Mechanisms controlling autoimmunity

Because pathogenic autoimmunity is the exception rather than the rule, mechanisms must exist which normally prevent the development of autoimmune disease. In this respect the immune system is able to distinguish self from nonself and, ultimately, becomes 'tolerant' towards most self antigens. However, as alluded to above, many of the tolerance mechanisms controlling autoimmunity may be less concerned with repression of all self reactive lymphocytes than with preventing the development of pathogenic T cells and autoantibodies. Indeed, there is evidence from studies in transgenic mice to suggest that, in situations in which high-affinity antiself B cells are anergized, low-affinity antiself B cells escape this tolerization process.

The danger model of immune responses proposes that, rather than discriminating self from nonself, the immune system primarily distinguishes between harmless and harmful. In this scenario, self would normally be considered harmless and would fail to trigger a response. However, a response to harmful situations would occur due to upregulation of costimulatory molecules on antigen-presenting dendritic cells following signals induced by microbial antigens, cell stress or necrotic cell death.

Although evidence for several different tolerance mechanisms exists, the relative role of each of these in controlling autoimmunity remains to be firmly established. For a long time it was thought that many self antigens were sequestered in 'privileged sites' and therefore shielded from the immune system. The advent of sensitive assay techniques allowed the detection of, for example, low levels of circulating thyroglobulin (an autoantigen previously thought to be completely sequestered within the thyroid). Nevertheless, it is believed that for a few self molecules, such as lens proteins, sperm and brain antigens, this concept largely holds true.

The 'forbidden clone' theory put forward by Burnet in the 1950s suggested that deletion of self reactive clones led to self tolerance. Although it is now clear that this is not a universal mechanism for avoiding autoimmunity, clonal deletion is known to occur for some self antigens. Mice bearing, for example, particular Mis antigens eliminate any T cells which are expressing T cell receptor (} chain variable region genes associated with recognition of these antigens. In situations where self reactive cells are not deleted they either become anergic or are actively suppressed by regulatory mechanisms which have evolved in order to restrain harmful autoimmunity. T cell-mediated suppression maintains control over both B lymphocyte and effector T lymphocyte responses, so that any defect in antigen-specific or idiotype-specific suppression might allow autoimmune responses to occur. Conversely, increases in helper T cell activity may allow normally quiescent self reactive lymphocytes to mount an autoimmune attack. In instances in which potentially autoreactive B lymphocytes normally remain inactive due to tolerance of the relative helper T cells, the provision of new carrier determinants can provide a 'bypass' mechanism allowing T cell help for autoantibody production. It has been shown that tolerance can be broken experimentally using chemically modified or hapten-conjugated protein antigens and it has been suggested, for example, that the Coombs' positivity of some patients treated with methyl dopa may be due to the drug complexing with erythrocyte antigens, thereby providing carrier determinants which will stimulate cognate T cell help. In other cases, T cell epitopes on the autoantigen may not be effectively presented during tolerance induction in the thymus and so potentially autoreactive T cell clones escape deletion. Only if higher levels of these normally 'cryptic' epitopes later become effectively presented in the periphery, due perhaps to altered processing or presentation of the self antigen, will autoimmune reactivity manifest itself. Furthermore, once initiated, the autoimmune response may spread to other epitopes on the same or different antigens, a process that could be fueled by the local production of inflammatory cytokines which might further lead to upregulation of cell surface molecules involved in antigen presentation and cellular activation.

Idiotypic networks may be important in the control of immune responses to autoantigen; defects in this regulatory network could provide a pathway by which self reactivity can arise. For example, antiidiotypes to DNA-specific autoantibodies have been described in the sera of patients with inactive systemic lupus erythematosus (SLE) which were absent in those with active disease, suggesting that the presence of these antibodies may influence the course of the disease. In the anti-insulin response seen in patients with insulin-dependent diabetes mellitus (IDDM), idiotypic determinants have been reported to be cyclically expressed even though the total amount of anti-insulin remained constant, again suggesting that idiotypic interactions are involved in regulating this response. In some instances pathogenic autoantibodies may be internal image anti-idiotypes which are directed against antiviral antibody and bind to the same cell surface molecule that is used as a receptor by the virus.

Major histocompatibility complex (MHC) class II gene products are normally expressed only on 'professional' antigen-presenting cells (APCs) but they are sometimes also aberrantly expressed on a variety of cell types during autoimmune disease. It has been shown that such cells themselves are then also able to present antigen. Aberrant expression of MHC class II may be the result of cytokine secretion by cells already involved in an ongoing inflammatory response, and might provide a mechanism for perpetuation of the disease.

Regardless of the cell type expressing MHC class II it is known that autoimmune disease is influenced by MHC (particularly class II) haplotype. As the majority of autoantigens are likely to be T dependent, the ability of self peptides to associate with self-MHC at a concentration necessary for T cell activation will be central to the induction of an immune response.

Individuals bearing HLA-DR4 are nearly six times more likely to develop rheumatoid arthritis (RA) than those lacking this haplotype. For some autoimmune diseases there appears to be a synergistic effect between MHC genes; individuals who bear HLA-DR3 or HLA-DR4 have an increased risk (of between 2 and 7) of developing IDDM but for someone bearing both these haplotypes the relative risk increases to 14. In IDDM the particular residue at position 57 of the DQ3 chain appears, in concert with other residues, to be important in determining disease susceptibility in some caucasian populations.

Molecular mimicry of self antigen by invading organisms can lead to a breakdown of self tolerance as seen in the cross-reactions between streptococcal M protein and cardiac myosin in rheumatic fever and between both brain and heart tissue and Trypanosoma cruzi in Chagas disease. Many other examples of autoantibodies cross-reacting with pathogens have been described. Cross-reactivity between self and foreign antigens is also seen for T lymphocytes as demonstrated by the existence of T cell clones specific for determinants on a mycobacterial hsp65 and a human hsp60 which share 48% amino acid sequence homology. Polyclonal lymphocyte activation occurs in response to some infections, for example with Epstein-Barr virus, and has been proposed as a possible mechanism involved in the development of autoimmunity. However, although some of the clones activated may be specific for self antigen these will usually be short lived and produce IgM antibodies of low affinity. Experiments involving neonatal thyroidectomy of autoimmune obese strain chickens demonstrated that the presence of autoantigen is required for the development of thyro-globulin autoantibodies and therefore in this instance these antibodies are not induced by nonspecific activation of B cells.

Somatic mutation of antibody variable region genes is a further mechanism by which autoantibodies may arise. It is known that a single, naturally occurring, point mutation can change an antibody with specificity for phosphorylcholine into an antibody that recognizes double-stranded DNA, protamine and cardiolipin. This antibody has therefore lost the ability to bind to bacterial antigen but acquired binding for self antigen. Despite the fact that autoantibodies are normally restricted in their epitopic specificity (for example to two or three paired determinants on human thyroglobulin) they are usually polyclonal. It is therefore unlikely that somatic mutation on its own provides an explanation for autoimmune disease, although triggering of idiotype-specific T helper cells might allow a single clone to initiate a polyclonal response via network interactions. It is generally accepted that the development of most autoimmune disease is multifactorial in nature. Some of the animal models suggest a role for ADCC or NK cells. Other factors that may influence the initiation and development of the disease are defects in immune regulation (for example TH 1/T, .2

Cell Bypass Theory

Figure 1 The multifactorial nature of autoimmunity. •, Autoanti-gen; APC, antigen-presenting cell ('professional' or aberrant class II expression); Th, helper T cell (antigen- or idiotype-spe-cific, carrier-specific for T cell bypass); Te, effector T cell (for example cytotoxic T cell); Ts, suppressor T cell; Bld, autoanti-body-secreting Id" B cell; B «idi anti-idiotypic B cell.

Figure 1 The multifactorial nature of autoimmunity. •, Autoanti-gen; APC, antigen-presenting cell ('professional' or aberrant class II expression); Th, helper T cell (antigen- or idiotype-spe-cific, carrier-specific for T cell bypass); Te, effector T cell (for example cytotoxic T cell); Ts, suppressor T cell; Bld, autoanti-body-secreting Id" B cell; B «idi anti-idiotypic B cell.

imbalance) and in the target antigen, sex hormones (autoimmunity is more common in females than in males), diet, and the time and nature of exposure to infectious agents. Some of the above concepts are drawn together in Figure 1.

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