Autoimmunity

Immunology AUTOIMMUNITY MAJOR HISTOCOMPATIBILITY COMPLEX (MHC) By virtue of genetic make-up, every individual has unique antigens on the cell surfaces. Some of these are called as histocompatibility (histo: tissue) antigens. These are responsible for determining whether one tissue is compatible with another or not. In human beings these antigens are called as human leukocyte antigens (HLA). Expression of histocompatibility antigens is controlled by genes or groups of genes (loci) located close together /linked on the same chromosomal strand. This segment of chromosome is called major histocompatibility complex (MHC). In humans is located on chromosome 6. Certain HLA antigens are also related to increased susceptibility to specific diseases. With the help of standard antisera, HLA types of an individual can be ascertained. An important medical application of HLA typing is transplantation where the donor and the recipient must be matched. This is done by tissue typing by various serological methods. Two main classes of HLA antigens are considered important: Class I antigens (HLA-A, HLA-B and HLA-C) and Class II antigens (HLA-DR, HLA-DP and HLADQ). Every individual has a unique pattern of HLA type. The existence of HLA antigens in humans denotes the presence of a system which recognises these as self and does not reject these. AUTOIMMUNITY The purpose of the immunological response is to protect the host and to discriminate between what is self and what is non-self for the host. The primary means by which the immune system recognises foreign antigens is through comparison with self major histocompatibility complex (MHC) determinants. Therefore, MHC serves as a 'yardstick' against which foreign determinants can be measured. Immune response against self-antigens becomes devastating. Recognition of selfdeterminants is normal and occurs during the generation of nearly all immune responses, whereas immunologic reactivity against self determinants can lead to autoimmune disease. The emergence of autoimmune disease is postulated to be due to mutation of a non-self reactive lymphocyte into self-reactive one, the activation of previous tolerant helper T cell or the inhibition of suppressor T cells. Criteria for Autoimmune Disease (Wltebsky's Postulates) After the name of the scientist who suggested these, the criteria are known as Witebsky's postulates. The disease must fulfill following criteria before it can be called as autoimmune disease: a. The autoimmune response must be regularly associated with the disease. b. A replica of the disease must be inducible in laboratory animals. c. Immuno-pathologic changes in the natural and experimental diseases should parallel each other. d. Transfer of autoimmune illness should be possible by the transfer of serum or lymphoid cells from the diseased individual to a normal recipient Relationship of HLA Types and Autoimmune Diseases On the basis of various studies in animals, it has been shown that a relationship exists between MHC and autoimmune diseases. A link between HLA types and autoimmune diseases has been suggested by studies in families and population with disease vis a vis normal healthy subjects. A few of the diseases having demonstrable relationship with various HLA types are: Relationship of HLA and autoimmune human diseases Disease Ankylosing spondylitis Reiter's syndrome Yersinia arthritis Salmonella arthritis Autoimmune thyroiditis

HLA type B 27 B 27 B 27 B 27 Bw35

Anterior uveitis Sjogren's syndrome Addison's disease G Graves' disease Multiple sclerosis

B 27 Dw3 B8 B8 B7

Ankylosing spondylitis is the commonest diseases and an individual with HLA-B27 type is at higher risk of contracting this disease. Some of the diseases are infectious but the pathology does not stem directly from infection but are sequelae which occur even after the infection has been eliminated. Immunological Features and Diagnosis of Autoimmune Diseases Many of the following immunological findings are associated with autoimmune diseases: • General hypergammaglobulinaemia • Specific cell directed immunoglobulins • Hypocomplementaemia-general or in specific complement component • Increase in activities associated with the activation of complement • Increase in chemotactic attraction to sites where gamma globulin and complement are bound to tissues • Appearance of T lymphocytes with self-directed activities. The serological tests directed toward identification of these unusual immunologic manifestations are useful screening procedures for the diagnosis of the autoimmune diseases. A few of the major autoimmune diseases falling at two ends of spectrum are mentioned below along with the selfantigen recognised by the immune system in each disease: Autoimmune diseases Autoimmune disease

Self-antigen

Organ specific diseases Hashimoto's thyroiditis

Thyroglobulin

Pernicious anaemia

Gastric parietal cells

Graves' disease

Thyroid stimulating hormone receptor

Juvenile insulin dependent diabetes

Pancreatic islet cells

Multiple sclerosis

Central nervous system myelin

Non-organ specific diseases SLE

DNA, RNA, RBCs, platelets, lymphocytes

Rheumatoid arthritis

Gamma globulin

Goodpasture's syndrome

Basement membrane

Autoimmune Diseases Hashimoto's Thyroiditis This was the first disease that satisfied Witebsky's criteria for an autoimmune disease. Hashimoto's disease is characterised physiologically by a deficiency in thyroid hormone and anatomically by an enlarged thyroid gland infilterated with plasma cells and lymphocytes. Thrombocytopenic Purpura

This is an illness characterised by thrombocytopenia and the appearance of purpuric or petechial haemorrhages in the skin and tissues. In infants, this condition can arise through alloimmunisation in much the same way that erythroblastosis fetalis develops, that is the transplacental migration of maternal antifetal thrombocyte globulins. An autoimmune form of thrombocytopenic purpura is seen in adults. Invariably the afflicted person is on a continued drug regimen of some sort. The offending drug may be aspirin, sulfonamide, quinine, antihistaminics. Myasthenia Gravis This is a disease in which a gradual progressive weakness of striated muscle is a prominent external sign and which becomes so severe that even eating is laborious. Myasthenia gravis patients exhibit a number of immunologic aberrations. Antinuclear antibodies, rheumatoid factors and antibodies that react with striated muscles are frequently detected. Commonest immunopathological feature is presence of antibody to acetylcholine receptor. Multiple Sclerosis Partial loss of vision, nystagmus, facial palsy and muscular in-coordination are a few of the varied symptoms of multiple sclerosis. Remissions and exacerbations are characteristics of this disease. The major pathologic feature is an inflammatory lesion of the myelin in the central nervous system. Glomerulonephritis There are three forms of immune diseases that involve the glomerulus. One is associated with antecedent Group A streptococcal infection, second is involved with heterologous antibodies versus glomerular basement membrane antigens and third is based on immune complex formation with foreign antigens, as in serum sickness or alloantigens, as in immune complex disease in which globulins precipitate within the kidney following infection with Group A streptococci, staphylococci, pneumococci or even malarial parasite. Rheumatoid Arthritis It is inflammatory disease of joints and connective tissue, amyloid deposition of tissues and permanent deformity of the joints may result. An autoantibody seen in this condition is an agglutinating agent known as rheumatoid factor (RF) which is a 19S-Ig compatible in all respects with IgM. Systemic Lupus Erythematosus An association of this disease with HLA-B8 has been observed in a large number of patients. Graves' Disease This disease is a form of hyperthyroidism and more common than Hashimoto's disease. It is now believed to be caused by a long acting thyroid stimulator (LATS)-an immunoglobulin found in the sera of majority of patients with Graves' disease. The LATS autoantibody is a type of enhancing antibody that operates at the cellular level, much like the thyroid stimulating hormone, to stimulate thyroid hormone release and thyrotoxicosis. Important features about autoimmunity: • 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" • Presence of autoantibody is n't always the cause of the disease,it could be incidental. • Autoimmune disease could be transitory (e.g. anaemia, thrombocytopenia) or chronic. • Once initiated, most autoimmune responses tend to be self perpetuating. • Their progress can be arrested by immunosuppresive therapy. • Autoimmune disease could be localised (organ specific) such as affecting only thyroid gland, skin, eye, nervous system or be non-organ specific such as SLE, Rheumatoid arthritis,polyarteritis nodosa, etc. • Their incidence is generally more in females. • By and large they are chronic and non-reversible. • Associated with elevated levels of immunoglobulins