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The molecular basis of susceptibility to rheumatoid arthritis: The conformational equivalence hypothesis

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Summary

This is an interpretive review of recent immunologic and molecular biologic data concerning the molecular basis of susceptibility to rheumatoid arthritis. The central point of view was taken that the :major histocompatibility complex (MHC) class II molecules encoding disease susceptibility function in an immune recognition event involving an antigen “X” that currently eludes characterization. The problem of understanding the meaning of the association of susceptibility with diverse MHC alleles such as DR4 (Dw4 and Dw14), DR1, and DRw10 is approached by detailed biochemical analysis that led to the identification of common stretches of amino acid sequence, presumably encoding conformationally equivalent structures. Non-classic MHC polymorphisms related to disease susceptibility but not associated with particular alleles such as identified by Ab109d6 proved especially valuable in suggesting new directions for attempting to understand the significance of these associations. Consideration is given to the possibility that a family of either slightly different or identical conformations encoded in eithercis ortrans cumulatively confer the liability to develop rheumatoid arthritis, and implying a highly non-classic mode of inheritance. The, available data do not permit a distinction between the possibilities that an antigen “X” was being presented to T cells or whether the distinctive conformations of the MHC class 11 molecule serve the same role as antigen “X” but are directly recognized by T cells. However, with additional data, some limited insight should be able to be inferred about the nature of an antigen “X” that specifically binds to the MHC conformation with a complementary interaction. It seems reasonable to consider the pathogenesis of rheumatoid arthritis as a typical immune response resulting from a simple immune recognition event of a single antigenic: molecule.

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References

  1. Andrews DW, Bono MR, Strominger JL (1982) A homozygous human cell line contains three subsets of HLA-DR-like antigens distinguishable by amino acid sequencing. Biochemistry 21: 6625

    PubMed  Google Scholar 

  2. Babbitt BP, Matsueda G, Haber E, Unanue ER, Allen PM (1986) Antigenic competition at the level of peptide-la binding. Proc Natl Acad Sci USA 83: 4509

    PubMed  Google Scholar 

  3. Bell JI, Denny DW Jr, McDevitt HO (1985) Structure and polymorphism of murine and human class II major histocompatibility antigens. Immunol Rev 84: 51

    PubMed  Google Scholar 

  4. Berzofsky JA, Cornette J, Margalit H, Berkower, I, Cease K, DeLisi C (1986) Molecular features of class II MHC-restricted T cell recognition of protein and peptide antigens: the importance of amphipathic structures. Curr Top Microbiol Immunol 130: 13

    PubMed  Google Scholar 

  5. Bjorkman PJ, Saper MA, Samraoui B, Bennett WS, Strominger JL, Wiley DC (1987) Structure of the human class I histocompatibility antigen, HLA-A2. Nature 329: 506

    PubMed  Google Scholar 

  6. Bodmer WF (1978) Evolution and function of the HLA system. Br Med Bull 34: 309

    PubMed  Google Scholar 

  7. Buus S, Colon S, Smith C, Freed JH, Miles JC, Gray HM (1986) Interaction between a “processed” ovalbumin peptide and la molecules. Proc Nail Acad Sci USA 83: 3968

    Google Scholar 

  8. Buus S, Sette A, Colon SM, Miles C, Grey HM (1987) The relation between major histocompatibility complex (MHC) restriction and the capacity of Ia to bind immunogenic peptides. Science 235: 1353

    PubMed  Google Scholar 

  9. Cease KB, Berkower I, York-Jolley J, Berzofsky JA (1986) T cell clones specific an amphipathic alpha-helical region of sperm whale myoglobin show differing fine specificities for synthetic peptides. A multiview/single structure interpretation of immunodominance. J Exp Med 164: 1779

    PubMed  Google Scholar 

  10. Cease KB, Buckenmeyer G, Berkower I, York-Jolley J, Berzofsky JA (1986) Immunologically relevant peptide antigen exists on the presenting cell in a manner accessible to macromolecules in solution. J Exp Med 164: 1440

    PubMed  Google Scholar 

  11. Christadoss P. Lindstrom JM, Melvold RW, Talal N (1985) Mutation at IA beta chain prevents experimental autoimmune myasthenia gravis. Immunogenetics 21: 33

    PubMed  Google Scholar 

  12. Dunham I, Sargent CA, Trowsdale J, Campbell RD (1987) Molecular mapping of the human major histocompatibility complex by pulsed-field gel electrophoresis. Proc Natl Acad Sci USA 84: 7237

    PubMed  Google Scholar 

  13. Gibofsky A, Winchester R, Hansen J, Patarroyo M, Dupont B, Paget S, Lahita R, Halper J, Fotino M, Yunis E, Kunkel HG (1978) Contrasting patterns of newer histocompatibility determinants in patients with rheumatoid arthritis and systemic lupus erythematosus. Arthritis Rheum, 21: 8123

    Google Scholar 

  14. Gibofsky A, Winchester RJ, Patarroyo M, Fotino M, Kunkel HG (1978) Disease associations of the la-like human alloantigens. Contrasting patterns in rheumatoid arthritis and systemic lupus erythematosus. J Exp Med 148: 1728

    PubMed  Google Scholar 

  15. Goronzy J, Weyand CM, Fathman CG (1986) Shared T cell recognition sites on human histocompatibility leukocyte antigen class II molecules of patients with seropositive rheumatoid arthritis. J Clin Invest 77: 1042

    PubMed  Google Scholar 

  16. Gorski J, Mach B (1986) Polymorphism of human la antigens: gene conversion between two DRß loci results in a new HLA-D/DR specificity. Nature 322: 67

    PubMed  Google Scholar 

  17. Gorski J, Tosi R, Strubin M, Rabourdin-Combe L, Mach B (1985) Serological and immunochemical analysis of the products of a single HLA DR-α and DR-β chain gene expressed in a mouse cell line after DNA-mediated cotransformation reveals that theβ chain carries a known supertypic specificity. J Exp Med 162: 105

    PubMed  Google Scholar 

  18. Gregersen PK, Shen M, Song QL, Merryman P, Degar S, Seki T, Maccari J, Goldberg D, Murphy H, Schwenzer J, Wang CY, Winchester RJ, Nepom GT, Silver J (1986) Molecular diversity of HLA-DR4 haplotypes. Proc Nail Acad Sci USA 83: 2642

    Google Scholar 

  19. Gregersen PK, Silver J, Winchester RJ (1987) The shared epitope hypothesis-an approach to understanding the molecular genetics of rheumatoid arthritis susceptibility. Arthritis Rheum 30: 1205

    Google Scholar 

  20. Groner JP, Watson AJ, Bach FH (1983) Dw/LD-related molecular polymorphism of DRAβ-chains. J Exp Med 157: 1687

    PubMed  Google Scholar 

  21. Harvey J, Lotze M, Arnett FC, Billingsley LM, Harvey E, Hsu SH, Sutton JD, Zizic TM, Stevens MB (1983) Rheumatoid arthritis in a Chippewa band: II. Field study with clinical serologic and HLA D correlations. J Rheumatol 10: 28

    PubMed  Google Scholar 

  22. Hochman PS, Huber BT (1984) A class II gene conversion event defines an antigen specific Ir gene epitope. J Exp Med 160: 1925

    PubMed  Google Scholar 

  23. Kappes D, Strominger JL (1988) Human class II major histocompatibility complex genes and proteins. In: Richardson CC (ed), Annual Review of Biochemistry, vol 57. Annual Reviews Inc. Palo Alto, pp 991–102a.

    Google Scholar 

  24. Karr RW, Rodey GE, Lee T, Schwartz BD (1980) Association of HLA-DRW4 with rheumatoid arthritis in black and white patients. Arthritis Rheum 23: 1241

    PubMed  Google Scholar 

  25. Khan MA, Kushener I, Ballou SP, Braun WF (1979) Familial rheumatoid arthritis and HLA-DRw4. Lancet I: 921

    Google Scholar 

  26. Knudsen PJ, McLean J, Strominger JL (1987) Analysis of the DRβ chains from two DRw6 cell lines (WT46 and WT52): recombination in vivo may have generated new haplotypes. Immunogenetics 25: 209

    PubMed  Google Scholar 

  27. Kornman AJ, Boss JM, Spies T, Sorrentino R, Okada K, Strominger JL (1985) Genetic complexity and expression of human class II histocompatibility antigens. Immunol Rev 85: 45

    PubMed  Google Scholar 

  28. Larhammar D, Servenius B, Rask L, Peterson PA (1985) Characterization of an HLA DRβ pseudogene. Proc Natl Acad Sci USA 82: 1475

    PubMed  Google Scholar 

  29. Lee JS, Trowsdale J, Travers PJ, Carey J, Grosveld F, Jenkins J, Bodmer WF (1982) Sequence of an HLA-DR α-chain cDNA clone and intron-exon organization of the corresponding gene. Nature 299: 750

    PubMed  Google Scholar 

  30. Lee SH, Gregersen PK, Shen HH, Nuñez-Roldan A, Silver J, Winchester RJ (1984) Strong association of rheumatoid arthritis with the presence of a polymorphic la epitope defined by a monoclonal antibody: comparison with the allodeterminant DR4. Rheumatol Int [Suppl] 4: 17

    Google Scholar 

  31. Legrand L, Lathrop GM, Marcelli BA, Dryll A, Bardin T, DeBeyre N, Poirier JC, Schmid M, Ryckewaert A, Dausset J (1984) HLA DR genotype risks in seropositive rheumatoid arthritis. Am J Hum Genet 36: 690

    PubMed  Google Scholar 

  32. Lindstrom J (1985) Immunobiology of myasthenia gravis, experimental autoimmune myasthenia gravis, and Lambert-Eaton syndrome. Annu Rev Immunol 3: 109

    PubMed  Google Scholar 

  33. Maeda, H, Juji T, Mitsui H, Sonozaki H, Okitsu K (1981) HLA DR4 and rheumatoid arthritis in Japanese people. Ann Rheum Dis 40: 299

    PubMed  Google Scholar 

  34. Matsuyama T, Schwenzer J, Silver J, Winchester R (1986) Structural relationships between the DRβ 1, and DRβ 2 subunits in DR4, 7 and w9 haplotypes and the DRw53(MT3) specificity. J Immunol 137: 934

    PubMed  Google Scholar 

  35. Matsuyama T, Winchester R, Lee S, Shookster L, Nuñez-Roldan A (1988) Identification of the DRw10 DRβ 1 chain allele as encoding a polymorphic class II MHC epitope otherwise restricted to DRβ 2 molecules of the DRw53 type. J Immunol 140: 537

    PubMed  Google Scholar 

  36. Mengle-Gaw L, Connor S, McDevitt HO, Fathman CG (1984) Gene conversion between murine class II major histocompatibility complex loci. Functional and molecular evidence from the BM12 mutant. J Exp Med 160: 1184

    PubMed  Google Scholar 

  37. Merryman P, Hayes R, Schwenzer J, Lee S, Matsuyama T, Gregersen P, Nuñez-Roldan A, Silver J, Winchester R (1985) Characterization of an unusual DRl haplotype found in rheumatoid arthritis. American Society for Histocompatibility and Immunogenetics - 12th Annual Meeting Abstracts p. 140

  38. Merryman P, Gregersen PK, Lee S, Silver J, Nuñez-Roldan A, Crapper R, Winchester R (1988) Nucleotide sequence of a DRw10β chain cDNA clone; identity of the third D region with that of the DRw53 allele of theβ 2 locus and as the probable site encoding a polymorphic MHC class II epitope. J Immunol 140: 2447

    PubMed  Google Scholar 

  39. Meunier HF, Carson S, Bodmer WF, Trowsdale J (1986) An isolatedβ 1 exon next to the DR α gene in the HLA-D region. Immunogenetics 23: 172

    PubMed  Google Scholar 

  40. Nepom BS, Nepom GT, Nickelson E, Antonelli P, Hansen JA (1983) Electrophoretic analysis of human HLA-DR antigens from HLA-DR homozygous cell lines. Correlation betweenβ chain diversity and HLA-D. Proc Natl Acad Sci USA 80: 6962

    PubMed  Google Scholar 

  41. Nepom GT, Seyfried CE, Holbeck SL, Wilske KR, Nepom BS (1987) Identification of HLADw14 genes in DR4+ rheumatoid arthritis. Lancet 1: 1002

    PubMed  Google Scholar 

  42. Perrault C, Cinderella (freely translated)

  43. Reinsmoen NL, Bach FH (1982) Five HLA-D clusters associated with HLA-DR4. Hum Immunol 4: 249

    PubMed  Google Scholar 

  44. Rollini P, Mach B, Gorski J (1985) Linkage map of three HLA-DR beta-chain genes: evidence for a recent duplication event. Proc Natl Acad Sci USA 82: 7197

    PubMed  Google Scholar 

  45. Sacha JA, Kirwan JR (1986) Multiple HLA associations and disease susceptibility. Dis Markers 4: 13

    PubMed  Google Scholar 

  46. Schamboeck A, Korman AJ, Kamb A, Strominger JL (1983) Organization of the transcriptional unit of a human class II histocompatibility antigen: HLA-DR heavy chain. Nucleic Acids Res 11: 8663

    PubMed  Google Scholar 

  47. Scherak O, Smolen JS, Mayr WR (1983) HLA DR antigens and disease patterns of rheumatoid arthritis. Rheumatol Int 3: 113

    PubMed  Google Scholar 

  48. Schiff B, Mizrachi Y, Orgad S, Yaron M, Gazit E (1982) Association of HLA-Aw31 and HLADRl with adult rheumatoid arthritis. Ann Rheum Dis 41: 403

    PubMed  Google Scholar 

  49. Shaw S, Kavathas P, Pollack MS, Charmot D, Mawas C, (1981) Family studies define a new histocompatibility locus, SB, between HLA-DR and GLO. Nature 293: 745

    PubMed  Google Scholar 

  50. Shookster, L, Matsuyama T, Burmester G, Winchester RJ (1987) Monoclonal antibody 1a3 recognizes a monomorphic epitope unique to DQ molecules. Hum Immunol 20: 59

    PubMed  Google Scholar 

  51. Stastny P (1976) Mixed lymphocyte cultures in rheumatoid arthritis. J Clin Invest 57: 1148

    PubMed  Google Scholar 

  52. Stastny P (1978) Association of the B-cell alloantigen DRw4 with rheumatoid arthritis. N Engl J Med 298: 869

    PubMed  Google Scholar 

  53. Stastny P (1980) Rheumatoid arthritis. In: Terasaki PI (ed) Histocompatibility testing. UCLA Tissue Typing Laboratory, Los Angeles, pp 681–686

    Google Scholar 

  54. Unanue ER, Allen PM (1987) The basis for the immunoregulatory role of macrophages and other accessory cells. Science 236: 554

    Google Scholar 

  55. Waters FJ, Winchester RJ, Nagase F, Thorbecke CJ, Bona CA (1984) Antigen presentation by murine and human cells to a murine T cell hybridoma: demonstration of a restriction element associated with an MHC class II determinant(s) shared by both species. Proc Nail Acad Sci USA 81: 7559

    Google Scholar 

  56. Winchester RJ (1977) B-lymphocyte allo-antigens, cellular expression, and disease significance with special reference to rheumatoid arthritis. Arthritis Rheum 20: 159s

    Google Scholar 

  57. Winchester RJ (1981) Genetic aspects of rheumatoid arthritis. Springer Semin Immunopathol 4: 89

    PubMed  Google Scholar 

  58. Winchester RJ (1988) The major histocompatibility complex. In: Kelley WN, Harris ED, Ruddy S, Sledge CB (eds) Textbook of rheumatology, 3rd edn. Saunders, Philadelphia (in press)

    Google Scholar 

  59. Woodrow JC, Nichol FE, Zaviropoulos G (1981) DR antigens and rheumatoid arthritis: a study of two populations. Br Med J 283: 1287

    Google Scholar 

  60. Zoschke D, Segall M (1986) Dw subtypes of DR4 in rheumatoid arthritis: evidence for a preferential association with Dw4. Hum Immunol 15: 118

    PubMed  Google Scholar 

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  1. Hospital for Joint Diseases, New York University Medical School, 301 East 17th Street, 10003, New York, NY, USA

    Robert J. Winchester & Peter K. Gregersen

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  1. Robert J. Winchester
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  2. Peter K. Gregersen
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Winchester, R.J., Gregersen, P.K. The molecular basis of susceptibility to rheumatoid arthritis: The conformational equivalence hypothesis. Springer Semin Immunopathol 10, 119–139 (1988). https://doi.org/10.1007/BF01857219

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