Breakdown of autotolerance

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The ability to tolerate autologous antigens, a central feature of the adaptive immune system, is guaranteed in redundant ways at the level of both the B and T lymphocyte system. It is thought to be the result of negative selection within the central lymphoid organs, i.e. bone marrow and thymus, where sensitive stages of developing B (slgM"1 slgD ") or T (CD44 CD 8' ) cell clones are eliminated by apoptosis due to high-affinity binding to autologous antigens. Autoreactive cell clones that escape these central selection processes for whatever reason are effectively controlled in their reactivity in the periphery, either passively by virtue of insufficient costimu-latory signals or by active suppressive immunoregulation. These peripheral mechanisms are not specific for autoantigens, but are identical to those that induce tolerance against any given foreign antigen. With regard to autoimmunity the interest has focused primarily on T lymphocytes, because of the central regulatory role of T helper cells in the immune response against protein antigens, and in view of the well-known association of autoimmune diseases with major histocompatibility complex (MHC) alleles differing in effectivity of antigen presentation to T cells.

Defective differentiation

According to the aforementioned concepts a breakdown in autotolerance can occur due to failures in thymic selection, and any factors that influence the survival of thymic lymphocytes could principally be expected to result in shifts in the peripheral T cell repertoire. As MHC molecules play an important role in the presentation of thymic autoantigens, changes in thymic selection may be one mechanism by which genes of the MHC influence autoimmune diseases. Nevertheless, it has to be stated that experimental data directly proving the occurrence of autoimmune reactions as a consequence of a disturbed intrathymic differentiation are lacking as yet.

Based on the finding that autoreactive lymphocytes of patients and experimental animals with organ-specific autoimmune diseases exhibited a limited number of V genes, it was debated whether autoimmunity may be the result of an abnormal immunoglobulin (Ig) or T cell receptor (TCR) repertoire. However, restriction fragment length polymorphism (RFLP) analysis performed in humans with autoimmune diseases did not indicate associations to certain Ig or TCR genes, and no consistent differences were detected in germline Ig genes of autoimmune mouse strains.

Peripheral loss of autotolerance

As to peripheral mechanisms, the loss of anergy against autoantigens may be the result of abnormal activation of T cells by antigen-presenting cells (APCs), such as dendritic cells, macrophages and B cells, that increase the expression of costimulatory surface molecules as a result of irritation, e.g. in the course of infections or local inflammatory reactions. In accordance with this notion is the established fact that the induction of experimental autoimmune diseases in animals requires immunization with autoantigens together with strong adjuvants that lead to activation of APCs. Also, nonprofessional APCs, such as epithelial cells, may lead to local activation of autoreactive T cells by virtue of inappropriate expression of immunostimulatory molecules, such as MHC class II determinants. Another strong indication for a crucial role of T cell activation comes from results proving that enhanced levels of interleu-kin-2 (IL-2) are able to abrogate a state of anergy against tissue autoantigens. Further peripheral mechanisms, not related to T cell activation, may be a resistance of lymphocytes to apoptosis as described in the MLR-Ipr/lpr mouse with systemic lupus erythematosus (SLE) symptoms and a defect in the expression of the fas apoptosis gene. However, no such association has been found in human SLE patients.

Peripheral tolerization of B lymphocytes results from antigenic stimulation without proper T cell help. Thus, a stimulus from autoreactive T helper cell clones may end the state of B cell autoanergy. Alternatively, certain foreign antigens may exhibit shared epitopes with autoantigens, and T helper cells specific for these shared epitopes may drive autotolerant B cells into activation.

Immunological cross-reactions between foreign microbial antigens and autoantigens are well known to be able to elicit humoral or cellular autoimmune responses, the classical example being rheumatic fever due to a 'normal' immune response against streptococcal antigens that is cross-reactive with myocardial protein. More recently, mycobacterial heat shock protein (hsp65) has gained interest as an antigen of possible relevance to pathogenic autoimmune responses in several diseases, including atherosclerosis.

Polyclonal, antigen-independent lymphocyte activation has been implicated in the activation of autoreactive lymphocytes and elicitation of autoimmune responses. Injection of mice with bacterial lipopolysaccharide (LPS), which is a polyclonal B cell activator in mice, has been shown to lead to the production of autoantibodies of various specificities. Even though these antibodies, due to the lack of T cell help, are of low affinity and nonpathogenic, the polyclonal B cell activation by 'LPS-like' bacterial substances may be at least one of the reasons for the close association of autoimmune and infectious diseases. Similarly the binding of bacterial superanti-gens to certain Vp chains of the T cell receptor has been discussed as a possible mechanism of autoimmunity at the T cell level. Finally, autoimmune phenomena are observed in the course of graft-ver-sus-host reactions, supposedly due to polyclonal B cell activation induced by alloactivated donor T helper cells.

A disturbed balance in helper and suppressor influences exerted by T regulator cells has long been implicated in the pathogenesis of autoimmune diseases. While the classical T helper/suppressor cell model was abandoned several years ago, it is now thought that the balance between T helper 1 (TH1) and T helper2 (TH2) cells is relevant to the maintenance of autotolerance, whereby TH2 cells under normal conditions are thought to keep autoreactive effector TH1 cells in line. Accordingly, quantitative or functional abnormalities in this balance may allow autoimmune reactions to occur. Investigations of joint lesions in rheumatoid arthritis (RA) patients seem to support this concept, as cloning studies identified the vast majority of infiltrating T cells as belonging to the TH1 subtype, whereas Tn2 clones were only rarely found. In contrast, synovial specimens from more benign, nondestructive types of arthritis were found to contain high levels of IL-4 mRNA. From this it was concluded that the local presence of functional TH2 cells may be critical for the self-limitation of the autoimmune process in the affected joints.

Besides their central roles in the effector phase of autoimmune processes (see below) cytokines are certainly critically involved in systemic and local im-munoregulation and thereby modulate the clinical outcome of an autoimmune disease. Furthermore, the above mentioned data on IL-2 suggest that they may also take part in the breakdown of self-tolerance. Recently, enhanced systemic levels of inflammatory cytokines (IL-10, IL-6, tumor necrosis factor a. (TNFa)) and soluble cytokine receptors (sIL-2R, sTNFR) were reported to significantly correlate with the clinical activity of RA in children, whereby the different clinical subtypes displayed different patterns.

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