Abstract
Multiple sclerosis (MS) is an autoimmune chronic inflammatory disease of the central nervous system (CNS). Cross-reactivity of neuronal proteins with exogenous antigens is considered one of the possible mechanisms of MS triggering. Previously, we showed that monoclonal myelin basic protein (MBP)-specific antibodies from MS patients cross-react with Epstein–Barr virus (EBV) latent membrane protein 1 (LMP1). In this study, we report that exposure of mice to LMP1 results in induction of myelin-reactive autoantibodies in vivo. We posit that chronic exposure or multiple acute exposures to viral antigen may redirect B cells from production of antiviral antibodies to antibodies, specific to myelin antigen. However, even in inbred animals, which are almost identical in terms of their genomes, such an effect is only observed in 20–50% of animals, indicating that this change occurs by chance, rather than systematically. Cross-immunoprecipitation analysis showed that only part of anti-MBP antibodies from LMP1-immunized mice might simultaneously bind LMP1. In contrast, the majority of anti-LMP1 antibodies from MBP-immunized mice bind MBP. De novo sequencing of anti-LMP1 and anti-MBP antibodies by mass spectrometry demonstrated enhanced clonal diversity in LMP1-immunized mice in comparison with MBP-immunized mice. We suggest that induction of MBP-reactive antibodies in LMP1-immunized mice may be caused by either Follicular dendritic cells (FDCs) or by T cells that are primed by myelin antigens directly in CNS. Our findings help to elucidate the still enigmatic link between EBV infection and MS development, suggesting that myelin-reactive antibodies raised as a response toward EBV protein LMP1 are not truly cross-reactive but are primarily caused by epitope spreading.
Highlights
B cells and, antibodies are involved in pathogenesis of a variety of autoimmune disorders
Antibodies from LMP1immunized mice bound both, initial antigen and myelin basic protein (MBP), regardless the immunization scheme, whereas in MBP-immunized mice antibodies toward latent membrane protein 1 (LMP1) arose only in the Chronic Immune Response (CIR) model mice
Levels of anti-MBP antibodies in mice immunized with LMP1 per the priming-booster scheme were similar in SJL and BALB/c mice
Summary
B cells and, antibodies are involved in pathogenesis of a variety of autoimmune disorders. These autoanibodies could be either a consequence of disease progression or directly participate in its development via different mechanisms such as antibody-mediated cell lysis, opsonization, cross-linking of Fc receptors, blocking or activation of cell receptors, and repair processes [1]. One of the possible mechanisms to overcome the immune tolerance post factum is a cross-reactivity caused by a molecular mimicry. This hypothesis suggests that B cells initially recruited to neutralize external pathogens after somatic mutations and maturation start to produce low-to-middle affinity cross-reactive antibodies able to recognize self-antigens. Lipo-oligosaccharides and gangliosides of Campylobacter jejuni may induce cross-reactive antibodies toward GM1, GM1b, and GAlNAc-GD1 in motor Guillain–Barre syndrome [14]
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