Maillard Nicolas, Wyatt Robert J, Julian Bruce A, Kiryluk Krzysztof, Gharavi Ali, Fremeaux-Bacchi Veronique, Novak Jan
University of Alabama at Birmingham, Departments of Microbiology and Medicine, Birmingham, Alabama; Université Jean Monnet, Groupe sur l'immunité des Muqueuses et Agents Pathogènes, St. Etienne, Pôle de Recherche et d'Enseignement Supérieur, Université de Lyon, Lyon, France;
University of Tennessee Health Science Center and Children's Foundation Research at the Le Bonheur Children's Hospital, Memphis, Tennessee;
J Am Soc Nephrol. 2015 Jul;26(7):1503-12. doi: 10.1681/ASN.2014101000. Epub 2015 Feb 18.
Complement activation has a role in the pathogenesis of IgA nephropathy, an autoimmune disease mediated by pathogenic immune complexes consisting of galactose-deficient IgA1 bound by antiglycan antibodies. Of three complement-activation pathways, the alternative and lectin pathways are involved in IgA nephropathy. IgA1 can activate both pathways in vitro, and pathway components are present in the mesangial immunodeposits, including properdin and factor H in the alternative pathway and mannan-binding lectin, mannan-binding lectin-associated serine proteases 1 and 2, and C4d in the lectin pathway. Genome-wide association studies identified deletion of complement factor H-related genes 1 and 3 as protective against the disease. Because the corresponding gene products compete with factor H in the regulation of the alternative pathway, it has been hypothesized that the absence of these genes could lead to more potent inhibition of complement by factor H. Complement activation can take place directly on IgA1-containing immune complexes in circulation and/or after their deposition in the mesangium. Notably, complement factors and their fragments may serve as biomarkers of IgA nephropathy in serum, urine, or renal tissue. A better understanding of the role of complement in IgA nephropathy may provide potential targets and rationale for development of complement-targeting therapy of the disease.
补体激活在IgA肾病的发病机制中起作用，IgA肾病是一种由缺乏半乳糖的IgA1与抗聚糖抗体结合形成的致病性免疫复合物介导的自身免疫性疾病。在三条补体激活途径中，替代途径和凝集素途径与IgA肾病有关。IgA1在体外可激活这两条途径，且途径成分存在于系膜免疫沉积物中，包括替代途径中的备解素和H因子，以及凝集素途径中的甘露聚糖结合凝集素、甘露聚糖结合凝集素相关丝氨酸蛋白酶1和2，还有C4d。全基因组关联研究确定补体因子H相关基因1和3的缺失对该病有保护作用。由于相应的基因产物在替代途径的调节中与H因子竞争，因此推测这些基因的缺失可能导致H因子对补体的抑制作用更强。补体激活可直接在循环中含IgA1的免疫复合物上发生和/或在其沉积于系膜后发生。值得注意的是，补体因子及其片段可能作为IgA肾病在血清、尿液或肾组织中的生物标志物。更好地理解补体在IgA肾病中的作用可能为开发针对该疾病的补体靶向治疗提供潜在靶点和理论依据。
