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: 10661504
• 负责人: JIRI F MESTECKY
• 金额: $ 9.17万
• 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/10661504
• 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; Body Fluids; CD19 gene; Cells; Central Africa; Characteristics; Child; Circulation; Country; Deposition; Development; Disease; Disparity; 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; Nepal; North America; Pathologic; Patients; Phenotype; Plasma; Polymers; Polysaccharides; Population; Prevalence; Probability; Proliferating; Property; Puberty; Race; Reporting; Serum; South American; Structure of glomerular mesangium; Surface Immunoglobulins; System; Time; Vaccines; age related; 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.

摘要 伊加肾病（IgAN）是一种自身免疫性疾病，其中伊加仅为IgA 1亚类， 改变的聚糖部分，并作为天然存在的抗聚糖抗体识别的抗原， IgG同种型，导致肾炎免疫复合物的形成。IgAN的发病率 显示出很大的地理和种族分布：这种疾病在欧洲，北美， 澳大利亚和选定的亚洲国家（特别是日本），但在非洲中部罕见， 例如印度、孟加拉国、尼泊尔和许多南美国家。令人惊讶的是， 与种族相关的疾病发病率降低仍然是个谜。非裔美国人，非洲黑人， 澳大利亚原住民，可能还有一些国家的罗马人，很少会患上IgAN。通过 通过对来自白色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 产生具有改变的聚糖的IgA 1的细胞被EB病毒（EBV）感染，EB病毒分泌 在其终末分化时，具有改变的聚糖部分的IgA 1。对于我们的工作假设来说，重要的是， 在白色患者IgA阳性细胞中检测到IgA、EBV感染细胞，而在健康成人中检测到IgA、EBV感染细胞 在非裔美国人中，EBV主要与IgM/IgD和IgG阳性B细胞相关。其原因 通过先前被忽视的伊加成熟的差异，揭示了显着的差异 系统与EBV感染的时间有关。血清伊加水平和伊加- 生产细胞严格依赖于年龄。儿童早期（1-5岁）伊加水平较低， IgA生成细胞和成人水平在青春期达到。然而，非洲裔美国人，非洲 澳大利亚土著黑人在生命的前2年感染EB病毒。因此在 在天然伊加缺乏时，EBV感染“非IgA阳性”细胞。事实上，我们报告说，在非洲， 美国成年人的EB病毒并不主要存在于伊加细胞中！目前，我们缺少的信息 关于伊加系统和表型的发育和成熟的特征， 与血清阴性白色人相比，血清阳性非裔美国人中EBV感染细胞的特征 孩子这一信息对于阐明IgAN的免疫发病机制和基础免疫治疗是必不可少的。 澄清种族差异。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 防止IgAN的发展。这将通过确定EBV对以下疾病的不同影响来实现： 血清学阳性和血清学阴性AA与不同种族白色儿童循环中伊加的特征 年龄此外，我们将确定EB病毒感染如何影响伊加细胞的表型和归巢潜力 来自血清阳性AA儿童的外周血。