IgA Nephropathy: Impact of EBV Infection on Racial Differences

摘要

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.