Major histocompatibility complex class II gene associations with anti-U1 small nuclear ribonucleoprotein antibody. Relationship to immunoreactivity with individual constituent proteins

Abstract

Objective: To better define immunogenetic associations with the anti-U1 ribonucleoprotein (U1 RNP) autoantibody response.

Methods: HLA class II alleles were determined by genotyping in 49 Japanese rheumatic disease patients with anti-U1 RNP antibody and 43 race-matched healthy controls. Immunoreactivities to U1 RNP constituent proteins (70K, A, B/B', and C) were detected by immunoblots using purified HeLa cell Sm antigen, and antibody titer was determined by passive hemagglutination assay.

Results: DQB1*0302 was significantly more frequent in anti-U1 RNP-positive patients than in controls (43% versus 14%; odds ratio [OR] = 4.6, corrected P = 0.03). All anti-U1 RNP-positive patients had either a DQB1*0601, *0602, *0301, *0302, or *0303 allele, which share tyrosine at position 30, and the amino acid sequence Thr, Arg, Ala, Glu, Leu, Asp, and Thr at positions 71-77 in the DQB1 beta 1 domain. In contrast, one of these alleles was found in 81% of the controls (OR = 24, P = 0.002). In addition, anti-U1 RNP antibody was associated with unique DQB1*0302; DRB1*0401 haplotype. Anti-70K reactivity and antibody titer were positively associated with a basic amino acid residue, arginine or histidine, at position 13 (DR2 or DR4) and were negatively associated with the amino acid sequence Ile, Leu, Glu, and Asp at positions 67-70, which was present in some of the DR5-, DR6-, and DR8-associated alleles, in the DRB1 beta 1 domain. Anti-C reactivity was strongly associated with DR2, particularly with DRB1*1502.

Conclusion: The several shared epitopes located on HLA-DRB1 and DQB1 genes control the anti-U1 RNP autoantibody response.