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.

摘要 IgA肾病是一种自身免疫性疾病，其中只有IgA1亚类的IgA含有 糖链改变的部分，主要是作为一种抗原被自然产生的抗糖链抗体识别 免疫球蛋白同型，导致肾炎免疫复合体的形成。IgA肾病的发病率 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)，但在中非很少见，在 印度、孟加拉国、尼泊尔和许多南美国家。令人惊讶的是，发音的 与种族相关的发病率下降仍然是个谜。非裔美国人，非裔黑人， 澳大利亚原住民，可能还有一些国家的罗曼人，很少患上IgAN。通过 我们发现，对白人IgAN患者、健康对照组和非裔美国人的血清和细胞进行了分析 产生糖链改变的IgA1的细胞感染了爱泼斯坦-巴尔病毒(EBV)，它分泌 在它们的末端分化时，IgA1的糖链部分发生了变化。对于我们的工作假设来说很重要，在 在白人患者的IgA阳性细胞中检测到IgN、EBV感染的细胞，而在健康成年人中检测到 在非裔美国人中，EBV主要与IgM/IGD和IgG阳性的B细胞有关。这样做的原因是 以前被忽视的免疫球蛋白A成熟的差异被揭示出来 与EBV感染的时间有关的系统。血清免疫球蛋白A水平及血清免疫球蛋白A抗体阳性率 产生的细胞严格依赖于年龄。儿童早期(1-5岁)的免疫球蛋白A水平较低 而产生IgA的细胞和成人的水平在青春期达到。然而，非裔美国人，非裔美国人 黑人，澳大利亚原住民在他们生命的头两年感染了EBV。因此，在 自然免疫球蛋白A缺乏的时间，EBV感染“非免疫球蛋白阳性”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IgA细胞中！目前，我们缺少这一信息 关于免疫球蛋白A系统和表型发育成熟的特点 血清阳性非裔美国人与血清阴性白人EB病毒感染细胞的特征比较 孩子们。这些信息对于阐明IgAN和BASIC的免疫发病机制是必不可少的。 澄清与种族有关的差异。因此，我们建议为我们的 工作假设：再障儿童的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 血清阳性和阴性再生障碍性贫血与不同性别白种儿童循环免疫球蛋白A特征 年龄。此外，我们还将确定EBV感染如何影响IgA细胞的表型和归巢潜能 来自血清阳性再生障碍性贫血儿童的外周血液。