Gammaherpesvirus infection drives age-associated B cells toward pathogenicity in EAE and MS

Abstract

While age-associated B cells (ABCs) are known to expand and persist following viral infection and during autoimmunity, their interactions are yet to be studied together in these contexts. Here, we directly compared CD11c + T-bet + ABCs using models of Epstein-Barr virus (EBV), gammaherpesvirus 68 (γHV68), multiple sclerosis (MS), and experimental autoimmune encephalomyelitis (EAE), and found that each drives the ABC population to opposing phenotypes. EBV infection has long been implicated in MS, and we have previously shown that latent γHV68 infection exacerbates EAE. Here, we demonstrate that ABCs are required for γHV68-enhanced disease. We then show that the circulating ABC population is expanded and phenotypically altered in people with relapsing MS. In this study, we show that viral infection and autoimmunity differentially affect the phenotype of ABCs in humans and mice, and we identify ABCs as functional mediators of viral-enhanced autoimmunity.

CD11c+ B cells in relapsing–remitting multiple sclerosis and effects of anti‐CD20 therapy

“…expansion of CD11c + B cells in MS has been reported in two studies; notably, CD21 was used in defining the subset in both studies. 14,15 The higher proportions of CD11c + B cells and plasmablasts in peripheral blood after anti-CD20 therapy is consistent with findings in other studies. 34,35 Plasmablasts have limited surface expression of CD20, which explains why some of them could be refractory to anti-CD20 therapy.…”

“…Furthermore, we did not find any association between age and CD11c + B‐cell frequency in neither controls nor untreated patients with RRMS. Peripheral blood expansion of CD11c + B cells in MS has been reported in two studies; notably, CD21 was used in defining the subset in both studies 14,15 …”

“…The implication of CD11c + B cells may depend on the context or subsets. Indeed, a study of experimental autoimmune encephalomyelitis found atypical B cells to be protective in experimental autoimmune encephalomyelitis but required for gammaherpesvirus‐mediated worsening of the disease 14 . In the autoimmune skin disease pemphigus, patients who relapsed after rituximab treatment had a higher frequency of CD11c + B cells at month 36 than those who were relapse‐free 41 .…”

“…Atypical B cells differ from conventional memory B cells in their expression of T‐bet and CD11c, increased expression of fraction crystallizable (Fc) receptor‐like 5 (FcRL5), increased ability to present antigen to T helper cells and their propensity to develop into plasma cells 9–12 . They have been found expanded with age, viral infections, and immune‐mediated conditions, and are proposed mediators of autoimmunity 10,12–14 . In MS, one study found CSF enrichment of atypical B cells and increased frequency in peripheral blood compared to healthy controls 15 .…”

Age-associated B cells are long-lasting effectors that impede latent γHV68 reactivation

“…1F-M). Previously, we demonstrated that ABCs display a sex bias during experimental autoimmune encephalomyelitis and at 35 days post-γHV68 infection in the spleen 30 . Here, we have extended this finding and shown that ABCs display female sex bias in both the circulation and spleen during lytic and latent γHV68 infection.…”