Specific combinations of HLA-DR2 and DR3 class II haplotypes contribute graded risk for disease susceptibility and autoantibodies in human SLE

Abstract

The human leukocyte antigen (HLA) Class II antigen presentation alleles DR and DQ are associated with susceptibility to systemic lupus erythematosus (SLE) and the production of lupus-related autoantibodies. Here, we explore the effect of different combinations of Class II risk haplotypes in a large, multi-center collection of 780 SLE families. Haplotypes bearing the DRB1*1501/DQB1*0602 (DR2) and DRB1*0301/ DQB1*0201 (DR3) alleles were present in nearly two-thirds of SLE cases and were significantly associated with disease susceptibility in both family-based and case-control study designs. DR3-containing haplotypes conferred higher risk for disease than DR2, and individual homozygous for DR3 or compound heterozygous for DR3 and DR2 showed the highest risk profile. DR2 haplotypes were also found to be associated with antibodies to the nuclear antigen Sm, and, as previously observed, DR3 genotypes were associated with Ro and La autoantibodies. Interestingly, SLE cases and unaffected family members who were DR2/DR3 compound heterozygotes showed particularly strong risk of developing antibodies to Ro, and were enriched for La and Sm. These data provide convincing evidence that particular combinations of HLA Class II DR2 and DR3 haplotypes are key determinants of autoantibody production and disease susceptibility in human SLE.

Immunodominant T‐cell epitopes of hnRNP‐A2 associated with disease activity in patients with rheumatoid arthritis

“…4), the major HLA-allele associated with severe and erosive RA in Japan [14]. Although patients with SLE may also be reactive to the hnRNP-A2 antigen [21], it is unlikely that they recognize the RA dominant epitope 117/120-133, since susceptibility to lupus is associated to HLA-DR2 (DR15) and DR3 [22] and peptides 117/120-133 are predicted extremely bad binders to these alleles (Fig. 4).…”

“…Immunization studies in DR4-Tg mice with the T-cell epitopes 117-133/120-133 and various B-cell epitopes (includ-ing peptide [19][20][21][22][23][24][25][26][27][28][29][30][31] are currently in progress in our laboratory to further elucidate the role of hnRNP-A2 in RA.…”

Late-onset systemic lupus erythematosus in the elderly

“…Эта точка зрения подтверждается и хорошо известной ассо-циацией СКВ с антигенами основного комплекса гистосов-местимости (major histocompatibility complex, MHC), в пер-вую очередь HLA-DR2 и HLA-DR3 [46].…”

“…Напри-мер, в некоторых группах больных СКВ с поражением почек было обнаружено повышение частоты аллелей DRB1*0301 и DRB1*1501 по сравнению со здоровым контролем, при этом наличие аллеля DRB1*1202 оказывало защитное действие в отношении развития нефрита [46][47][48][49]. Высказываются пред-положения, что пожилые и молодые больные могут иметь различные генетические детерминанты заболевания и отве-чать на различные триггерные механизмы.…”

Antigen-Presenting Cells and their Fcγ and Toll-Like Receptors: Leading Suspects in Autoimmunity

“…Polymorphisms of these determine the fitting of certain epitopes and thus their presentation by APCs to T cells. Therefore these polymorphisms determine the production of specific auto-antibodies against nuclear antigens and the risk of developing SLE [18,19]. Linked to the aberrant tissue deposition of ICs in SLE, preliminary evidence associates variants of Fc RIIa and IIIa with the development of SLE [20,21].…”