Acute rheumatic fever (ARF) and chronic rheumatic heart disease (RHD) are autoimmune sequelae of a Group A streptococcal infection with significant global mortality and poorly understood pathogenesis. Immunoglobulin and complement deposition were observed in ARF/RHD valve tissue over 50 years ago, yet contemporary investigations have been lacking. This study applied systems immunology to investigate the relationships between the complement system and immunoglobulin in ARF. Patients were stratified by C-reactive protein (CRP) concentration into high (≥10 μg mL-1 ) and low (<10 μg mL-1 ) groups to distinguish those with clinically significant inflammatory processes from those with abating inflammation. The circulating concentrations of 17 complement factors and six immunoglobulin isotypes and subclasses were measured in ARF patients and highly matched healthy controls using multiplex bead-based immunoassays. An integrative statistical approach combining feature selection and principal component analysis revealed a linked IgG3-C4 response in ARF patients with high CRP that was absent in controls. Strikingly, both IgG3 and C4 were elevated above clinical reference ranges, suggesting these features are a marker of ARF-associated inflammation. Humoral immunity in response to M protein, an antigen implicated in ARF pathogenesis, was completely polarized to IgG3 in the patient group. Furthermore, the anti-M-protein IgG3 response was correlated with circulating IgG3 concentration, highlighting a potential role for this potent immunoglobulin subclass in disease. In conclusion, a linked IgG3-C4 response appears important in the initial, inflammatory stage of ARF and may have immediate utility as a clinical biomarker given the lack of specific diagnostic tests currently available.

中文翻译：

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系统免疫学揭示了急性风湿热患者中存在相关的IgG3-C4反应。

急性风湿热（ARF）和慢性风湿性心脏病（RHD）是A组链球菌感染的自身免疫后遗症，具有显着的总体死亡率和发病机理。50年前，在ARF / RHD瓣膜组织中观察到了免疫球蛋白和补体沉积，但目前尚缺乏现代研究。这项研究应用系统免疫学来研究ARF中补体系统与免疫球蛋白之间的关系。通过C反应蛋白（CRP）浓度将患者分为高组（≥10μgmL-1）和低组（<10μgmL-1），以区分具有临床显着炎症过程的患者和减轻炎症的患者。使用基于多重磁珠的免疫测定法在ARF患者和高度匹配的健康对照组中测量了17种补体因子和6种免疫球蛋白同种型和亚类的循环浓度。结合了特征选择和主成分分析的综合统计方法显示，在高CRP的ARF患者中，对照中没有相关的IgG3-C4反应。令人惊讶的是，IgG3和C4均升高到高于临床参考范围，表明这些特征是ARF相关炎症的标志。在患者组中，对M蛋白（一种与ARF发病机制有关的抗原）的体液免疫反应与IgG3完全极化。此外，抗M蛋白IgG3反应与循环IgG3浓度相关，强调了这种有效的免疫球蛋白亚类在疾病中的潜在作用。总之，在目前ARF的初始炎症阶段，连接的IgG3-C4反应似乎很重要，并且由于缺乏当前可用的特定诊断测试，可能直接用作临床生物标志物。