• We are sorry, but NCBI web applications do not support your browser and may not function properly. More information
Logo of pnasPNASInfo for AuthorsSubscriptionsAboutThis Article
Proc Natl Acad Sci U S A. Dec 1989; 86(24): 10049–10053.
PMCID: PMC298641

HLA-DR4 subtype frequencies in rheumatoid arthritis indicate that DRB1 is the major susceptibility locus within the HLA class II region.


Susceptibility to rheumatoid arthritis (RA) may be due to the presence of shared functional epitopes common to the HLA-DR beta chains of several RA-associated haplotypes. We have obtained direct evidence for this hypothesis by using the polymerase chain reaction and sequencing the DRB1 and DQB1 genes from RA patients. A highly conserved epitope present on DR beta chains of DR4 and DR1 haplotypes was found in 83% of 149 patients with classical or definite RA but was found in only 46% of 100 control individuals (P less than 0.0001). Two Dw subtypes of DR4 (Dw4 and Dw14) were associated with disease susceptibility but two other subtypes (Dw10 and Dw13) were not. Sequence differences between these subtypes implicate those residues around the putative antigen binding site of the DR beta molecule in the pathogenesis of RA. These data provide a basis for understanding host susceptibility to RA at a molecular level.

Full text

Full text is available as a scanned copy of the original print version. Get a printable copy (PDF file) of the complete article (1.1M), or click on a page image below to browse page by page. Links to PubMed are also available for Selected References.

Images in this article

Click on the image to see a larger version.

Selected References

These references are in PubMed. This may not be the complete list of references from this article.
  • Schenning L, Larhammar D, Bill P, Wiman K, Jonsson AK, Rask L, Peterson PA. Both alpha and beta chains of HLA-DC class II histocompatibility antigens display extensive polymorphism in their amino-terminal domains. EMBO J. 1984 Feb;3(2):447–452. [PMC free article] [PubMed]
  • Benoist CO, Mathis DJ, Kanter MR, Williams VE, 2nd, McDevitt HO. Regions of allelic hypervariability in the murine A alpha immune response gene. Cell. 1983 Aug;34(1):169–177. [PubMed]
  • Bell JI, Denney D, Jr, Foster L, Belt T, Todd JA, McDevitt HO. Allelic variation in the DR subregion of the human major histocompatibility complex. Proc Natl Acad Sci U S A. 1987 Sep;84(17):6234–6238. [PMC free article] [PubMed]
  • Brown JH, Jardetzky T, Saper MA, Samraoui B, Bjorkman PJ, Wiley DC. A hypothetical model of the foreign antigen binding site of class II histocompatibility molecules. Nature. 1988 Apr 28;332(6167):845–850. [PubMed]
  • Gorski J, Mach B. Polymorphism of human Ia antigens: gene conversion between two DR beta loci results in a new HLA-D/DR specificity. Nature. 1986 Jul 3;322(6074):67–70. [PubMed]
  • Bell JI, Todd JA, McDevitt HO. The molecular basis of HLA-disease association. Adv Hum Genet. 1989;18:1–41. [PubMed]
  • Todd JA, Bell JI, McDevitt HO. HLA-DQ beta gene contributes to susceptibility and resistance to insulin-dependent diabetes mellitus. Nature. 1987 Oct 15;329(6140):599–604. [PubMed]
  • Horn GT, Bugawan TL, Long CM, Erlich HA. Allelic sequence variation of the HLA-DQ loci: relationship to serology and to insulin-dependent diabetes susceptibility. Proc Natl Acad Sci U S A. 1988 Aug;85(16):6012–6016. [PMC free article] [PubMed]
  • Gregersen PK, Silver J, Winchester RJ. The shared epitope hypothesis. An approach to understanding the molecular genetics of susceptibility to rheumatoid arthritis. Arthritis Rheum. 1987 Nov;30(11):1205–1213. [PubMed]
  • Todd JA, Acha-Orbea H, Bell JI, Chao N, Fronek Z, Jacob CO, McDermott M, Sinha AA, Timmerman L, Steinman L, et al. A molecular basis for MHC class II--associated autoimmunity. Science. 1988 May 20;240(4855):1003–1009. [PubMed]
  • Nepom GT, Byers P, Seyfried C, Healey LA, Wilske KR, Stage D, Nepom BS. HLA genes associated with rheumatoid arthritis. Identification of susceptibility alleles using specific oligonucleotide probes. Arthritis Rheum. 1989 Jan;32(1):15–21. [PubMed]
  • ROPES MW, BENNETT GA, COBB S, JACOX R, JESSAR RA. 1958 Revision of diagnostic criteria for rheumatoid arthritis. Bull Rheum Dis. 1958 Dec;9(4):175–176. [PubMed]
  • Saiki RK, Gelfand DH, Stoffel S, Scharf SJ, Higuchi R, Horn GT, Mullis KB, Erlich HA. Primer-directed enzymatic amplification of DNA with a thermostable DNA polymerase. Science. 1988 Jan 29;239(4839):487–491. [PubMed]
  • Waye MM, Verhoeyen ME, Jones PT, Winter G. EcoK selection vectors for shotgun cloning into M13 and deletion mutagenesis. Nucleic Acids Res. 1985 Dec 9;13(23):8561–8571. [PMC free article] [PubMed]
  • MANTEL N, HAENSZEL W. Statistical aspects of the analysis of data from retrospective studies of disease. J Natl Cancer Inst. 1959 Apr;22(4):719–748. [PubMed]
  • Gregersen PK, Shen M, Song QL, Merryman P, Degar S, Seki T, Maccari J, Goldberg D, Murphy H, Schwenzer J, et al. Molecular diversity of HLA-DR4 haplotypes. Proc Natl Acad Sci U S A. 1986 Apr;83(8):2642–2646. [PMC free article] [PubMed]
  • Dobloug JH, Førre O, Kåss E, Thorsby E. HLA antigens and rheumatoid arthritis. Association between HLA-DRw4 positivity and IgM rheumatoid factor production. Arthritis Rheum. 1980 Mar;23(3):309–313. [PubMed]
  • McMichael AJ, Sasazuki T, McDevitt HO, Payne RO. Increased frequency of HLA-Cw3 and HLA-Dw4 in rheumatoid arthritis. Arthritis Rheum. 1977 Jun;20(5):1037–1042. [PubMed]
  • Jaraquemada D, Ollier W, Awad J, Young A, Silman A, Roitt IM, Corbett M, Hay F, Cosh JA, Maini RN, et al. HLA and rheumatoid arthritis: a combined analysis of 440 British patients. Ann Rheum Dis. 1986 Aug;45(8):627–636. [PMC free article] [PubMed]
  • Nepom GT, Seyfried CE, Holbeck SL, Wilske KR, Nepom BS. Identification of HLA-Dw14 genes in DR4+ rheumatoid arthritis. Lancet. 1986 Nov 1;2(8514):1002–1005. [PubMed]
  • Woodrow JC, Nichol FE, Zaphiropoulos G. DR antigens and rheumatoid arthritis: a study of two populations. Br Med J (Clin Res Ed) 1981 Nov 14;283(6302):1287–1288. [PMC free article] [PubMed]
  • Duquesnoy RJ, Marrari M, Hackbarth S, Zeevi A. Serological and cellular definition of a new HLA-DR associated determinant, MC1, and its association with rheumatoid arthritis. Hum Immunol. 1984 Jul;10(3):165–176. [PubMed]
  • Goronzy J, Weyand CM, Fathman CG. Shared T cell recognition sites on human histocompatibility leukocyte antigen class II molecules of patients with seropositive rheumatoid arthritis. J Clin Invest. 1986 Mar;77(3):1042–1049. [PMC free article] [PubMed]
  • Lee SH, Gregersen PK, Shen HH, Nunez-Roldan A, Silver J, Winchester RJ. Strong association of rheumatoid arthritis with the presence of a polymorphic Ia epitope defined by a monoclonal antibody: comparison with the allodeterminant DR4. Rheumatol Int. 1984;4 (Suppl):17–23. [PubMed]
  • Lee SH, Matsuyama T, Logalbo P, Silver J, Winchester RJ. Ia antigens and susceptibility to rheumatoid arthritis. Clin Rheum Dis. 1985 Dec;11(3):645–664. [PubMed]
  • Ohta N, Nishimura YK, Tanimoto K, Horiuchi Y, Abe C, Shiokawa Y, Abe T, Katagiri M, Yoshiki T, Sasazuki T. Association between HLA and Japanese patients with rheumatoid arthritis. Hum Immunol. 1982 Oct;5(2):123–132. [PubMed]
  • Schiff B, Mizrachi Y, Orgad S, Yaron M, Gazit E. Association of HLA-Aw31 and HLA-DR1 with adult rheumatoid arthritis. Ann Rheum Dis. 1982 Aug;41(4):403–404. [PMC free article] [PubMed]
  • Nepom BS, Palmer J, Kim SJ, Hansen JA, Holbeck SL, Nepom GT. Specific genomic markers for the HLA-DQ subregion discriminate between DR4+ insulin-dependent diabetes mellitus and DR4+ seropositive juvenile rheumatoid arthritis. J Exp Med. 1986 Jul 1;164(1):345–350. [PMC free article] [PubMed]
  • Singal DP, D'Souza M, Reid B, Bensen WG, Kassam YB, Adachi JD. HLA-DQ beta-chain polymorphism in HLA-DR4 haplotypes associated with rheumatoid arthritis. Lancet. 1987 Nov 14;2(8568):1118–1120. [PubMed]
  • Sansom DM, Bidwell JL, Maddison PJ, Campion G, Klouda PT, Bradley BA. HLA DQ alpha and DQ beta restriction fragment length polymorphisms associated with Felty's syndrome and DR4-positive rheumatoid arthritis. Hum Immunol. 1987 Aug;19(4):269–278. [PubMed]
  • Jajić Z, Jajić I. Antigens of HLA-DR locus in rheumatoid arthritis. Br J Rheumatol. 1988;27 (Suppl 2):139–140. [PubMed]
  • Kirwan JR, Silman AJ. Epidemiological, sociological and environmental aspects of rheumatoid arthritis and osteoarthrosis. Baillieres Clin Rheumatol. 1987 Dec;1(3):467–489. [PubMed]
  • Bjorkman PJ, Saper MA, Samraoui B, Bennett WS, Strominger JL, Wiley DC. Structure of the human class I histocompatibility antigen, HLA-A2. Nature. 1987 Oct 8;329(6139):506–512. [PubMed]
  • Bjorkman PJ, Saper MA, Samraoui B, Bennett WS, Strominger JL, Wiley DC. The foreign antigen binding site and T cell recognition regions of class I histocompatibility antigens. Nature. 1987 Oct 8;329(6139):512–518. [PubMed]
  • Grennan DM, Sanders PA. Rheumatoid arthritis. Baillieres Clin Rheumatol. 1988 Dec;2(3):585–601. [PubMed]

Articles from Proceedings of the National Academy of Sciences of the United States of America are provided here courtesy of National Academy of Sciences


Related citations in PubMed

See reviews...See all...

Cited by other articles in PMC

See all...


  • MedGen
    Related information in MedGen
  • PubMed
    PubMed citations for these articles

Recent Activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...