Department of Immunology, Faculty of Medicine and Dentistry, University Hospital Olomouc, Palacky University Olomouc, Olomouc, Czechia.
Department of Internal Medicine III Nephrology, Rheumatology and Endocrinology, University Hospital Olomouc, Palacky University Olomouc, Olomouc, Czechia.
Front Immunol. 2020 Feb 28;11:267. doi: 10.3389/fimmu.2020.00267. eCollection 2020.
IgA nephropathy (IgAN) is the dominant type of primary glomerulonephritis worldwide. However, IgAN rarely affects African Blacks and is uncommon in African Americans. Polymeric IgA1 with galactose-deficient hinge-region glycans is recognized as auto-antigen by glycan-specific antibodies, leading to formation of circulating immune complexes with nephritogenic consequences. Because human B cells infected with Epstein-Barr virus (EBV) secrete galactose-deficient IgA1, we examined peripheral blood B cells from adult IgAN patients, and relevant controls, for the presence of EBV and their phenotypic markers. We found that IgAN patients had more lymphoblasts/plasmablasts that were surface-positive for IgA, infected with EBV, and displayed increased expression of homing receptors for targeting the upper respiratory tract. Upon polyclonal stimulation, these cells produced more galactose-deficient IgA1 than did cells from healthy controls. Unexpectedly, in healthy African Americans, EBV was detected preferentially in surface IgM- and IgD-positive cells. Importantly, most African Blacks and African Americans acquire EBV within 2 years of birth. At that time, the IgA system is naturally deficient, manifested as low serum IgA levels and few IgA-producing cells. Consequently, EBV infects cells secreting immunoglobulins other than IgA. Our novel data implicate Epstein-Barr virus infected IgA cells as the source of galactose-deficient IgA1 and basis for expression of relevant homing receptors. Moreover, the temporal sequence of racial-specific differences in Epstein-Barr virus infection as related to the naturally delayed maturation of the IgA system explains the racial disparity in the prevalence of IgAN.
IgA 肾病（IgAN）是全球主要的原发性肾小球肾炎。然而，IgAN 很少影响非洲黑人，在非裔美国人中也不常见。具有半乳糖缺乏铰链区聚糖的聚合 IgA1 被糖基特异性抗体识别为自身抗原，导致形成具有肾炎后果的循环免疫复合物。由于感染 Epstein-Barr 病毒（EBV）的人类 B 细胞会分泌缺乏半乳糖的 IgA1，我们检查了成人 IgAN 患者和相关对照者的外周血 B 细胞中 EBV 的存在及其表型标志物。我们发现 IgAN 患者具有更多的淋巴母细胞/浆母细胞，这些细胞表面呈阳性的 IgA 被 EBV 感染，并显示出针对上呼吸道的归巢受体表达增加。在多克隆刺激下，这些细胞产生的缺乏半乳糖的 IgA1 比来自健康对照者的细胞多。出乎意料的是，在健康的非裔美国人中，EBV 优先存在于表面 IgM 和 IgD 阳性细胞中。重要的是，大多数非洲黑人和非裔美国人在出生后 2 年内获得 EBV。此时，IgA 系统自然缺乏，表现为血清 IgA 水平低，产生 IgA 的细胞少。因此，EBV 感染除 IgA 以外的免疫球蛋白分泌细胞。我们的新数据表明，感染 EBV 的 IgA 细胞是缺乏半乳糖的 IgA1 的来源，也是相关归巢受体表达的基础。此外，EBV 感染的种族特异性差异与 IgA 系统自然延迟成熟的时间顺序解释了 IgAN 在不同种族中的患病率差异。
