Protection against severe disease is conferred by DERAA-bearing HLA-DRB1 alleles among HLA-DQ3 and HLA-DQ5 positive rheumatoid arthritis patients

Experimental studies in transgenic mice have suggested that HLA-DQ predispo ses to rheumatoid arthritis (RA), but could also modulate disease severity by presenting peptides derived from self-DR molecules. In particular, a sho rt amino acid sequence, (70)DERAA(74), in the third hypervariable region of HLA-DRB1 confers protection for the disease, while particular HLA-DQ [DQB1 *0501/DQA1*01 (DQ5) and DQB1*03/ DQA1*03 (DQ3)] molecules predispose to the disease We have therefore analyzed the allelic distribution of HLA-DRB1, D QA1, and DQB1 and the presence of rheumatoid factor and nodules among 199 G erman RA patients and 196 healthy controls. Our results show that HLA-DQB1* 03/DQA1*'03 (or DRB1*0.4) predisposes to RA more than HLA-DQB1*0501/DQA1*01 (i.e., DRB1*01 and DRB1*10). Homozygosity for DQ3 confers tile strongest g enetic risk for RA (OR = 19.79 compared to OR = 10.05 for two doses of shar ed epitope (SE) positive HLA-DRB1 alleles). Furthermore patients carrying b oth predisposing DQ and (70)DERAA(74)-positive HLA-DRB1 allt les are more o ften rheumatoid factor (RF) negative than patients carrying predisposing DQ alleles alone. Only one out of 14 patients (7%) with a protective combinat ion (DQ3/(70)DERAA(74) and DQ5/(70)DERAA(74)) had rheumatoid nodules compar ed to 67 out of 114 patients (46.5%) with predisposing DQ alleles alone (OR = 0.12, 95% CI: 0.02-0.72, P = 0.004). These results demonstrate a protect ive role of (70)DERAA(74) positive DRB1 alleles against disease severity am ong RA patients. (C) American Society for Histocompatibility and Immunogene tics, 2001. Published by Elsevier Science Inc.