Autoimmunity PDF

# Autoimmunity Self-antigens are not ordinarily immunogenic. Ehrlich (1901) observed that goats produced antibodies against erythrocytes from other goats but not against their own, and postulated the concept of 'horror autotoxicus'. But he did not regard autoimmunisation as an impossibility and e...

# Autoimmunity Self-antigens are not ordinarily immunogenic. Ehrlich (1901) observed that goats produced antibodies against erythrocytes from other goats but not against their own, and postulated the concept of 'horror autotoxicus'. But he did not regard autoimmunisation as an impossibility and even envisaged its pathogenic possibility. ## Autoimmunity Definition Autoimmunity is a condition in which structural or functional damage is produced by the action of immunologically competent cells or antibodies against the normal components of the body. Autoimmunity literally means 'protection against self' but it actually implies 'injury to self' and therefore it has been criticised as a contradiction in terms. 'Autoallergy' has been suggested as an acceptable alternative but the term autoimmunity has the sanction of wide usage. ## Earliest Example of Autoimmunity The earliest example of autoimmunity was the observation by Metalnikoff (1900) that guinea pigs injected with their own spermatozoa produced sperm immobilising antibodies. Donath and Landsteiner (1904) identified circulating autoantibodies in paroxysmal cold hemoglobinuria -a hemolysin which binds with the patient's erythrocytes at low temperatures and produces complement dependent hemolysis on warming. This was the first description of an autoimmune disease in human beings. Dameshek and Schwartz (1938) established the autoimmune basis of acute hemolytic anemia. With the discovery of Coombs test for incomplete antibodies it became possible to demonstrate globulins bound to the surface of erythrocytes in this condition. ## Autoimmunisation in Experimental Animals Autoimmunisation could be induced in experimental animals by injection of self-antigens along with the complete Freund's adjuvant. The use of sensitive serological techniques led to the demonstration of autoantibodies in several diseases and even in a proportion of healthy individuals. Some autoantibodies, such as the antiidiotypic antibody may even be essential for the normal functioning of the immune system. ## Autoimmunity as a Pathogenic Mechanism When the concept of autoimmunity came to be accepted as a pathogenic mechanism, a large number of diseases were suggested to have an autoimmune etiology, based on the finding of autoantibodies in the patients. This was soon recognized to be untenable as autoantibodies could be often incidental or the result, and not the cause of disease. ## Criteria for Putative Autoimmune Diseases Criteria were proposed for proving the authenticity of putative autoimmune diseases, similar to Koch's postulates in infectious diseases. These were found to be not applicable in the case of such spontaneous and multifactorial conditions as autoimmune diseases. It may be proper to restrict the term 'autoimmune diseases' to those where autoimmune processes, humoral or cellular, are shown to be responsible for the pathogenesis, rather than merely associated. This is not strictly adhered to. Moreover, the border between autoimmunity and hypersensitivity is largely ill-defined or even nonexistent. ## Features of Autoimmune Diseases Diseases of autoimmune origin usually exhibit the following features: 1. An elevated level of immunoglobulins. 2. Demonstrable autoantibodies. 3. Deposition of immunoglobulins or their derivatives at sites of election, such as renal glomeruli. 4. Accumulation of lymphocytes and plasma cells at the sites of lesion. 5. Benefit from corticosteroid or other immunosuppressive therapy. 6. The occurrence of more than one type of autoimmune lesion in an individual. 7. A genetic predisposition towards autoimmunity. 8. Incidence higher among females. 9. Chronicity. Usually nonreversible. ## Mechanisms of Autoimmunisation Cells or tissues may undergo antigenic alteration as a result of physical, chemical or biological influences. Such altered or 'neoantigens' may elicit an immune response. Neoantigens can arise in a variety of ways. * Physical agents such as irradiation can cause antigenic alteration. * Photosensitivity and cold allergy may represent sensitization to self-antigens, altered by light and cold, respectively. * Several chemicals, including drugs, can combine with cells and tissues and alter their antigenic nature. * Contact dermatitis, which is traditionally considered a type of delayed hypersensitivity, can also be taken to be an autoimmune response to skin antigens altered by their combination with chemical allergens. * Drug induced anemias, leucopenias and thrombocytopenias often have an autoimmune basis. * Infectious microorganisms, particularly viruses and other intracellular pathogens, may induce alteration of cell antigens. * Viral infections, such as infectious mononucleosis, are known to often precede autoimmune diseases. * Bacterial enzymes also induce alteration of cell antigens. Neuraminidases formed by myxoviruses and many bacteria act on erythrocytes releasing the T antigen. * The almost universal occurrence of T agglutinins in human sera is believed to represent a harmless autoimmune response following infections. * Neoantigens may also arise by mutation. Such mutant cells may be immunogenic. ## Immunological Damage from Cross-reacting Antigens Immunological damage may result from immune responses induced by cross-reacting foreign antigens. The fortuitous similarity between some foreign and self-antigens is the basis of the 'cross reacting antigen' theory of autoimmunity. Organ specific antigens are present in several species. Injection of heterologous organ specific antigens may induce an immune response damaging the particular organ or tissue in the host. * An example is the neurological injury that used to be a complication of antirabic immunization in human beings with the neural vaccine of infected sheep brain tissue partially denatured by treatment with phenol. Its injection elicits an immune response against sheep brain antigens. This may cause damage to the individual's nerve tissue due to the cross-reaction between human and sheep brain antigens. ## Immunological Injury due to Infections Immunological injury due to cross-reacting antigens can also follow infections. * Streptococcal M proteins and the heart muscle share antigenic characteristics. The immune response induced by repeated streptococcal infection can therefore damage the heart. * Nephritogenic strains of streptococci possess antigens found in the renal glomeruli. Infection with such strains may lead to glomerulonephritis due to the antigenic sharing. ## Molecular Mimicry A related type of autoimmunisation is 'molecular mimicry' which is due to the presence in some infecting microorganisms and self-antigens, of epitopes with identical peptide sequences (instead of similarities in 'cross-reactions'). Examples of such homologous sequences are seen in * arthritogenic Shigella flexneri and HLA-B27, * Mycobacterium tuberculosis and joint membranes, * Coxsackie B and myocardium. ## Polyclonal B Cell Activation Another hypothesis is polyclonal B cell activation. While an antigen generally activates only its corresponding B cell, certain stimuli nonspecifically turn on multiple B cell clones. Such stimuli include * chemicals (for example, 2-mercaptoethanol), * bacterial products(PPD, lipopolysaccharide), * enzymes (trypsin), * antibiotics (nystatin) * infections with some bacteria (mycoplasma), * viruses (EB virus) * parasites (malaria). Multiple nonspecific antibodies form during some infectious diseases, such as antihuman erythrocyte cold antibodies in mycoplasma pneumonia and antisheep erythrocyte antibody in infectious mononucleosis. These polyclonal antibodies are IgM in nature, similar to the 'natural antibodies' produced by CD5+ B cells. ## Breakdown of Immunological Homeostasis Breakdown of immunological homeostasis may lead to cessation of tolerance and the emergence of forbidden clones of immunocompetent cells capable of mounting immune response against self-antigens. Autoimmunisation may result when tolerance to a self-antigen is abrogated, as for instance by the injection of the self-antigen with Freund's adjuvant. ## Enhanced Helper T-Cell and Decreased Suppressor T-Cell Functions Enhanced helper T cell and decreased suppressor T cell functions have been suggested as causes of autoimmunity. Defects in the thymus, in stem cell development and macrophage function have also been postulated as causes.. ## Sequestered Antigens Certain self-antigens are present in closed systems and are not accessible to the immune apparatus. These are known as sequestered antigens. * An example is the lens antigen of the eye. The lens protein is enclosed in its capsule and does not circulate in the blood. Hence immunological tolerance against this antigen is not established during fetal life. * When the antigen leaks out, following penetrating injury, it may induce an immune response causing damage to the lens of the other eye. * An example of 'sequestration in time' is seen with sperm antigens. As spermatozoa develop only with puberty, the antigen cannot induce tolerance during fetal life. * The sperm antigen is therefore not recognised as self and when it enters the circulation, it is immunogenic. * This is believed to be the pathogenesis of orchitis following mumps. The virus damages the basement membrane of seminiferous tubules leading to the leakage of sperms and initiation of an immune response resulting in orchitis. ## Defects in the Idiotype-Antiidiotype Network Defects in the idiotype-antiidiotype network have also been said to lead to autoimmunity. Genetic factors such as defective Ir or immunoglobulin genes have also been postulated. ## Genetic Factors in Autoimmunity In human autoimmune diseases and in animal models, genetic factors appear to influence the development and fate of autoimmune states. In spite of so many different possible mechanisms proposed, their actual role in autoimmunity, if any, has not been established. ## Animal Models of Autoimmunity Many animal models of spontaneous and induced autoimmunity have contributed to an understanding of this condition. Examples of spontaneous autoimmune diseases in animals are * autoimmune hemolytic anemia in the ~~New~~ **New Zealand** Black (NZB) mouse strain, * systemic lupus erythematosus in NZB X NZW cross, * insulin dependent diabetes mellitus in the nonobese diabetic (NOD) mouse, * and thyroiditis in the obese strain (OS) chicken. Experimentally, autoimmunity can be induced in many animal species by injecting tissue extracts in the complete Freund's adjuvant-for example, * experimental allergic encephalomyelitis with brain or spinal cord extracts, * and thyroiditis with thyroid gland extract. ## Classification of Autoimmune Diseases Based on the site of involvement and nature of lesions, autoimmune diseases may be classified as * hemocytolytic, * localised (or organ specific), * systemic (or nonorgan specific), * and transitory diseases. ## Hemocytolytic Autoimmune Diseases * Autoimmune hemolytic anemias: * Autoantibodies against erythrocytes are demonstrable in this condition. * Serologically, two groups of autoimmune anemias can be distinguished, characterised by 'cold' and 'warm' antibodies, respectively. * The cold autoantibodies are, generally, complete agglutinating antibodies belonging to the IgM class and agglutinate erythrocytes at 4 °C but not at 37 °C. Cold agglutinins were first detected by Donath and Landsteiner in paroxysmal cold hemoglobinuria. This condition, which used to frequently accompany syphilitic infection, is seldom seen nowadays. Cold agglutinins are also seen in primary atypical pneumonia, trypanosomiasis and blackwater fever. * Warm autoantibodies are generally incomplete, nonagglutinating antibodies usually belonging to the IgG class. They can be shown coating the erythrocytes in the direct Coombs test. Warm antierythrocyte antibodies are frequently seen in patients taking certain drugs such as sulphonamides, antibiotics, and alpha methyl dopa. * In autoimmune anemias, the red cells coated with antibodies are prematurely destroyed in the spleen and liver. Complement dependent intravascular hemolysis appears to be a rare event. * Autoimmune thrombocytopenia: Autoantibodies directed against platelets occur in idiopathic thrombocytopenic purpura. Sedormid purpura is an instance of immune response against drug induced neoantigens on platelets. This condition is traditionally considered an antibody mediated hypersensitivity. * Autoimmune leucopenia: Nonagglutinating antileucocyte antibodies can be demonstrated in the serum of patients with systemic lupus erythematosus and rheumatoid arthritis. ## Localized (Organ Specific) Autoimmune Diseases ### Autoimmune Diseases of the Thyroid Gland 1. Hashimoto's disease (Lymphadenoid goitre): * This is the most typical and best studied of organ-specific autoimmune diseases. * In 1956, Roitt and Doniach in England demonstrated antithyroglobulin antibodies in the sera of patients by precipitation in gel, and Witebsky and Rose in the USA by the more sensitive passive hemagglutination test. * The latter workers also reproduced the disease in rabbits by immunization with autologous thyroid tissue obtained by hemithyroidectomy. * Hashimoto's disease occurs more frequently in females and is associated with an enlargement of the thyroid gland and symptoms of hypothyroidism or frank myxedema. * Histologically, the glandular structure is replaced by lymphoid tissue consisting of lymphocytes, histiocytes and plasma cells. Antibodies with different specificities have been found in this condition. They include antibodies that react with thyroglobulin, a second acinar colloid, microsomal antigen and a thyroid cell surface component. 2. Thyrotoxicosis (Graves' disease): * The majority of patients with thyrotoxicosis possess antibody to thyroglobulin. Lymphocytic infiltration is common in thyrotoxic glands. * The immunological basis of thyrotoxicosis is supported by the identification of the 'long acting thyroid stimulator' (LATS) which is an IgG antibody to the thyroid membrane antigen. Combination of LATS with the surface membrane of thyroid cells seems to stimulate excessive hormone secretion. ## Autoimmune Diseases of the Adrenals * Addison's disease: * The immunological basis of Addison's disease is suggested by lymphocytic infiltration of the adrenal glands and the presence of circulating antibodies directed against the cells of the zona glomerulosa. Similar lesions can be produced in experimental animals by immunization with adrenal tissue in Freund's adjuvant. ## Autoimmune Orchitis * Autoimmune orchitis: * Experimental allergic orchitis with progressive damage to germinal epithelium and aspermatogenesis can be induced in guinea pigs by the injection of autogenous or allogeneic testes with Freund's adjuvant. * A similar condition sometimes follows mumps orchitis. Lymphocytic infiltration of the testes and circulating antibodies to the sperms and germinal cells can be demonstrated in this condition. ## Myasthenia Gravis * Myasthenia gravis: * In this disease, there is an abnormal fatiguability of muscles due to malfunction of the myoneural junction. * An antibody against acetyl choline receptor on myoneural junctions of striated muscles is present in these patients. * This prevents acetyl choline from combining with its receptor, and impairs muscular contraction. * The thymus shows lymphoid hyperplasia and numerous germinal centres. * Infants born to affected mothers show symptoms of the disease but recover spontaneously by the age of two months, coinciding with the disappearance of maternal antibodies. * This suggests that the pathogenic factor in neonatal myasthenia may be the autoantibody passively acquired from the mother. ## Autoimmune Diseases of the Eye * Autoimmune diseases of the eye: * Two types of autoimmune diseases are seen in the eye. * Cataract surgery sometimes leads to intraocular inflammation caused by the autoimmune response to the lens protein. This is known as phacoanaphylaxis. * Perforating injuries of the eye, particularly those involving the iris or ciliary bodies are often followed by sympathetic ophthalmia in the opposite eye. * The disease can be produced in experimental animals by immunisation with uveal or retinal tissue in Freund's adjuvant and can be passively transferred with the spleen or lymph node cells but not with serum. ## Pernicious Anemia * Pernicious anemia: * Two types of autoantibodies are present in this condition. * The first is directed against the parietal cells of the gastric mucosa. * This is believed to cause achlorhydria and atrophic gastritis. * The second type of antibody is directed against the intrinsic factor and prevents absorption of vitamin B, either by blocking its attachment to the gastric intrinsic factor or by binding to the B, intrinsic factor complex and interfering with its uptake by the intestinal mucosa. ## Autoimmune Diseases of the Nervous System * Autoimmune diseases of the nervous system: * The 'neuroparalytic accidents' following rabies vaccination represent injury to the nervous system by the immune response against the sheep nervous tissue in the vaccine, which cross reacts with human nerve tissue. * An essentially similar condition, experimental allergic encephalomyelitis (EAE), can be produced in animals by immunisation with nervous tissue in Freund's adjuvant. The encephalogenic protein has been identified as the myelin basic protein (MBP) which shows no species specificity. * Idiopathic polyneuritis (Guillain-Barre syndrome) is considered an autoimmune response against the peripheral nervous tissue. It can be reproduced in experimental animals by immunisation with peripheral nervous tissue in an adjuvant. ## Autoimmune Diseases of the Skin * Autoimmune diseases of the skin: * Three serious diseases of the skin are considered to have an autoimmune basis. * Pemphigus vulgaris may be caused by an antibody to the intercellular cement substance. * In bullous pemphigoid, antibodies directed against the dermal epithelial junction have been demonstrated. * Specific antibodies in dermatitis herpetiformis have not been identified. ## Systemic (Nonorgan Specific) Autoimmune Diseases This group includes conditions characterised by immune response against a variety of self-antigens and damage to several organs and tissue systems. Klemperer (1942) classified a number of diseases of unknown origin with the common feature of connective tissue lesions as 'collagen diseases'. Included in this category are * systemic lupus erythematosus (SLE), * rheumatoid arthritis, * polyarteritis nodosa, * Sjogren's syndrome, * dermatomyositis * and scleroderma. All these conditions are associated with generalised autoimmune processes. ## Systemic Lupus Erythematosus * Systemic lupus erythematosus: * This is a chronic, multisystem disease with remissions and exacerbations, terminating fatally. * Patients have a variety of autoantibodies directed against cell nuclei, intracytoplasmic cell constituents, immunoglobulins, thyroid and other organ specific antigens. * Biological false positive reaction is seen in standard tests for syphilis. * The abundance and variety of autoantibodies suggest a breakdown in the central control of immunological homeostasis. The first immunological feature identified in SLE was the LE cell phenomenon described in 1948. The LE cell is a neutrophil containing a large, pale, homogeneous body (LE body) almost filling the cytoplasm. The LE body is the immunologically damaged nucleus of a leucocyte. Sometimes, instead of being intracellular, the LE body can be seen free, surrounded by a rosette of neutrophils. The fact that LE cell formation is due to an antibody (LE factor) present in SLE can be demonstrated by incubating normal blood with serum from an SLE patient. The nuclei of some leucocytes can be seen to swell and become p*ale* and spherical. Neutrophils can be observed to surround these damaged cells, strip away the cytoplasm and engulf the free nucleus to form LE cells. Giemsa stained smears of blood or bone marrow can demonstrate LE cells, but its sensitivity is so low that this test has been replaced by other antibody tests for diagnosis. Immunofluorescent tests for antinuclear antibody (ANA) show up different patterns of staining, such as homogeneous (diffuse), peripheral (outline), speckled and nucleolar staining patterns. ANA tests are sensitive but not specific for SLE, as they may be positive in many other autoimmune conditions, viral infections, chronic inflammatory processes, as well as in persons using certain medicines and in the aged. ## Anti-DNA Antibodies Anti-DNA antibodies are tested by RIA or ELISA. Three major types of these antibodies are seen those reacting with single stranded (ss), double stranded (ds) and both ss and ds DNA. Of these, high titre anti-ds DNA antibody is relatively specific for SLE. Another SLE specific antibody is anti-sm antibody. ## Rheumatoid Arthritis * Rheumatoid arthritis: * This is a symmetric polyarthritis with muscle wasting and subcutaneous nodules, commonly associated with serositis, myocarditis, vasculitis and other disseminated lesions. * It is found more commonly in women. * The synovial membranes of the affected joints are swollen and edematous, with dense infiltration of lymphocytes and plasma cells. * A striking feature is the presence of a circulating autoantibody called the 'Rheumatoid factor' (RF). * This is usually a 19s IgM, though IgG, and IgA RF have also been demonstrated. RF acts as an antibody against the Fc fragment of immunoglobulins. They combine usually with IgG though some types of RF are directed towards other immunoglobulin classes. RF reacts with autologous, isologous or heterologous immunoglobulins. RF is generally considered to be an immunoglobulin behaving as antibody to determinants present in the patient's own IgG molecules, though some configurational alteration of IgG may be required before its reactivity with RF becomes demonstrable. * RF is detected by agglutination tests using, as antigens, particles coated with globulins. * In the Rose-Waaler test, the original technique for detection of RF, sheep erythrocytes coated with a subagglutinating dose of antierythrocyte antibody (amboceptor) are used as the antigen in an agglutination test. * In modifications of the test, latex and bentonite are used as the carrier particles for IgG. Antinuclear antibodies are frequently found in rheumatoid arthritis. ## Polyarteritis Nodosa * Polyarteritis nodosa: * This is a necrotising angiitis involving medium sized arteries, ending fatally due to coronary thrombosis, cerebral hemorrhage or gastrointestinal bleeding. * Polyarteritis is seen as a component of serum sickness and other toxic complex diseases. * Immune complexes of hepatitis B virus antigen (Hbs Ag) in affected tissues, including the kidneys, have been demonstrated in 30-40 per cent of patients. * Though it has been suggested that polyarteritis nodosa may be an autoimmune disease, the autoantibody responsible has not been identified. * Sjogren syndrome: This is a triad of conjunctivitis sicca, dryness of the mouth, with or without salivary gland enlargement, and rheumatoid arthritis. * The syndrome may occur in association with other collagen diseases. * Antinuclear antibodies and rheumatoid factor commonly occur in sera. ## Transitory Autoimmune Processes These include conditions such as anemia, thrombocytopenia or nephritis that follow certain infections or drug therapy. The infecting agent or drug induces antigenic alteration in some self-antigens. The immune response set up causes tissue damage. The disease is transient and undergoes spontaneous cure when the infection is controlled or the drug withdrawn. ## Pathogenesis of Autoimmune Disease Many diseases are considered to be of autoimmune origin, based on their association with cellular or humoral immune responses against self-antigens. Autoantibodies are more easily detected than cellular autosensitisation. However, the mere presence of autoantibodies during the course of a disease does not prove their etiological role. Autoantibody formation may be a result of tissue injury and the antibody may help in promoting immune elimination of the damaged cell or tissue elements. A typical example is lepromatous leprosy in which large amounts of autoantibodies are regularly found. It has been said that but for the lepra bacillus, lepromatous leprosy may have been proposed as an autoimmune disease. The relative importance of humoral and cellular immune processes in the etiology of autoimmune diseases is not known. Antibodies may cause damage by the cytolytic or cytotoxic (type 2) and toxic complex (type 3) reactions. They are obviously important in hemocytolytic autoimmune diseases. Another mechanism of autoimmune tissue damage is by sensitised T lymphocytes (type 4 reaction). It is likely that humoral and cellular immune responses may act synergistically in the production of some autoimmune diseases. For example, experimental orchitis can be induced only when both types of immune responses are operative. Once initiated, most autoimmune responses tend to be self perpetuating. Their progress can be arrested by immunosuppressive therapy, though the degree of response to such therapy varies in different diseases.