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 被改变的聚糖部分，并用作自然发生的抗糖抗体识别的抗原 IgG同种型，导致形成肾源性免疫复合物。伊根的事件 展示出色的地理和种族分布：这种疾病在欧洲，北美很常见， 澳大利亚和选定的亚洲国家（尤其是日本），但在中非很少见，在 印度，孟加拉国，尼泊尔和许多南美国家等国家。出人意料的是，这是明显的 与种族相关的疾病事件下降仍然是神秘的。非洲裔美国人，非洲黑人， 澳大利亚原住民和可能在某些国家的罗马尼人很少会因Igan而生病。经过 对白色Igan患者，健康对照组和非裔美国人的血清和细胞的分析，我们发现 用改变的聚糖产生IGA1的细胞感染了爱泼斯坦 - 巴尔病毒（EBV），该病毒秘密 在其终极分化后，IgA1用聚糖部分改变。重要的是我们的工作假设， 在白人患者的IgA阳性细胞中检测到IGAN，在健康成人中检测到EBV感染的细胞 非裔美国人，EBV主要与IgM/IgD和IgG阳性B细胞有关。原因 通过先前无视IGA的成熟差异揭示了显着差异 与EBV感染的时间有关的系统。血清IgA的水平和IgA-的频率 产生细胞严格取决于年龄。幼儿（1-5岁）的IGA水平较低 在青春期，产生IGA的细胞和成人水平。但是，非洲人，非洲人 黑人，澳大利亚原住民在生命的头两年中被EBV感染。因此，在 天然IgA缺乏的时间，EBV感染“非IGA阳性”细胞。确实，我们报告了非洲 美国成年人EBV在IGA细胞中没有主要发现！目前，我们缺少信息 关注IgA系统和表型的发展和成熟的特征 与血清神经白色相比 孩子们。此信息对于阐明Igan和基本的免疫发病生成至关重要 澄清种族依赖的差异。因此，我们建议为我们的 工作假设，即AA儿童的EBV感染主要仅限于非siga+ b细胞，因此 防止Igan的发展。这将通过确定EBV的差异影响来实现 IgA循环中的IgA特征与不同的白人儿童循环 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。