Interrelationship of major histocompatibility complex class II alleles and autoantibodies in four ethnic groups with various forms of myositis

Abstract

Objective. To examine interrelationships among myositis subsets, autoantibodies, and major histocompatibility complex (MHC) class 1 1 alleles across ethnic lines, and to localize genetic susceptibility (presence of HLA-DR versus DQ) to myositis within the MHC class 1 1 region.Methods. MHC class I1 alleles (HLA-DRBZ, DQM, and DQBI, detected by DNA oligotyping) and myositis-specific autoantibodies (MSA) were determined in 224 patients with various myositis syndromes, including 89 whites, 89 African-Americans, 25 MexicanAmericans, and 21 Japanese.Results. Anti-Jo-1 (histidyl-transfer RNA [tRNA] synthetase) and other MSAs (anti-PL-12, anti-PL-7, anti-OJ, anti-EJ, anti-KJ, anti-tRNA, and antisignal recognition particle) were equally distributed among the races, but occurred more often in patients with polymyositis (PM) than in those with dermatomyositis (DM) or other myositis syndromes. MSA frequencies were significantly positively associated with anti-Ro (SS-A) (P = 0.002), and significantly negatively associated with anti-U1 RNP (P = 0.003). Frequencies of the HLA-DRBI *0301 (DR3), DQAZ*0501, and DQBl*O2OISupported by grants from the Muscular Dystrophy Association, the RGK Foundation, NIH grants R-29AR-39325, AR-32214, and AI-27181, and medical research funds from (DQ2) alleles (and haplotype) were each increased in white patients with myositis, especially those with PM, but most strikingly in those with MSAs. However, in the other ethnic groups, except the Japanese group, only frequencies of HLA-DQAI *0501 and the structurally similar DQAI *0402 alleles were significantly increased. The presence of HLA-D@iI*0501 or *040I was most significantly associated with anti-Jo-1, anti-PLU, and other MSAs, compared with myositis patients without MSAs (P = 0.0008,Pc,, = 0.01, odds ratio [OR] = 3.7), and with normal, ethnically matched controls (P = 3 X lo-', P,,, = 1 x OR = 6.5). Among MSApositive patients who were negative for HLADQAl*O501 and *0401, including Japanese patients, the HLA-D&iI *OI02 and *OI03 alleles predominated. In addition, there appeared to be a negative association of the HLA-DR2 alleles (DRBI*I501 and *1503) with PM (P = 0.007, P,,, not significant, OR = 039), but not with DM or myositis overall.Conclusion. By transracial gene mapping, genetic susceptibility to anti-Jo-1 and other MSAs in patients with myositis can be localized within the MHC region to the HLA-DQ4I locus.Polymyositis (PM) and dermatomyositis (DM) are idiopathic inflammatory myopathies that are characterized clinically by proximal muscle weakness, elevations in the level of serum muscle enzymes, especially creatine kinase (CK), and typical abnormal findings on electromyography. Histopathologic analysis has revealed that affected skeletal muscles are infiltrated by inflammatory mononuclear cells, predominantly CDS+ T lymphocytes, and that those muscles show myofibril degeneration, regeneration, and/or necrosis. Similar clinical and histopathologic features of myositis have been observed in association with malignancies, other connective ti...

Immunogenetic risk and protective factors for juvenile dermatomyositis in Caucasians

“…In large studies of North American Caucasian patients with adult idiopathic inflammatory myopathy, DRB1*0301 and its linked allele DQA1*0501 were also risk factors for adult DM, including in patients with specific autoantibodies as part of the 8.1 ancestral haplotype (6,19). Although class I or class III MHC typing data were not available in the present study, these risk factors are likely part of the 8.1 ancestral haplotype in juvenile DM.…”

Global surface ultraviolet radiation intensity may modulate the clinical and immunologic expression of autoimmune muscle disease

“…Certain polymorphic immune response genes, known as human leukocyte antigens (HLA) and Gm/Km markers on immunoglobulins, have been associated with myositis and some myositis-specific autoantibody groups (13,14,17,31), and there is increasing evidence that such genetic risk factors may differ in certain ethnogeographic populations (31). The strongest known genetic risk factors for both DM and PM in Caucasians are the HLA-DRB1*0301 and HLA-DQA1*0501 alleles, which are in linkage disequilibrium (13,14), while the strongest known risk factors for DM and PM in Mesoamericans are Gm 1, Gm 17, Gm 21, and Km 3 (31). Since genetic risk factors are the same for both DM and PM in all populations that have been studied, inherent differences in the frequencies of these alleles in different ethnic groups cannot explain the wide variations in the proportion of DM around the world seen in our study.…”

“…DM is distinguished clinically from PM by the presence of pathognomonic photosensitive rashes (11). These 2 forms of IIM, which share common genetic risk factors (13,14), may differ in pathogenesis. Muscle and skin biopsies from DM patients demonstrate vasculopathy with perivascular inflammation of B cells and CD4ϩ T cells and possible complement-mediated vascular endothelial cell damage resulting in focal capillary dropout, whereas PM is characterized pathologically by anamnestically activated CD8ϩ cytotoxic T cells that likely invade and destroy myocytes via perforinmediated mechanisms (15,16).…”

Polymyositis/Dermatomiositis: Differential Diagnosis

“…Данные об особен-ностях органной патологии отсутствуют [35,36]. Удовле-творительный инициальный ответ на терапию ГК с после-дующим развитием частичной стероидорезистентости, а также частые обострения на фоне снижения дозы ГК обу-словливают трудности терапевтической тактики, которая требует раннего п о д к л ю ч е н и я иммуносупрес-сивных препа-ратов [37,38].…”