Breakdown of Tolerance and Autoimmunit

Our bodies essentially distinguish between self and non self determinants. A breakdown of self recognition mechanisms leads to the development of autoimmunity which in turn leads to the production of autoantibodies against self antigens and autoreactive T cells. It is known that not all autoantibodies are pathogenic and that only certain kinds of autoantibodies are capable of producing a lesion. To be pathogenic an antibody must have very particular physical and structural features (Schwartz et al 1989, Shoenfeld 1990). Apart from occurring in disease, natural autoantibodies have also been found to occur in the bloodstream of normal healthy individuals. These natural autoantibodies are mainly IgM molecules and they react with several autoantigens including actin, tubulin and albumin as well as single stranded (ss) DNA (Temynck and Avrameas 1986). As compared to natural antibodies, pathogenic disease specific autoantibodies are of IgG isotype (only IgG can enter tissue) and show high affinity to a particular antigen. However not all pathogenic antibodies are IgG. Cold agglutinins (CA) constitute a heterogenous group of autoantibodies, usually of the IgM class, that recognize the developmentally regulated i and 1 antigens

expressed on the membranes of cord and adult blood cells respectively. Monoclonal IgM paraproteins associated with B cell neoplasias often display pathogenic CA activity and cause agglutination and intravascular haemolysis (Williams et al 1968, Feizi et al 1979, Leoni et al 1991). In studies by Pascual et al (1992), they have demonstrated that the VH4-21 gene segment which encodes heavy chains expressing the 9G4 idiotype, is essential for CA activity.

Autoimmunity is considered to be an inherent property of the normal immune system whereas an autoimmune disease is the culmination of a pathological process. A variety of mechanisms may be responsible for initiating and/or perpetuating autoantibody development which are as follows.

Molecular mimicry - this term has been used variously to describe a sharing by a foreign and a self protein - identity or structural epitopes. Molecular mimicry may thus be instrumental in the breakdown of tolerance and induction of autoimmunity and development of autoantibodies. For instance, infection with Group A streptococcus in rheumatic fever can lead to inflammation of the joints as well as inflammation of the endocardium. Some of the anti-streptococcal response seen in this infection, especially in high responders, is seen to be directed against host cardiac antigens which happen to have areas of structure similar to those of the streptococcal M protein (Kraus et al 1989).

Tissue injury following mechanical trauma or infection may release antigens that have been previously hidden (such as the retinal antigen of the eye) from the immune system thus provoking anti-self responses. For example, autoimmune uveitis can be induced in mice following immunization with the retinal soluble

antigen (SAg), and the interphotoreceptor retinoid-binding protein (IRBP) (Caspi R et al 1990).

Abnormal polyclonal stimulation of natural autoantibody producing cells followed by somatic mutation, isotype switching and autoantigen driven selection may also lead to the development of autoantibodies. Polyclonal B cell activation may precede and predict the development of autoimmune disease. In studies by Klinman et al (1990) 109 autoimmune-prone (NZB X NZW)F1 X NZB backcross mice were hemi-splenectomized at 10 weeks and the number and antigenic specificity of their Ig-secreting B cells quantitated by ELISA spot assay. Of the 61 mice that had polyclonally increased numbers of Ig-secreting cells/spleen, 31 died by 6 months. In contrast, 0/48 backcross mice with normal numbers of Ig-secreting B cells at 10 weeks died over the same period (P less than 0.001), Polyclonally activated mice also developed proteinuria earlier and more frequently than littermates with normal numbers of Ig-secreting cells (P less than 0.001). As adults, backcross mice with proteinuria expressed repertoires skewed towards the production of anti-DNA antibodies. At 10 weeks these same mice expressed repertoires marked by polyclonal activation rather than preferential anti-DNA production. These findings indicate that autoimmune disease in SLE is accompanied by the autoantigen-driven production of autoantibodies but is preceded and predicted by polyclonal B cell activation.

Apoptosis represents a physiologic mechanism for elimination of potentially autoreactive lymphocytes during development. Excess cells after completion of an immune response are also eliminated by apoptosis. A dysregulation in apoptosis may lead to autoimmunity. Several autoantigens

recognized by autoantibodies produced in autoimmune disorders such as SLE are present in apoptotic blebs and are degraded by interleukin -1 Peon verting enzyme like proteases. Cleavage by these enzymes may define a class of autoantigens. Cleavage of these autoantigens may target these molecules for an autoimmune response by revealing immunocryptic fragments (Casiola-Rosen 1995). Fas (also known as Apo 1 and CD 95 ) is a cell surface receptor involved in apoptotic cell death. Mouse strains with mutations in the genes for Fas and Fas ligand (ie Ipr and gld respectively) produce autoantibodies similar to those found in SLF patients and also show lymphoproliferation (Watanabe-Fukunaga et al 1992, Takahashi et al 1994). Mutations in Fas have also been found to be associated with human lymphoproliferative syndrome and autoimmunity (Rieux-Laucat et al 1995).

The goal of the humoral immune response is to bind and process foreign antigen and immune complex (IC) formation is a part of this process. Immune complexes are normally removed effectively by the mononuclear phagocytic system (MPS) and abnormalities in the processing of IC may result in their persistence and deposition outside the MPS, causing inflammation and tissue damage. Abnormal IC clearance has been implicated in the pathogenesis of autoimmune diseases, such as SLF (Atkinson et al 1986). In studies by Davies et al (1992) the clearance of large soluble IC (comprising hepatitis B surface antigen (HBsAg)/anti-HBsAg) radiolabeled with ^^^I was examined in 12 normal subjects and 10 patients with SLF. IC localization was analyzed by static and dynamic gamma-scintigraphy. Initial IC clearance from blood was more rapid in patients than normals due to more rapid uptake in the liver. However, in the SLF

group, up to 12% of complexes were released from the liver after 30-50 min. Splenic uptake of immune complexes was reduced in the patients and there was reduced ability to retain IC in this organ. Plasma complement levels and erythrocyte complement receptor type 1 numbers were reduced in the patients, resulting in defective opsonization of IC and reduced red cell binding in vivo. These observations support the hypothesis that IC handling is abnormal in SLE. Other reasons for an autoinunune response may include defective immunoregulation as observed in acquired immune deficiency syndrome (AIDS).

T cells are alerted to the presence of foreign or self antigens when they are displayed on the surface of antigen presenting cells. Several cell types facilitate the antigen presenting process. These include mononuclear cells such as macrophages (found in tissues), monocytes (found in blood), B cells, follicular dendritic cells which are non phagocytic and are located in the germinal centres of the lymph nodes and langerhans cells which are found primarily in the skin. HLA class I and II molecules expressed by antigen presenting cells present antigen fragments to T cells leading to an immune response (Janeway 1997b). Cytokines produced by T helper cells have been implicated in the pathogenesis of autoimmune diseases (Romagnani 1994). Cytokines such as IL-4 may cause increased antigen presentation and activation of the immune system leading to autoimmunity. In studies by Falcone et al (2001), they showed that pancreatic expression of IL-4 activated self reactive T cells by increasing islet antigen presentation by macrophages and dendritic cells and triggered autoimmune diabetes in non obese diabetic mice (NOD).