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.

The pathophysiology of photosensitivity in lupus erythematosus

“…molecules participate in the anti-Ro response (292)(293)(294). Diversification of the Ro/SSA and LA/SSB antibody response has also been linked to specific HLA class II phenotypes (295).…”

Prolactin Up-Regulates Cathepsin B and D Expression in Minor Salivary Glands of Patients with Sjögren's Syndrome

“…The events that lead to SS autoimmune responses are not clearly established, but genetic, endocrine, and viral factors are relevant (Fox and Kang, 1992). The development of SS is strongly associated with major histocompatibility complex (MHC) class II genes and, particularly, human leukocyte antigen (HLA)-DR and -DQ alleles (Foster et al, 1993;Kerttula et al, 1996;Reveille and Arnett, 1992;Rischmueller et al, 1998). These molecules play a central role in the initiation and maintenance of immune responses in that they present proteolytically processed antigen peptides to CD4 T lymphocytes, which are the most frequent infiltrating cells in SS (Adamson et al, 1983).…”

T cell epitopes of the La/SSB autoantigen in humanized transgenic mice expressing the hLa class II haplotype DRB1*0301/DQB1*0201

“…Documented associations between antiLa autoantibodies and particular HLA class II alleles are likely to reflect presentation of selected T cell determinants. In a previous study of SS, 91% of patients with anti-Ro and precipitating levels of anti-La were found to express DR3, and Ͼ90% of these patients also expressed DQ2 (6). In SLE patients, anti-Ro without anti-La is commonly associated with DR2 and DQ1, while the presence of autoantibodies to both La and Ro is associated with DR3.…”

“…Paraformaldehyde-fixed, EpsteinBarr virus-transformed B cells (1 ϫ 10 6 /well) expressing DR3 and DQ2 were incubated with previously described mycobacterial peptides, MT65kDa [3][4][5][6][7][8][9][10][11][12][13] (DR3 specific) or MB65kDa 243-265 Y (DQ2 specific) (23), at concentrations calculated to give 50% maximal binding and unlabeled competitive hLa peptides at 100-fold molar excess. Samples were incubated for 24 hours at 37°C followed by lysis in PBS containing 50 mM Tris (pH 8.0), 0.5M NaCl, 0.5% Ipegal 630 (Sigma, St. Louis, MO), and protease inhibitors (Complete Cocktail Tablets; Roche, Basel, Switzerland).…”