activity of digestive enzymes or following a respiratory burst that releases free radicals into the phagolysosome.[38][39] Phagocytosis evolved as a means of acquiring nutrients, but this role was extended in phagocytes to include engulfment of pathogens as a defense mechanism.[40] Phagocytosis probably represents the oldest form of host defense, as phagocytes have been identified in both vertebrate and invertebrate animals.[41]
Neutrophils and macrophages are phagocytes that travel throughout the body in pursuit of invading pathogens.[42] Neutrophils are normally found in the bloodstream and are the most abundant type of phagocyte, normally representing 50% to 60% of the total circulating leukocytes.[43] During the acute phase of inflammation, particularly as a result of bacterial infection, neutrophils migrate toward the site of inflammation in a process called chemotaxis, and are usually the first cells to arrive at the scene of infection. Macrophages are versatile cells that reside within tissues and produce a wide array of chemicals including enzymes, complement proteins, and regulatory factors such as interleukin 1.[44] Macrophages also act as scavengers, ridding the body of worn-out cells and other debris, and as antigen-presenting cells that activate the adaptive immune system.[12]
Dendritic cells (DC) are phagocytes in tissues that are in contact with the external environment; therefore, they are located mainly in the skin, nose, lungs, stomach, and intestines.[45] They are named for their resemblance to neuronal dendrites, as both have many spine-like projections, but dendritic cells are io way connected to the nervous system. Dendritic cells serve as a link between the bodily tissues and the innate and adaptive immune systems, as they present antigen to T cells, one of the key cell types of the adaptive immune system.[45]
Mast cells reside in connective tissues and mucous membranes, and regulate the inflammatory response.[46] They are most often associated with allergy and anaphylaxis.[43] Basophils and eosinophils are related to neutrophils. They secrete chemical mediators that are involved in defending against parasites and play a role in allergic reactions, such as asthma.[47] Natural killer (NK cells) cells are leukocytes that attack and destroy tumor cells, or cells that have been infected by viruses.[48]
[edit] Adaptive immune system
For more details on this topic, see Adaptive immune system.
The adaptive immune system evolved in early vertebrates and allows for a stronger immune response as well as immunological memory, where each pathogen is “remembered” by a signature antigen.[49] The adaptive immune response is antigen-specific and requires the recognition of specific “non-self” antigens during a process called antigen presentation. Antigen specificity allows for the generation of responses that are tailored to specific pathogens or pathogen-infected cells. The ability to mount these tailored responses is maintained in the body by “memory cells”. Should a pathogen infect the body more than once, these specific memory cells are used to quickly eliminate it.
[edit] Lymphocytes
The cells of the adaptive immune system are special types of leukocytes, called lymphocytes. B cells and T cells are the major types of lymphocytes and are derived from hematopoietic stem cells in the bone marrow.[35] B cells are involved in the humoral immune response, whereas T cells are involved in cell-mediated immune response.
Both B cells and T cells carry receptor molecules that recognize specific targets. T cells recognize a “non-self” target, such as a pathogen, only after antigens (small fragments of the pathogen) have been processed and presented in combination with a “self” receptor called a major histocompatibility complex (MHC) molecule. There are two major subtypes of T cells: the killer T cell and the helper T cell. Killer T cells only recognize antigens coupled to Class I MHC molecules, while helper T cells only recognize antigens coupled to Class II MHC molecules. These two mechanisms of antigen presentation reflect the different roles of the two types of T cell. A third, minor subtype are the γδ T cells that recognize intact antigens that are not bound to MHC receptors.[50]
In contrast, the B cell antigen-specific receptor is an antibody molecule on the B cell surface, and recognizes whole pathogens without any need for antigen processing. Each lineage of B cell expresses a different antibody, so the complete set of B cell antigen receptors represent all the antibodies that the body can manufacture.[35]
[edit] Killer T cells
Killer T cells are a sub-group of T cells that kill cells that are infected with viruses (and other pathogens), or are otherwise damaged or dysfunctional.[51] As with B cells, each type of T cell recognizes a different antigen. Killer T cells are activated when their T cell receptor (TCR) binds to this specific antigen in a complex with the MHC Class I receptor of another cell. Recognition of this MHC:antigen complex is aided by a co-receptor on the T cell, called CD8. The T cell then travels throughout the body in search of cells where the MHC I receptors bear this antigen. When an activated T cell contacts such cells, it releases cytotoxins, such as perforin, which form pores in the target cell’s plasma membrane, allowing ions, water and toxins to enter. The entry of another toxin called granulysin (a protease) induces the target cell to undergo apoptosis.[52] T cell killing of host cells is particularly important in preventing the replication of viruses. T cell activation is tightly controlled and generally requires a very strong MHC/antigen activation signal, or additional activation signals provided by “helper” T cells (see below).[52]
[edit] Helper T cells
Function of T helper cells: Antigen-presenting cells (APCs) present antigen on their Class II MHC molecules (MHC2). Helper T cells recognize these, with the help of their expression of CD4 co-receptor (CD4+). The activation of a resting helper T cell causes it to release cytokines and other stimulatory signals (green arrows) that stimulate the activity of macrophages, killer T cells and B cells, the latter producing antibodies. The stimulation of B cells and macrophages succeeds a proliferation of T helper cells.
Helper T cells regulate both the innate and adaptive immune responses and help determine which immune responses the body makes to a particular pathogen.[53][54] These cells have no cytotoxic activity and do not kill infected cells or clear pathogens directly. They instead control the immune response by directing other cells to perform these tasks.
Helper T cells express T cell receptors (TCR) that recognize antigen bound to Class II MHC molecules. The MHC:antigen complex is also recognized by the helper cell’s CD4 co-receptor, which recruits molecules inside the T cell (e.g., Lck) that are responsible for the T cell’s activation. Helper T cells have a weaker association with the MHC:antigen complex than observed for killer T cells, meaning many receptors (around 200–300) on the helper T cell must be bound by an MHC:antigen in order to activate the helper cell, while killer T cells can be activated by engagement of a single MHC:antigen molecule. Helper T cell activation also requires longer duration of engagement with an antigen-presenting cell.[55] The activation of a resting helper T cell causes it to release cytokines that influence the activity of many cell types. Cytokine signals produced by helper T cells enhance the microbicidal function of macrophages and the activity of killer T cells.[14] In addition, helper T cell activation causes an upregulation of molecules expressed on the T cell’s surface, such as CD40 ligand (also called CD154), which provide extra stimulatory signals typically required to activate antibody-producing B cells.[56]
[edit] γδ T cells
γδ T cells possess an alternative T cell receptor (TCR) as opposed to CD4+ and CD8+ (αβ) T cells and share the characteristics of helper T cells, cytotoxic T cells and NK cells. The conditions that produce responses from γδ T cells are not fully understood. Like other ‘unconventional’ T cell subsets bearing invariant TCRs, such as CD1d-restricted Natural Killer T cells, γδ T cells straddle the border between innate and adaptive immunity.[57] On one hand, γδ T cells are a component of adaptive immunity as they rearrange TCR genes to produce receptor diversity and can also develop a memory phenotype. On the other hand, the various subsets are also part of the innate immune system, as restricted TCR or NK receptors may be used as pattern recognition receptors. For example, large numbers of human Vγ9/Vδ2 T cells respond within hours to common molecules produced by microbes, and highly restricted Vδ1+ T cells in epithelia respond to stressed epithelial cells.[50]
An antibody is made up of two heavy chains and two light chains. The unique variable region allows an antibody to recognize its matching antigen.[58]
[edit] B lymphocytes and antibodies
A B cell identifies pathogens when antibodies on its surface bind to a specific foreign antigen.[59] This antigen/antibody complex is taken up by the B cell and processed by proteolysis into peptides. The B cell then displays these antigenic peptides on its surface MHC class II molecules. This combination of MHC and antigen attracts a matching helper T cell, which releases lymphokines and activates the B cell.[60] As the activated B cell then begins to divide, its offspring (plasma cells) secrete millions of copies of the antibody that recognizes this antigen. These antibodies circulate in blood plasma and lymph, bind to pathogens expressing the antigen and mark them for destruction by complement activation or for uptake and destruction by phagocytes. Antibodies can also neutralize challenges directly, by binding to bacterial toxins or by interfering with the receptors that viruses and bacteria use to infect cells.[61]
[edit] Alternative adaptive immune system
Although the classical molecules of the adaptive immune system (e.g., antibodies and T cell receptors) exist only in jawed vertebrates, a distinct lymphocyte-derived molecule has been discovered in primitive jawless vertebrates, such as the lamprey and hagfish. These animals possess a large array of molecules called variable lymphocyte receptors (VLRs) that, like the antigen receptors of jawed vertebrates, are produced from only a small number (one or two) of genes. These molecules are believed to bind pathogenic antigens in a similar way to antibodies, and with the same degree of specificity.[62]
[edit] Immunological memory
For more details on this topic, see Immunity (medical).
When B cells and T cells are activated and begin to replicate, some of their offspring become long-lived memory cells. Throughout the lifetime of an animal, these memory cells remember each specific pathogen encountered and can mount a strong response if the pathogen is detected again. This is “adaptive” because it occurs during the lifetime of an individual as an adaptation to infection with that pathogen and prepares the immune system for future challenges. Immunological memory can be in the form of either passive short-term memory or active long-term memory.
[edit] Passive memory
Newborn infants have no prior exposure to microbes and are particularly vulnerable to infection. Several layers of passive protection are provided by the mother. During pregnancy, a particular type of antibody, called IgG, is transported from mother to baby directly across the placenta, so human babies have high levels of antibodies even at birth, with the same range of antigen specificities as their mother.[63] Breast milk or colostrum also contains antibodies that are transferred to the gut of the infant and protect against bacterial infections until the newborn can synthesize its own antibodies.[64] This is passive immunity because the fetus does not actually make any memory cells or antibodies—it only borrows them. This passive immunity is usually short-term, lasting from a few days up to several months. In medicine, protective passive immunity can also be transferred artificially from one individual to another via antibody-rich serum.[65]
The time-course of an immune response begins with the initial pathogen encounter, (or initial vaccination) and leads to the formation and maintenance of active immunological memory.
[edit] Active memory and immunization
Long-term active memory is acquired following infection by activation of B and T cells. Active immunity can also be generated artificially, through vaccination. The principle behind vaccination (also called immunization) is to introduce an antigen from a pathogen in order to stimulate the immune system and develop specific immunity against that particular pathogen without causing disease associated with that organism.[14] This deliberate induction of an immune response is successful because it exploits the natural specificity of the immune system, as well as its inducibility. With infectious disease remaining one of the leading causes of death in the human population, vaccination represents the most effective manipulation of the immune system mankind has developed.[35][66]
Most viral vaccines are based on live attenuated viruses, while many bacterial vaccines are based on acellular components of micro-organisms, including harmless toxin components.[14] Since many antigens derived from acellular vaccines do not strongly induce the adaptive response, most bacterial vaccines are provided with additional adjuvants that activate the antigen-presenting cells of the innate immune system and maximize immunogenicity.[67]
[edit] Disorders of human immunity
The immune system is a remarkably effective structure that incorporates specificity, inducibility and adaptation. Failures of host defense do occur, however, and fall into three broad categories: immunodeficiencies, autoimmunity, and hypersensitivities.
[edit] Immunodeficiencies
For more details on this topic, see Immunodeficiency.
Immunodeficiencies occur when one or more of the components of the immune system are inactive. The ability of the immune system to respond to pathogens is diminished in both the young and the elderly, with immune responses beginning to decline at around 50 years of age due to immunosenescence.[68][69] In developed countries, obesity, alcoholism, and drug use are common causes of poor immune function.[69] However, malnutrition is the most common cause of immunodeficiency in developing countries.[69] Diets lacking sufficient protein are associated with impaired cell-mediated immunity, complement activity, phagocyte function, IgA antibody concentrations, and cytokine production. Additionally, the loss of the thymus at an early age through genetic mutation or surgical removal results in severe immunodeficiency and a high susceptibility to infection.[70]
Immunodeficiencies can also be inherited or ‘acquired’.[14] Chronic granulomatous disease, where phagocytes have a reduced ability to destroy pathogens, is an example of an inherited, or congenital, immunodeficiency. AIDS and some types of cancer cause acquired immunodeficiency.[71][72]
[edit] Autoimmunity
For more details on this topic, see Autoimmunity.
Overactive immune responses comprise the other end of immune dysfunction, particularly the autoimmune disorders. Here, the immune system fails to properly distinguish between self and non-self, and attacks part of the body. Under normal circumstances, many T cells and antibodies react with “self” peptides.[73] One of the functions of specialized cells (located in the thymus and bone marrow) is to present young lymphocytes with self antigens produced throughout the body and to eliminate those cells that recognize self-antigens, preventing autoimmunity.[59]
[edit] Hypersensitivity
For more details on this topic, see Hypersensitivity.
Hypersensitivity is an immune response that damages the body’s own tissues. They are divided into four classes (Type I – IV) based on the mechanisms involved and the time course of the hypersensitive reaction. Type I hypersensitivity is an immediate or anaphylactic reaction, often associated with allergy. Symptoms can range from mild discomfort to death. Type I hypersensitivity is mediated by IgE, which triggers degranulation of mast cells and basophils when cross-linked by antigen.[74] Type II hypersensitivity occurs when antibodies bind to antigens on the patient’s own cells, marking them for destruction. This is also called antibody-dependent (or cytotoxic) hypersensitivity, and is mediated by IgG and IgM antibodies.[74] Immune complexes (aggregations of antigens, complement proteins, and IgG and IgM antibodies) deposited in various tissues trigger Type III hypersensitivity reactions.[74] Type IV hypersensitivity (also known as cell-mediated or delayed type hypersensitivity) usually takes between two and three days to develop. Type IV reactions are involved in many autoimmune and infectious diseases, but may also involve contact dermatitis (poison ivy). These reactions are mediated by T cells, monocytes, and macrophages.[74]
[edit] Other mechanisms
For more details on this topic, see Innate immune system#Other forms of innate immunity.
It is likely that a multicomponent, adaptive immune system arose with the first vertebrates, as invertebrates do not generate lymphocytes or an antibody-based humoral response.[1] Many species, however, utilize mechanisms that appear to be precursors of these aspects of vertebrate immunity. Immune systems appear even in the structurally most simple forms of life, with bacteria using a unique defense mechanism, called the restriction modification system to protect themselves from viral pathogens, called bacteriophages.[75] Prokaryotes also possess acquired immunity, through a system that uses CRISPR sequences to retain fragments of the genomes of phage that they have come into contact with in the past, which allows them to block virus replication through a form of RNA interference.[76][77]
Pattern recognition receptors are proteins used by nearly all organisms to identify molecules associated with pathogens. Antimicrobial peptides called defensins are an evolutionarily conserved component of the innate immune response found in all animals and plants, and represent the main form of invertebrate systemic immunity.[1] The complement system and phagocytic cells are also used by most forms of invertebrate life. Ribonucleases and the RNA interference pathway are conserved across all eukaryotes, and are thought to play a role in the immune response to viruses.[78]
Unlike animals, plants lack phagocytic cells, but many plant immune responses involve systemic chemical signals that are sent through a plant.[79] Individual plant cells respond to molecules associated with pathogens known as Pathogen-associated molecular patterns or PAMPs.[80] When a part of a plant becomes infected, the plant produces a localized hypersensitive response, whereby cells at the site of infection undergo rapid apoptosis to prevent the spread of the disease to other parts of the plant. Systemic acquired resistance (SAR) is a type of defensive response used by plants that renders the entire plant resistant to a particular infectious agent.[79] RNA silencing mechanisms are particularly important in this systemic response as they can block virus replication.[81]
[edit] Tumor immunology
Further information: Cancer immunology
Macrophages have identified a cancer cell (the large, spiky mass). Upon fusing with the cancer cell, the macrophages (smaller white cells) inject toxins that kill the tumor cell. Immunotherapy for the treatment of cancer is an active area of medical research.[82]
Another important role of the immune system is to identify and eliminate tumors. The transformed cells of tumors express antigens that are not found oormal cells. To the immune system, these antigens appear foreign, and their presence causes immune cells to attack the transformed tumor cells. The antigens expressed by tumors have several sources;[83] some are derived from oncogenic viruses like human papillomavirus, which causes cervical cancer,[84] while others are the organism’s own proteins that occur at low levels iormal cells but reach high levels in tumor cells. One example is an enzyme called tyrosinase that, when expressed at high levels, transforms certain skin cells (e.g. melanocytes) into tumors called melanomas.[85][86] A third possible source of tumor antigens are proteins normally important for regulating cell growth and survival, that commonly mutate into cancer inducing molecules called oncogenes.[83][87][88]
The main response of the immune system to tumors is to destroy the abnormal cells using killer T cells, sometimes with the assistance of helper T cells.[86][89] Tumor antigens are presented on MHC class I molecules in a similar way to viral antigens. This allows killer T cells to recognize the tumor cell as abnormal.[90] NK cells also kill tumorous cells in a similar way, especially if the tumor cells have fewer MHC class I molecules on their surface thaormal; this is a common phenomenon with tumors.[91] Sometimes antibodies are generated against tumor cells allowing for their destruction by the complement system.[87]
Clearly, some tumors evade the immune system and go on to become cancers.[92] Tumor cells often have a reduced number of MHC class I molecules on their surface, thus avoiding detection by killer T cells.[90] Some tumor cells also release products that inhibit the immune response; for example by secreting the cytokine TGF-β, which suppresses the activity of macrophages and lymphocytes.[93] In addition, immunological tolerance may develop against tumor antigens, so the immune system no longer attacks the tumor cells.[92]
Paradoxically, macrophages can promote tumor growth [94] when tumor cells send out cytokines that attract macrophages, which then generate cytokines and growth factors that nurture tumor development. In addition, a combination of hypoxia in the tumor and a cytokine produced by macrophages induces tumor cells to decrease production of a protein that blocks metastasis and thereby assists spread of cancer cells.
[edit] Physiological regulation
Hormones can act as immunomodulators, altering the sensitivity of the immune system. For example, female sex hormones are known immunostimulators of both adaptive[95] and innate immune responses.[96] Some autoimmune diseases such as lupus erythematosus strike women preferentially, and their onset often coincides with puberty. By contrast, male sex hormones such as testosterone seem to be immunosuppressive.[97] Other hormones appear to regulate the immune system as well, most notably prolactin, growth hormone and vitamin D.[98][99]
When a T-cell encounters a foreign pathogen, it extends a vitamin D receptor. This is essentially a signaling device that allows the T-cell to bind to the active form of vitamin D, the steroid hormone calcitriol. T-cells have a symbiotic relationship with vitamin D. Not only does the T-cell extend a vitamin D receptor, in essence asking to bind to the steroid hormone version of vitamin D, calcitriol, but the T-cell expresses the gene CYP27B1, which is the gene responsible for converting the pre-hormone version of vitamin D, calcidiol into the steroid hormone version, calcitriol. Only after binding to calcitriol can T-cells perform their intended function. Other immune system cells that are known to express CYP27B1 and thus activate vitamin D calcidiol, are dendritic cells, keratinocytes and macrophages.[100][101]
It is conjectured that a progressive decline in hormone levels with age is partially responsible for weakened immune responses in aging individuals.[102] Conversely, some hormones are regulated by the immune system, notably thyroid hormone activity.[103] The age-related decline in immune function is also related to dropping vitamin D levels in the elderly. As people age, two things happen that negatively affect their vitamin D levels. First, they stay indoors more due to decreased activity levels. This means that they get less sun and therefore produce less cholecalciferol via UVB radiation. Second, as a person ages the skin becomes less adept at producing vitamin D.[104]
The immune system is affected by sleep and rest,[105] and sleep deprivation is detrimental to immune function.[106] Complex feedback loops involving cytokines, such as interleukin-1 and tumor necrosis factor-α produced in response to infection, appear to also play a role in the regulation of non-rapid eye movement (REM) sleep.[107] Thus the immune response to infection may result in changes to the sleep cycle, including an increase in slow-wave sleep relative to REM sleep.[108]
[edit] Nutrition and diet
Overnutrition is associated with diseases such as diabetes and obesity, which are known to affect immune function. More moderate malnutrition, as well as certain specific trace mineral and nutrient deficiencies, can also compromise the immune response.[109][page needed]
Foods rich in certain fatty acids may foster a healthy immune system.[110] Likewise, fetal undernourishment can cause a lifelong impairment of the immune system.[111]
[edit] Manipulation in medicine
The immunosuppressive drug dexamethasone
The immune response can be manipulated to suppress unwanted responses resulting from autoimmunity, allergy, and transplant rejection, and to stimulate protective responses against pathogens that largely elude the immune system (see immunization). Immunosuppressive drugs are used to control autoimmune disorders or inflammation when excessive tissue damage occurs, and to prevent transplant rejection after an organ transplant.[35][112]
Anti-inflammatory drugs are often used to control the effects of inflammation. Glucocorticoids are the most powerful of these drugs; however, these drugs can have many undesirable side effects, such as central obesity, hyperglycemia, osteoporosis, and their use must be tightly controlled.[113] Lower doses of anti-inflammatory drugs are often used in conjunction with cytotoxic or immunosuppressive drugs such as methotrexate or azathioprine. Cytotoxic drugs inhibit the immune response by killing dividing cells such as activated T cells. However, the killing is indiscriminate and other constantly dividing cells and their organs are affected, which causes toxic side effects.[112] Immunosuppressive drugs such as ciclosporin prevent T cells from responding to signals correctly by inhibiting signal transduction pathways.[114]
Larger drugs (>500 Da) can provoke a neutralizing immune response, particularly if the drugs are administered repeatedly, or in larger doses. This limits the effectiveness of drugs based on larger peptides and proteins (which are typically larger than 6000 Da). In some cases, the drug itself is not immunogenic, but may be co-administered with an immunogenic compound, as is sometimes the case for Taxol. Computational methods have been developed to predict the immunogenicity of peptides and proteins, which are particularly useful in designing therapeutic antibodies, assessing likely virulence of mutations in viral coat particles, and validation of proposed peptide-based drug treatments. Early techniques relied mainly on the observation that hydrophilic amino acids are overrepresented in epitope regions than hydrophobic amino acids;[115] however, more recent developments rely on machine learning techniques using databases of existing known epitopes, usually on well-studied virus proteins, as a training set.[116] A publicly accessible database has been established for the cataloguing of epitopes from pathogens known to be recognizable by B cells.[117] The emerging field of bioinformatics-based studies of immunogenicity is referred to as immunoinformatics.[118] Immunoproteomics is the study of large sets of proteins (proteomics) involved in the immune response.
[edit] Manipulation by pathogens
The success of any pathogen depends on its ability to elude host immune responses. Therefore, pathogens evolved several methods that allow them to successfully infect a host, while evading detection or destruction by the immune system.[119] Bacteria often overcome physical barriers by secreting enzymes that digest the barrier, for example, by using a type II secretion system.[120] Alternatively, using a type III secretion system, they may insert a hollow tube into the host cell, providing a direct route for proteins to move from the pathogen to the host. These proteins are often used to shut down host defenses.[121]
An evasion strategy used by several pathogens to avoid the innate immune system is to hide within the cells of their host (also called intracellular pathogenesis). Here, a pathogen spends most of its life-cycle inside host cells, where it is shielded from direct contact with immune cells, antibodies and complement. Some examples of intracellular pathogens include viruses, the food poisoning bacterium Salmonella and the eukaryotic parasites that cause malaria (Plasmodium falciparum) and leishmaniasis (Leishmania spp.). Other bacteria, such as Mycobacterium tuberculosis, live inside a protective capsule that prevents lysis by complement.[122] Many pathogens secrete compounds that diminish or misdirect the host’s immune response.[119] Some bacteria form biofilms to protect themselves from the cells and proteins of the immune system. Such biofilms are present in many successful infections, e.g., the chronic Pseudomonas aeruginosa and Burkholderia cenocepacia infections characteristic of cystic fibrosis.[123] Other bacteria generate surface proteins that bind to antibodies, rendering them ineffective; examples include Streptococcus (protein G), Staphylococcus aureus (protein A), and Peptostreptococcus magnus (protein L).[124]
The mechanisms used to evade the adaptive immune system are more complicated. The simplest approach is to rapidly change non-essential epitopes (amino acids and/or sugars) on the surface of the pathogen, while keeping essential epitopes concealed. This is called antigenic variation. An example is HIV, which mutates rapidly, so the proteins on its viral envelope that are essential for entry into its host target cell are constantly changing. These frequent changes in antigens may explain the failures of vaccines directed at this virus.[125] The parasite Trypanosoma brucei uses a similar strategy, constantly switching one type of surface protein for another, allowing it to stay one step ahead of the antibody response.[126] Masking antigens with host molecules is another common strategy for avoiding detection by the immune system. In HIV, the envelope that covers the virion is formed from the outermost membrane of the host cell; such “self-cloaked” viruses make it difficult for the immune system to identify them as “non-self” structures.[127]
[edit] See also
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[edit] References
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