Low copy numbers of complement C4 and C4A deficiency are risk factors for myositis, its subgroups and autoantibodies.
Low copy numbers of complement C4 and C4A deficiency are risk factors for myositis, its subgroups and autoantibodies.
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DOI：
10.1136/ard-2022-222935
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发表时间：
2023-02
影响因子：
27.4
通讯作者：
中科院分区：
文献类型：
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特发性炎性肌病（IIM）是一组自身免疫性疾病，其特征在于肌炎相关的自身抗体加上白细胞浸润到肌肉和/或皮肤中，导致血管和肌纤维的破坏、慢性虚弱和疲劳。虽然补体介导的毛细血管内皮细胞的破坏与儿童和成人皮肌炎有关，但补体C4在IIM病理学中的复杂多样性尚不清楚。我们阐明了基因拷贝数（GCN）的变化，总C4，C4 A和C4 B，长和短的基因在1644例IIM白人患者，加上3526匹配的健康对照使用实时PCR或Southern印迹分析。采用单向免疫扩散法测定血浆补体水平。大量的研究人群有助于确定各种C4 GCN群体的分布模式。C4 T（C4 T =2+3）和C4 A缺乏（C4 A =0+1）的低GCN与IIM风险增加密切相关，OR等于2.58（2.28-2.91），C4 T为p=5.0×10−53，C4 A缺乏为2.82（2.48-3.21），p=7.0×10−57。关联分析和回归分析显示，在C4 A缺陷的患者中，HLA-DR 3的存在作为IIM的危险因素变得不显著，除了包涵体肌炎（IBM），其中98.2%的患者具有HLA-DR 3，OR为11.02（1.44-84.4）。IIM患者C4蛋白水平和IIM相关自身抗体的组内分析显示，抗Jo-1或抗PM/Scl患者的C4血浆浓度显著低于无这些自身抗体的患者。 C4 A缺陷与皮肌炎有关，HLA-DRB 1 *03在IBM中很重要，C4 A缺陷和HLA-DRB 1 *03交互作用地促进多发性肌炎的风险。
Idiopathic inflammatory myopathies (IIM) are a group of autoimmune diseases characterised by myositis-related autoantibodies plus infiltration of leucocytes into muscles and/or the skin, leading to the destruction of blood vessels and muscle fibres, chronic weakness and fatigue. While complement-mediated destruction of capillary endothelia is implicated in paediatric and adult dermatomyositis, the complex diversity of complement C4 in IIM pathology was unknown. We elucidated the gene copy number (GCN) variations of total C4, C4A and C4B, long and short genes in 1644 Caucasian patients with IIM, plus 3526 matched healthy controls using real-time PCR or Southern blot analyses. Plasma complement levels were determined by single radial immunodiffusion. The large study populations helped establish the distribution patterns of various C4 GCN groups. Low GCNs of C4T (C4T=2+3) and C4A deficiency (C4A=0+1) were strongly correlated with increased risk of IIM with OR equalled to 2.58 (2.28–2.91), p=5.0×10−53 for C4T, and 2.82 (2.48–3.21), p=7.0×10−57 for C4A deficiency. Contingency and regression analyses showed that among patients with C4A deficiency, the presence of HLA-DR3 became insignificant as a risk factor in IIM except for inclusion body myositis (IBM), by which 98.2% had HLA-DR3 with an OR of 11.02 (1.44–84.4). Intragroup analyses of patients with IIM for C4 protein levels and IIM-related autoantibodies showed that those with anti-Jo-1 or with anti-PM/Scl had significantly lower C4 plasma concentrations than those without these autoantibodies. C4A deficiency is relevant in dermatomyositis, HLA-DRB1*03 is important in IBM and both C4A deficiency and HLA-DRB1*03 contribute interactively to risk of polymyositis.
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影响因子：
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作者：
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