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 ß1 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 DQB*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 ß1 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.

Human leukocyte antigen haplotype and autoantibodies of a family with systemic lupus erythematosus

“…In the Japanese population in particular, a significant genetic linkage between HLA DQB1 *0302 and anti-RNP has been shown to exist. 8 Miyagawa et al 9 reported that the haplotype DRB1 *08032 / DQA1 *0103 / DQB1 *0601 exhibited associations with anti-SS-B (with anti-SS-A together), and in their study, all the Japanese patients who were positive for anti-SS-A possessed at least one DQB1 *06 or *03 subtypes that shared the same amino acid residues at positions 71-77 of the DQB1 chain. Pt-1 and Pt-3 were positive for anti-dsDNA and lupus nephritis (nephrotic syndrome).…”

HLA class II genes associated with anticentromere antibody in Japanese patients with systemic sclerosis (scleroderma).

“…'8 The numbers of alleles defined by this method are 44 (DRB1), 13 19). When an association with a particular specificity had been reported previously, the p value was not corrected."…”

Blotting patterns of IgG anti-(U1)RNP antibodies in mixed connective tissue disease

“…It has also been demonstrated that levels of autoantibodies to snRNP polypeptides are independently regulated [9,32]. Moreover, no disease-specific difference in HLA class II gene control of the anti-(U1)RNP autoantibody response has been demonstrated for either anti-70-kD or anti-C reactivities, and has also been hypothesized for anti-A and anti-B/B' reactivities [13].…”

“…Nevertheless, controversy still exists as to whether positivity to the 70-kD polypeptide alone or concurrently to the three U1 snRNP specific polypeptides is specific for MCTD [5,[8][9][10][11]. Moreover, it has been suggested that immunoreactivities to individual U1 snRNP constituent proteins are not disease-specific and are controlled by distinct HLA class II genes [12,13].…”