IgA Nephropathy: Impact of EBV Infection on Racial Differences

IgA 肾病：EBV 感染对种族差异的影响

• 批准号: 10429362
• 负责人: JIRI F MESTECKY
• 金额: $ 22.28万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-07 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10429362
• 关键词: Aborigine; Acetylgalactosamine; Adolescence; Adult; Affect; Africa; African; African American; African American population; Age; Antibodies; Antigen-Antibody Complex; Antigens; Asia; Asian; Australia; Autoantigens; Autoimmune Diseases; B-Lymphocytes; Bangladesh; Biochemical; Black Populations; Black race; Blood Cells; Blood Circulation; Body Fluids; CD19 gene; Cells; Central Africa; Characteristics; Child; Country; Deposition; Development; Disease; Epstein-Barr Virus Infections; Europe; Far East; Frequencies; Future; Galactose; Geographic Distribution; Geography; Glomerulonephritis; Homing; Human Herpesvirus 4; IGA Glomerulonephritis; IgA Deficiency; IgA1; IgA2; Immune response; Immunoglobulin A; Immunoglobulin D; Immunoglobulin G; Immunoglobulin M; In Vitro; Incidence; India; Infection; Interleukin-10; Intervention; J-Chain Immunoglobulins; Japan; Kidney Diseases; Leukocytes; Link; Lymphoid Tissue; Mucous Membrane; N-terminal; Nepal; North America; Pathologic; Patients; Phenotype; Plasma; Polymers; Polysaccharides; Population; Prevalence; Property; Puberty; Reporting; Serum; South American; Structure of glomerular mesangium; Surface; Surface Immunoglobulins; System; Time; Vaccines; age related; base; early childhood; epidemiologic data; in vivo; lymphoblast; mesangial cell; mouse model; peripheral blood; prevent; racial difference; receptor; residence; seropositive; transforming virus

ABSTRACT IgA nephropathy (IgAN) is an autoimmune disease in which IgA exclusively of the IgA1 subclass contains altered glycan moiety and serves as an antigen recognized by naturally occurring anti-glycan antibodies mostly of the IgG isotype, leading to the formation of nephritogenic immune complexes. The incidence of IgAN displays a great geographical and racial distribution: the disease is common in Europe, North America, Australia and selected Asian countries (especially Japan), but is rare in central Africa and uncommon in countries such as India, Bangladesh, Nepal and many South American countries. Surprisingly the pronounced racially-associated decreased incidence of the disease remains enigmatic. African Americans, African Blacks, Australian Aborigines and probably Romanines in some countries only rarely become ill with IgAN. By analyses of sera and cells from White IgAN patients, healthy controls and African Americans, we discovered that the cells producing IgA1 with altered glycans are infected with the Epstein-Barr virus (EBV), which secrete upon their terminal differentiation, IgA1 with altered glycan moiety. Importantly for our working hypothesis, in IgAN, EBV-infected cells were detected in the IgA-positive cells from White patients, while in the healthy adult African Americans, EBV was primarily associated with IgM/IgD and IgG-positive B cells. The reason for this remarkable disparity was revealed through the previously disregarded difference in the maturation of the IgA system as related to the timing of EBV infection. The levels of serum IgA and the frequency of the IgA- producing cells are strictly dependent on the age. Children at the early age (1-5 years) have low levels of IgA and IgA-producing cells and the adult levels are attained at puberty. However, African Americans, African Blacks, Australian Aborigines become infected with EBV during the first 2 years of their lives. Therefore, at the time of natural IgA deficiency, EBV infects “non-IgA-positive” cells. Indeed, we reported that in the African American adults EBV is not dominantly found in the IgA cells! Currently, we are missing the information concerning the characteristics of the development and maturation of the IgA system and phenotypic characteristics of EBV-infected cells in seropositive African Americans as compared to seronegative White children. This information is essential for the elucidation of the immunopathogenesis of IgAN and basic clarification of racially-dependent differences. Therefore, we propose to provide experimental evidence for our working hypothesis that the EBV infection of AA children is mainly restricted to the non-sIgA+ B cells and thus prevents the development of IgAN. This will be accomplished by determining the differential impact of EBV on the IgA characteristics in circulation of seropositive and seronegative AA versus White children of different ages. In addition, we will determine how EBV infection affects the phenotype and homing potential of IgA cells from peripheral blood of seropositive AA children.

抽象的 IgA 肾病 (IgAN) 是一种自身免疫性疾病，其中仅 IgA1 亚类包含 IgA 改变的聚糖部分并作为主要被天然存在的抗聚糖抗体识别的抗原 IgG 同种型，导致肾炎性免疫复合物的形成。 IgAN 的发病率 显示出很大的地理和种族分布：该疾病在欧洲、北美、 澳大利亚和某些亚洲国家（尤其是日本），但在中部非洲很少见，在非洲也不常见 印度、孟加拉国、尼泊尔和许多南美国家等国家。令人惊讶的是发音 与种族相关的疾病发病率下降仍然是个谜。非裔美国人、非洲黑人、 澳大利亚原住民以及一些国家的罗马人很少患 IgAN。经过 通过对白人 IgAN 患者、健康对照者和非裔美国人的血清和细胞进行分析，我们发现 产生具有改变聚糖的 IgA1 的细胞感染了 Epstein-Barr 病毒 (EBV)，该病毒分泌 在其终末分化时，IgA1 具有改变的聚糖部分。对于我们的工作假设来说重要的是， 在白人患者的 IgA 阳性细胞中检测到 IgAN、EBV 感染细胞，而在健康成人中则检测到 IgAN、EBV 感染细胞。 非裔美国人中，EBV 主要与 IgM/IgD 和 IgG 阳性 B 细胞相关。这样做的原因 先前被忽视的 IgA 成熟度差异揭示了显着的差异 系统与 EBV 感染时间相关。血清 IgA 水平和 IgA 频率 产生细胞严格取决于年龄。幼儿（1-5 岁）的儿童 IgA 水平较低 IgA 产生细胞在青春期达到成人水平。然而，非裔美国人、非洲人 黑人、澳大利亚原住民在出生后的头两年会感染 EBV。因此，在 当天然 IgA 缺乏时，EBV 会感染“非 IgA 阳性”细胞。事实上，我们报道过，在非洲 美国成年人 EBV 并不主要存在于 IgA 细胞中！目前，我们缺少信息 关于IgA系统发育和成熟的特征以及表型 与血清阴性白人相比，血清阳性非裔美国人中 EBV 感染细胞的特征 孩子们。该信息对于阐明 IgAN 的免疫发病机制和基本原理至关重要。 澄清种族依赖性差异。因此，我们建议为我们的研究提供实验证据 工作假设：AA 儿童的 EBV 感染主要限于非 sIgA+ B 细胞，因此 阻止 IgAN 的发展。这将通过确定 EBV 对 血清阳性和血清阴性 AA 与不同种族白人儿童循环中的 IgA 特征 年龄。此外，我们将确定 EBV 感染如何影响 IgA 细胞的表型和归巢潜力 来自血清阳性 AA 儿童的外周血。