HLA class II phenotype controls diversification of the autoantibody response in primary Sjögren's syndrome (pSS)

Abstract

The coexistence of anti-La (SS-B) and anti-Ro (SS-A) autoantibodies in pSS is probably explained by intermolecular spreading of autoimmunity toward different components of the La/Ro ribonucleoprotein (RNP). In order to evaluate the role of the HLA class II phenotype in controlling diversification of this autoantibody response, 80 patients with pSS were typed by polymerase chain reaction sequence-specific oligonucleotide (PCR-SSO) at the HLA class II loci DRB1, DQA1 and DQB1. Serum samples were examined for anti-La and anti-Ro by counterimmunoelectrophoresis and by ELISA using purified recombinant La and 60-kD Ro proteins. Patient sera were classified according to the extent of diversification of the anti-La, anti-Ro response including the presence or absence of precipitating anti-La antibodies. Immunogenic characteristics of these stratified groups were then studied. All patients with pSS, with or without autoantibodies to Ro and La, were found to have at least one of the HLA-DRB1 types DR2, DR3 or DR5. The HLA DR3-DQA1*0501-DQB1*02 (DR3-DQ2) haplotype was primarily associated with a diversified La/Ro RNP response containing precipitating autoantibodies to La (P<0.001); whereas the haplotype HLA DR2-DQA1*0102-DQB1*0602 (DR2-DQ1) was associated with a less diversified La/Ro RNP response containing non-precipitating (restricted epitope) anti-La autoantibodies (P<0.001). Anti-La-positive patients lacking both HLA-DR2 and HLA-DR3 all expressed the HLA-DQA1*0501 allele, which was present at increasing frequency with greater diversification of the anti-La/Ro autoantibody response. The association of distinct HLA haplotypes with different degrees of autoantibody diversification in patients with pSS suggests a model of HLA-restricted presentation of La/Ro peptide determinants to autoreactive helper T cells. We propose that non-precipitating anti-La responses are driven by limited intermolecular help from DR2-DQ1-restricted T helper cells recognizing Ro determinants. On the other hand, we speculate that the more diversified, precipitating anti-La responses obtain more efficient cognate T help from DR3-DQ2-restricted T helper cells recognizing La determinants, where HLA-DQA1*0501 may be a critical determinant for antigen presentation.

Fig. 1

Model showing HLA-restricted control of anti-La/Ro autoantibody diversification. (a) The model proposes that anti-La/Ro autoimmunity can be initiated when anti-Ro T cells are activated and provide helper signals for Ro-specific B cells presenting HLA-DR2- or -DQ1-restricted processed Ro peptides (upper panel). Ro-specific B cells selectively bind La/Ro RNPs through their membrane immunoglobulin, which then undergoes receptor-mediated endocytosis leading to antigen processing and presentation of captured proteins. La-specific B cells also take up La/Ro RNP via their mIg receptor and also present HLA-DR2- or -DQ1-restricted Ro peptides to Ro-specific T helper cells, thereby gaining intermolecular help for anti-La antibody production (lower panel). The latter intermolecular help is limited because there is a pool of free La which restricts the number of anti-La B cells able to take up La and Ro together. This results in the production of low-titre, low-affinity, pauciclonal anti-La antibodies lacking the ability to form latticed precipitates. (b) Anti-Ro autoimmunity can also be initiated by T helper cells recognizing Ro peptides presented by DR3 or DQ2 (lower panel), but it is proposed that these HLA molecules also present La peptides (upper panel). Thus, high-affinity precipitating anti-La antibody responses are driven by La-specific T helper cells following presentation of HLA-DR3-DQ2-restricted processed La peptides by a broad range of La-specific B cells.