Influence of HLA DRB1 alleles in the susceptibility of rheumatoid arthritis and the regulation of antibodies against citrullinated proteins and rheumatoid factor

We studied 408 patients (235 with RA, 173 non-RA) and 269 controls. ACPA, RF and HLA-DR typing were determined.We found an increased frequency of HLA DRB1 alleles with the shared epitope (SE) in ACPA-positive RA. Inversely, HLA DRB1 alleles encoding DERAA sequences were more frequent in controls than in ACPA-positive RA, and a similar trend was found for HLA DR3. However, these results could not be confirmed after stratification for the presence of the SE, probably due to the relatively low number of patients. These data may suggest that the presence of these alleles may confer a protective role for ACPA-positive RA. In RA patients we observed association between SE alleles and ACPA titers in a dose-dependent effect. The presence of HLA DR3 or DERAA-encoding alleles was associated with markedly reduced ACPA levels. No association between RF titers and HLA DR3 or DERAA-encoding alleles was found.HLA DRB1 alleles with the SE are associated with production of ACPA. DERAA-encoding HLA-DR alleles and HLA DR3 may be protective for ACPA-positive RA.Rheumatoid arthritis (RA) is a complex autoimmune disease that develops from the combined effects of genetic and environmental factors. It is estimated that the heritability of RA accounts for about 50% to 60%, and the most important genetic risk factors are the HLA class II molecules, which contribute to one third of the total genetic susceptibility [1,2]. There is extensive evidence for the association between certain HLA-DRB1 alleles with a conserved amino acid sequence (Q/RK/RRAA) at residues 70 to 74 in the third hypervariable region of the DRβ1 chain, the so-called shared epitope (SE), and susceptibility to and severity of RA [3,4].Autoimmunity in RA is characterized by the presence of autoantibodies. Rheumatoid factor (RF) is not specific to RA as it may be present in other diseases and in healthy older individuals [5]. In contrast, anti-citrullinated protein antibodies (ACPAs) seem to play a pivotal role in the pathogene