Suggestions for Future Research Directions Resulting from This Workshop BENJAMIN D. SCHWARTZ, M.D., Ph.D. .st Louis, Missouri FRANK C. ARN~T-T, M.D. Houston, Texas MUHAMMAD ASIM KHAN, M.D. C/eve/and, O/M GERALD T. NEPOM, M.D., Ph.D. Seattle, khington PETER STASTNY, M.D. Da//as, Texas LAWRENCE E. SHULMAN, M.D., Ph.D. Bethesda, Mary/and

s everal directions for future research were sug- gested by the discussions of the concepts that

were presented at this workshop. l As molecular biology has been applied increasingly to the study of human leukocyte antigen (HLA), it has become clear that the number of HLA alleles is much larger than originally appreciated, and that differ- ences between alleles may be reflected in a change of only a single amino acid. However, this minimal varia- tion may be responsible for changing an allele from one that is neutral or protective of disease to one that can predispose to disease. New HLA alleles should continue to be sought, so that the actual HLA allele predisposing to each rheumatic disease can be deter- mined. l Epidemiologic studies have established that HLA disease associations vary among different ethnic groups. Comparison of the HLA molecules associated with a given disease in various ethnic groups, how- ever, has shown that these molecules, though distinct, share stretches of sequence of amino acids. Correla- tion of the position of these sequences with proposed HLA crystal structures suggests that these sequences interact with the T cell receptor, and thus constitute epitopes. The sharing of these epitopes by the differ- ent HLA molecules associated with a given disease suggests that epitopes, rather than entire HLA mole- cules, may be the elements predisposing to disease. Therefore, HLA alleles should continue to be se- quenced so that epitopes predisposing to rheumatic disease can be identified. l T cell receptors display remarkable diversity and recognize peptides in the context of HLA molecules. The data indicating HLA-disease predisposition also suggest that particular T cell receptor alleles will be

correlated with these diseases. At present, the study of T cell receptor-disease associations is limited by the lack of T cell receptor allele markers and the paucity of T cell receptor sequences. Accordingly, T cell re- ceptor alleles need to be identified so that T cell re- ceptor-disease associations may be sought. l The establishment of HLA and T cell receptor asso- ciations with disease has also been restricted because of the small numbers of patients with a given disease available for study by an individual investigator. A central data bank needs to be organized under the aus- pices of The National Institute of Arthritis and Mus- culoskeletal and Skin Diseases to which all investiga- tors studying the immunogenetics of rheumatic dis- eases could contribute their data. Significant associa- tions between HLA alleles, T cell receptor alleles, and rheumatic disease could then emerge rapidly. l It is widely presumed that exogenous antigens act as triggers (in the context of particular HLA and T cell receptor molecules) to cause disease. Computer searches have suggested that certain amino acid se- quences are shared between microbial organisms and predisposing HLA molecules. Moreover, data have been obtained that imply that this homology may be important in the development of disease. The search for additional microbial organisms and other exoge- nous agents that are etiologic for the rheumatic dis- eases needs to be expanded. l The understanding of the development of HLA- associated diseases has been hampered by the paucity of animal models. Transgenic technology provides opportunities previously unavailable to develop such animal models. The development of such animal mod- els by transgenic and other methods needs to be vigor- ously pursued.

From the Howard Hughes Medical Institute Laboratories and Department of Medi- cine, Division of Rheumatology, Washington University School of Medicine, St. Louis, Missouri: Division of Rheumatoloav and Clinical Immunoaenetics and Deoartment of Internal Medicine, The UniversiF of Texas Medical S&o01 at Houston, Houston, Texas; Department of Medicine, Division of Rheumatology, Case Western Reserve University, Cleveland, Ohio; Immunology Research Program, Virginia Mason Research Center, Seattle, Washington: Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas; and National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, Maryland. Requests for reprints should be addressed to Dr. Benjamin D. Schwartz, Division of Rheumatology, Box 8045, Washington University School of Medicine, 4566 Scott Avenue, St. Louis, Missouri 63110.

December 23, 1988 The American Journal of Medicine Volume 85 (suppl 6A) 61