Frontiers in Immunology (Feb 2020)

Role of Epstein-Barr Virus in Pathogenesis and Racial Distribution of IgA Nephropathy

  • Katerina Zachova,
  • Petr Kosztyu,
  • Josef Zadrazil,
  • Karel Matousovic,
  • Karel Vondrak,
  • Petr Hubacek,
  • Bruce A. Julian,
  • Zina Moldoveanu,
  • Zdenek Novak,
  • Klara Kostovcikova,
  • Milan Raska,
  • Milan Raska,
  • Jiri Mestecky,
  • Jiri Mestecky,
  • Jiri Mestecky

DOI
https://doi.org/10.3389/fimmu.2020.00267
Journal volume & issue
Vol. 11

Abstract

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IgA nephropathy (IgAN) is the dominant type of primary glomerulonephritis worldwide. However, IgAN rarely affects African Blacks and is uncommon in African Americans. Polymeric IgA1 with galactose-deficient hinge-region glycans is recognized as auto-antigen by glycan-specific antibodies, leading to formation of circulating immune complexes with nephritogenic consequences. Because human B cells infected in vitro with Epstein-Barr virus (EBV) secrete galactose-deficient IgA1, we examined peripheral blood B cells from adult IgAN patients, and relevant controls, for the presence of EBV and their phenotypic markers. We found that IgAN patients had more lymphoblasts/plasmablasts that were surface-positive for IgA, infected with EBV, and displayed increased expression of homing receptors for targeting the upper respiratory tract. Upon polyclonal stimulation, these cells produced more galactose-deficient IgA1 than did cells from healthy controls. Unexpectedly, in healthy African Americans, EBV was detected preferentially in surface IgM- and IgD-positive cells. Importantly, most African Blacks and African Americans acquire EBV within 2 years of birth. At that time, the IgA system is naturally deficient, manifested as low serum IgA levels and few IgA-producing cells. Consequently, EBV infects cells secreting immunoglobulins other than IgA. Our novel data implicate Epstein-Barr virus infected IgA+ cells as the source of galactose-deficient IgA1 and basis for expression of relevant homing receptors. Moreover, the temporal sequence of racial-specific differences in Epstein-Barr virus infection as related to the naturally delayed maturation of the IgA system explains the racial disparity in the prevalence of IgAN.

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