Escape from =Horror Autotoxicus': Pathogenesis and Treatment of Autoimmune Disease Minireview (1995)

Lawrence Steinman Department of Neurology and Neurological Sciences Beckman Center for Molecular and Genetic Medicine Stanford University School of Medicine Stanford, California 94305-5429 At the beginning of the twentieth century, Ehrlich intro- duced the concept ofhorror autotoxicus. He argued that the immune system was prevented from mounting an at- tack against the tissues it was designed to protect. At mid- century, Burnet formulated his clonal selection theory, which assumed that self-reactive lymphocytes were elimi- nated. We now know that autoreactive T and B cells can be readily detected, even in healthy individuals. Potent regulatory mechanisms that keep these cells in check have been discovered. When these controls fail, autoim- mune disease ensues. Of adults in Europe and North America, 5% (more than two thirds of them women) suffer from autoimmune diseases. Fortunately, our understand- ing of the pathogenesis of these diseases is increasing rapidly, and elegant strategies for treatment are being tested in the clinic. The Natural Occurrence of Autoreactive T Cells: Passing through Thymic Selection Many, but not all, self-reactive T cells are eliminated by negative selection in the thymus. In the process of nega- tive selection, self-reactive T cells die when they encounter self-antigen in the thymus. However, autoreactive T cells that have escaped thymic selection are not exceptional (Pette et al,, 1990), In healthy individuals, self-tolerance is thus maintained in part through mechanisms acting out- side the thymus that keep these autoreactive lymphocytes under control. It was thought that self-reactive cells may escape negative selection because the self-antigen is not expressed in the thymus. However, there are two well- characterized circumstances in which self-antigens that are expressed in the thymus are recognized by T cells that migrate to the periphery. Myelin basic protein (MBP) and acetylcholine receptor (AChR) are present in the thy- mus during development of the immune system (Pribyl et al., 1993), and T cells with specificity for these antigens are detectable in the blood of normal laboratory animals and healthy humans. However, sometimes the mecha- nisms that keep these autoreactive T cells under control fail. Several factors can contribute to such failure, includ- ing the inheritance of certain genetic alleles and exposure to certain pathogens. Genes Conferring Susceptibility to Autoimmune Disease Susceptibility to several autoimmune diseases is linked to the major histocompatability compex (M HC) class II H LA genes. Perhaps the two clearest examples of HLA class II associations with disease are seen with insulin-dependent diabetes mellitus (IDDM) and pemphigus vulgaris (PV). In 1987 McDevitt, Todd, and Bell, as well as Ehrlich indepen- dently, observed that resistance to IDDM correlates with the presence of the amino acid aepartate at postition 57 of the HLA-DQ molecule. In contrast, HLA-DQ~ chains with serine, alanine, or valine at position 57 are associated with an increased risk of IDDM (Nepom and Ehrlich, 1991). In PV, a unique HLA-DQJ3 allele, differing from closely related alleles at position 57, was found exclusively in pa- tients with PV. The crystal structure of HLA class II illumi- nates the importance of residue 57, which is situated at one side of the HLA-binding groove. Only certain autoanti- gens bearing a specific characteristic net charge, appro- priate size, and hydrophilicity would be accommodated in the groove when particular amino acids are situated at position 57. Moreover, position 57 is aligned to interact with amino acids in the a chain. The influence of certain DQ~ and DQI~ sequences in combination promotes sus- ceptibility or resistance to IDDM and PV. Several genes outside the MHC influence develop- ment of autoimmune disease. Susceptibility to IDDM has been linked to at least seven distinct loci in humans (Da- vies et al., 1994), with MHC class II having the strongest influence. In NOD mice, which develop IDDM spontane- ously, susceptibility is associated with several genes, though MHC class II has the strongest linkage. One gene conferring susceptibility to IDDM, named bcg, determines resistance or susceptibility to infectious diseases, includ- ing Leishmania, Salmonella, and tuberculosis (Cornall et al., 1991). The interaction of disease susceptibility genes and environmental factors is critical in autoimmune disease. A Role for Microbes in the A utoimmune Response Microbial superantigens trigger clinical relapses in autoim- mune disease. In experimental autoimmune encephalo- myelitis (EAE), T cells expressing V~8 T cell receptors (TCRs) engage a fragment of MBP, leading to demyelin- ation and paralysis. The bacterial superantigen staphylo- coccal enterotoxin B activates VI38-expressing T cells. It had been assumed that antigens such as MBP were tected from the immune system by virtue of their predomi- nant expression in the central nervous system, which is separated in part from the immune system by the blood- brain barrier. However, T cells that are exposed to MBP in the thymus and that are then activated by exogenous factors (like microbial superantigen) traverse the blood- brain barrier and thus may encounter MBP at the site of disease, where they can induce clinical relapses. Micro- bial activation of autoreactive T cells may be a widespread phenomenon responsible for the relapsing-remitting na- ture of many autoimmune diseases. Marrack has pro- posed a mechanism for the pathogenesis of rheumatoid arthritis (RA) in which an unknown superantigen activates disease-mediating T cells and allows these activated cells to enter the synovial tissue, where they persist because of reactivation by autoantigens (Paliard et al., 1991). A superantigen associated with pancreatic islets may be in- volved in the pathogenesis of IDDM (Conrad et al., 1994). The significance of infectious pathogens in autoimmu- nity was demonstrated in two genetically engineered strains of mice. I nterleukin-2 (IL-2) knockout mice develop inflammatory bowel disease, resembling ulcerative colitis, though the inflammatory bowel disease is not seen in