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Myelin antigen capture in the CNS by B cells expressing EBV latent membrane protein 1 leads to demyelinating lesion formation [scRNA-Seq]

ABSTRACT: The efficacy of B cell depletion therapies, and association with the B lymphotropic Epstein- Barr virus (EBV) implicate B cells in the demyelinating autoimmune disease multiple sclerosis. After observing myelin-reactive B cells in the naïve human repertoire, we studied how such cells behave in the central nervous system. In mice, viral infections induce infiltration of B cells independent of phenotype and specificity into the otherwise lymphocyte-poor brain, and myelin-reactive B cells then capture antigen directly from parenchyma. Trafficking of these antigen-loaded B cells to draining lymph nodes was not observed, and without T cell help, antigen-capturing B cells die rapidly. CD40L signaling or EBV latent membrane protein 1 (LMP1) can override this checkpoint, leading to in situ plasma cell differentiation and antibody-mediated, demyelinating lesion formation. These observations explain the dependency of disease incidence on prior EBV infection, and the increased risk associated with brain infections, and suggest possible treatment strategies.

ORGANISM(S): Mus musculus

PROVIDER: GSE286541 | GEO | 2026/01/13

REPOSITORIES: GEO

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Project description:The Epstein Barr virus (EBV) encoded latent membrane protein-1 (LMP1) is a functional homologue of the tumor necrosis factor receptor family and contributes substantially to the oncogenic potential of EBV through activation of Nuclear Factor-kappaB (NF-kappaB). MicroRNAs (miRNAs) are a class of small RNA molecules that are involved in the regulation of cellular processes such as growth, development, and apoptosis, and have recently been linked to cancer phenotypes. Through miRNA microarray analysis, we demonstrate that LMP1 dysregulates the expression of several cellular miRNAs, including the most highly regulated of these, miR-146a. Quantitative RT-PCR analysis confirmed induced expression of miR-146a by LMP1. Analysis of miR-146a expression in EBV latency type III and type I cell lines revealed substantial expression of miR-146a in type III (which express LMP1) but not in type I cell lines. Reporter studies demonstrated that LMP1 induces miR-146a predominantly through two NF-kappaB binding sites in the miR-146a promoter and identified a role for an OCT-1 site in conferring basal and induced expression. Array analysis of cellular mRNAs expressed in Akata cells transduced with an miR-146a expressing retrovirus identified genes that are directly or indirectly regulated by miR-146a, including a group of interferon responsive genes that are inhibited by miR-146a. Since miR-146a is known to be induced by agents that activate the interferon response pathway (including LMP1), these results suggest that miR-146a functions in a negative feedback loop to modulate the intensity and/or duration of the interferon response. Keywords: Analysis of gene expression changes altered by the microRNA, miR-146a EBV positive Burkitt's lymphoma cell line, Akata, was infected with the control retrovirus, pEhyg, or the miR-146a expressing retrovirus, pEhyg-miR-146a. Two infections were carried out for control retrovirus and two infections were carried out with the pEhyg-miR-146a retrovirus. Total RNA was prepared from each of the 4 infections. Control and miR-146a infection set 1 was subjected to dual color array analysis on chip 1. Control and miR-146a infection set 2 was subjected to dual color array analysis on second array of chip 1. Dye swaps of each of these were carried out on two arrays from a second chip (chip 2).

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Myelin antigen capture in the CNS by B cells expressing EBV latent membrane protein 1 leads to demyelinating lesion formation [scRNA-Seq]

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