AUTOIMMUNE DISORDERS

1.            Responses to Self antigens

a.            Autoimmune disease occurs when a specific adaptive immune response is mounted against self antigens.

b.         When a sustained immune response develops against self antigens, it is usually impossible for immune effector mechanisms to eliminate the antigen completely.

c.            Autoimmune diseases can be caused by autoantibodies or by autoimmune T cells.

d.            Mechanisms of tissue damage:

i.          direct attack on the cells bearing the antigen.

ii.            immune-complex formation.

iii.         local inflammation.

e.            Autoimmune diseases occur in people:

i.          with a genetic pre-disposition that is determined by their MHC genes.

ii.          who are exposed to an environmental agent which triggers a cross-reacting immune response against some component of normal tissue.

f.          Genetic causes:

i.          many autoimmune diseases exhibit a marked familial incidence, which suggests a genetic predisposition to these disorders.

ii.          there is a strong association of some diseases with certain human leukocyte antigen (HLA) specificities, especially the class II genes.

iii.         for example, rheumatoid arthritis occurs predominantly in individuals carrying the HLA-DR4 gene.

g.            Molecular mimicry:

i.          this explains the phenomenon that the environmental trigger resembles a component of the body sufficiently that an immune attack is directed against the cross-reacting body component.

ii.          one example is the relationship between the M protein of Streptococcus pyogenes and the myosin of cardiac muscle.

iii.            antibodies against certain M proteins cross-react with cardiac myosin, leading to rheumatic fever.

2.            Mechanisms for Autoimmunity

a.         Release of sequestered antigens:

i.          certain tissues, e.g., sperm, central nervous system, and the lens and uveal tract of the eye, are sequestered so that their antigens are not exposed to the immune system.

ii.          these are known as immunologically privileged sites.

iii.         when such antigens enter the circulation accidentally, e.g. after damage, they elicit both humoral and cellular responses, producing aspermatogenesis and encephalitis.

b.         Escape of Tolerance at the T cell level:

i.            unresponsiveness to a self antigen may be maintained by tolerance at the T cell level.

ii.          such tolerance may be terminated by cross-reactions, i.e., when the host responds to antigens that cross-react with tolerated self antigens.

iii.         in normal immune regulation, suppressor T cells may limit an immune response to self antigens.

iv.         if suppressor T cell functions decrease, antibodies to self antigens, e.g. an antibody to normal IgG, may be formed.

v.         such antibody (IgM or IgG) occurs in rheumatoid arthritis, in which antigen-antibody complexes form in joints.

c.         B cells in an anergic state can be stimulated to produce antibody by activation of helper T cells which produce:

i.            interleukins

ii.            costimulatory proteins such as CD28.

3.         Tissue damage in Autoimmune diseases

a.         Cause of Tissue injury:

i.            autoimmune diseases are mediated by sustained adaptive immune responses specific for self antigens.

ii.          tissue injury results because the antigen is an intrinsic component of the body and consequently the effector mechanisms of the immune system are directed at self tissues.

iii.            because the adaptive immune response is incapable of removing the offending autoantigens from the body, the immune response persists and there is a constant supply of new autoantigen, which amplifies the response.

b.         Lysis by complement:

i.          IgG or IgM responses to autoantigens located to cell surfaces or extracellular matrix cause the tissue damage.

ii.          in autoimmune hemolytic anemia, antibodies to self antigens on red blood cells trigger red blood cell destruction.

iv.         this occurs through lysis by complement and accelerated clearance of red cells from circulation through interaction with Fc receptors on cell of the reticuloendothelial system.

v.         in autoimmune thrombocytopenic purpura, autoantibodies to the fibrinogen receptor on platelets cause thrombocytopenia.

c.            Stimulation of Inflammatory responses:

i.          the binding of IgG and IgM autoantibodies to cells in tissues causes inflammatory injury by different mechanisms.

ii.            traveling phagocytes bearing Fc and C3 receptors may bind and be activated by cells bearing autoantibodies and fixed complement fragments.

iii.            chemoattractants such as leukotriene B4 and the complement component C5a are generated following complement activation in tissues that specifically attract and activate inflammatory leukocytes.

iv.         tissue injury may then result from the products of activated leukocytes and by antibody-dependent cellular cytotoxicity mediated by natural killer cells.

d.         Binding to receptor:

i.          this occurs when the autoantibody binds to a cell-surface receptor.

ii.            antibody binding to a receptor can either stimulate the receptor or block its stimulation by its natural ligand.

iii.         in Graves’ disease, autoantibody to the thyroid-stimulating hormone receptor on thyroid cells stimulates the production of excessive thyroid hormone.

iv.         in myasthenia gravis, autoantibodies to the acetylcholine receptor found at neuromuscular junctions drive the internalization and intracellular degradation of acetylcholine receptors.

e.            Antibodies to extracellular antigens:

i.            antibody responses to extracellular matrix molecules are infrequent but can be very damaging when they occur.

ii.          in Goodpasture’s syndrome, antibodies are formed to basement membrane collagen and these bind to the basement membranes of renal glomeruli, causing a fatal disease if untreated.

iii.            inflammatory injury to the glomerulus in this disease is mediated by complement activation and neutrophil influx.

iv.         in systemic lupus erythematosus (SLE), chronic IgG antibody production is directed at self antigens present in all nucleated cells, affecting many organs.

f.          Immune complexes are produced whenever there is an antibody response to a soluble antigen.

g.         Failure to clear the immune complexes occurs:

i.            following injection of large amounts of antigen leading to the formation of large amounts of immune complexes that overwhelm the normal clearance mechanisms.

ii.          immune response is incapable of clearing infection as in bacterial endocarditis, the persistent release of bacterial antigens from the valve infection triggers a strong antibody response, causing widespread immune complex injury in the body.

iii.         in SLE, a wide range of autoantibodies is produced to common cellular components such as the nucleosome, splicesosome and ribonucleoprotein complex, so that large numbers of small immune complexes are produced continuously.

4.            Important Autoimmune diseases

5.            Treatment

a.         The basis for the treatment of autoimmune diseases is to reduce the patient’s immune response sufficiently to eliminate the symptoms.

b.            Corticosteroids, such as prednisone, are the mainstay of treatment, to which antimetabolites, such as azathioprine and methotrexate, can be added.

c.         The latter are nucleoside analogues that inhibit DNA synthesis in the immune cells.

d.            Immunosuppressive therapy must be given cautiously because of the risk of opportunistic infections.