Abstract
Immune-mediated pathology has been thought to be an important factor contributing to Duchenne muscular dystrophy (DMD). Allele frequencies of certain HLA types are known to differ between patients with dystrophinopathies and healthy controls with low-resolution HLA gene typing data in limit reports. Using Polymerase chain reactionsequence based typing (PCR-SBT) to genotype 64 children with DMD in HLA-A, -B,-C, -DRB1, and -DQB1 locus and 503 healthy controls in HLA-A, -B, -DRB1 locus, this study aimed to investigate associations of specific HLA alleles with, and their possible roles in the development and clinical phenotypic severity of DMD. The χ2 test was used to evaluate the distribution of allele frequencies in HLA-A, -B, -DRB1 locus between the patients and healthy controls. A significantly higher frequency of HLA-B*07:05 was found in children with DMD compared to that in controls (OR = 16.2, 95%CI = 2.9–89.3, P < 0.046). More importantly, significantly higher frequencies of HLA-A*29:01 (OR = 77.308, 95%CI = 6.794–879.731, P < 0.0160) and HLA-B*07:05 (OR = 60.240, 95%CI = 9.637–376.535, P < 2.41*10−3) was found in patients with de novo mutations (n = 14) compared to controls while no difference of HLA alleles frequency ware indicated between patients with inherited mutation and control. The result indicates that HLA alleles is associated with pathogenesis of DMD especially DMD with de novo mutation. We use Vignos scale to estimate the lower limb motor function of patients. The impact of HLA alleles on score of Vignos scale of DMD children was estimated by multiple linear regression. Our study indicates that HLA-A*02:01 may have a dampening effect on the clinical phenotypic severity of DMD, evidenced by the presence of HLA-A*02:01 being associated with lower Vignos score. Our study demonstrates that certain HLA alleles are indeed associated with the pathogenesis and clinical phenotypic severity of DMD.
Highlights
Duchenne muscular dystrophy (DMD) is an X-linked genetic disorder caused by mutations in the dystrophin gene (DMD, MIM# 300377)
Patients suffering from DMD, Becker muscular dystrophy (BMD) and other inflammatory myopathies display consistently high expression levels of class I major histocompatibility complex (MHC) on muscle cells, whereas, normal muscles do not express these molecules; besides this, muscle biopsies of DMD and BMD patients indicate that in these disorders, endothelial cells express class II MHCs which are not expressed either in normal muscle or in patients with neurological disorders [17]
Up-regulation of TLR7 accompanied by activation of inflammatory signaling pathways is known to elevate the expression of class I and II MHCs [18]
Summary
Duchenne muscular dystrophy (DMD) is an X-linked genetic disorder caused by mutations in the dystrophin gene (DMD, MIM# 300377). The innate immune system is found to be strongly activated in DMD patients even before the onset of clinical symptoms; this activation includes accumulation of immune cell including CD4+ and CD8+ T cells, macrophages, eosinophils, and natural killer T cells, altered signaling pathways via Toll-like receptors (TLRs) and nuclear factor κB (NFκB) and altered expressions for inflammatory cytokines and major histocompatibility complex (MHC) molecules [7]. The immune system is likely to be an important factor influencing the outcomes of some gene therapies and stem cell therapies for DMD since these methods can introduce exogenous protein in patients and animal models and stimulate the immunity [9, 10]. Inflammation is a hallmark of dystrophic muscular disorders, the mechanisms of its influence on muscle fiber pathology, and the involvement of factors mediating these immune mechanisms are as yet not fully understood
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