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

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

doi:10.3389/fimmu.2020.00267

Abstract

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.

Highlights

The most common cause of glomerulonephritis in the world, Immunoglobulin A nephropathy (IgAN), is an autoimmune disease in which IgA1-containing circulating immune complexes (CIC) deposit in the glomerular mesangium to induce tissue injury, [1,2,3,4,5], culminating in end-stage renal disease in 20–40% of patients within 20 years of the biopsy diagnosis [3]
The percentage of peripheral-blood Epstein-Barr virus (EBV)-encoded small RNAs (EBER)+ CD19+ cells related to sIg isotype indicated a preferential association with sIgA+ cells for IgA nephropathy (IgAN) patients that was not found for non-IgAN patients and White healthy controls (Figure 1D)
There were few LB/PB cells compared to the numbers of naïve and memory B cells (Figure 1E), LB/PB comprised the majority of the EBER+ population from IgAN patients (Figure 1F)

Summary

Introduction

The most common cause of glomerulonephritis in the world, Immunoglobulin A nephropathy (IgAN), is an autoimmune disease in which IgA1-containing circulating immune complexes (CIC) deposit in the glomerular mesangium to induce tissue injury, [1,2,3,4,5], culminating in end-stage renal disease in 20–40% of patients within 20 years of the biopsy diagnosis [3]. The O-glycans in the hinge region of the heavy chains of the pIgA1 are deficient in galactose (Gd-IgA1) and are recognized as autoantigen by IgG or IgA antibodies to form nephritogenic CIC [1,2,3, 5, 7,8,9,10,11,12,13,14,15,16,17,18,19,20]. IgAN is the most common form of glomerulonephritis in many countries [2, 3, 22,23,24,25,26], its prevalence displays a surprisingly unique geographical distribution. Environmental and genetic factors have been considered in these remarkable geographically related differences [24,25,26]

Methods

Results

Conclusion