MAJOR HISTOCOMPATIBILITY COMPLEX CLASS-II GENE ASSOCIATIONS WITH ANTI-U1 SMALL NUCLEAR RIBONUCLEOPROTEIN ANTIBODY - RELATIONSHIP TO IMMUNOREACTIVITY WITH INDIVIDUAL CONSTITUENT PROTEINS

Objective. To better define immunogenetic associations with the anti-U 1 ribonucleoprotein (U1 RNP) autoantibody response. Methods. HLA class II alleles were determined by genotyping in 49 Japanese rheumatic dis ease patients with anti-U1 RNP antibody and 43 race-matched healthy co ntrols. Immunoreactivities to U1 RNP constituent proteins (70K, A, B/B ', and C) were detected by immunoblots using purified HeLa cell Sm ant igen, and antibody titer was determined by passive hemagglutination as say. Results. DQB10302 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 eithe r a DQB10601, *0602, *0301, *0302, or *0303 allele, which share tyros ine at position 30, and the amino acid sequence Thr, Arg, Ala, Glu, Le u, Asp, and Thr at positions 71-77 in the DQB1 beta 1 domain. In contr ast, 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 uniqu e DQB10302; DRB1*0401 haplotype. Anti-70K reactivity and antibody tit er were positively associated with a basic amino acid residue, arginin e or histidine, at position 13 (DR2 or DR4) and were negatively associ ated with the amino acid sequence Ile, Leu, Glu, and Bsp 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 as sociated with DR2, particularly with DRB11502. Conclusion. The severa l shared epitopes located on HLA-DRB1 and DQB1 genes control the anti- U1 RNP autoantibody response.