Abstract
BackgroundClinical studies of B cell depletion in Multiple Sclerosis (MS) have revealed that B Lymphocytes are involved in the neuro-inflammatory process, yet it remains unclear how B cells can exert pro- and anti-inflammatory functions during MS. Experimental Autoimmune Encephalomyelitis (EAE) is an animal model of MS whereby myelin-specific T cells become activated and subsequently migrate to the Central Nervous System (CNS) where they perform pro-inflammatory functions such as cytokine secretion. Typically EAE is induced by immunization of mice of a susceptible genetic background with peptide antigen emulsified in Complete Freund's Adjuvant. However, novel roles for B-lymphocytes in EAE may also be explored by immunization with full-length myelin oligodendrocyte glycoprotein (MOG) that contains the B cell conformational epitope. Here we show that full length MOG immunization promotes a chronic disease in mice that depends on antigen-driven secondary diversification of the B cell receptor.MethodsActivation-Induced Deaminase (AID) is an enzyme that is essential for antigen-driven secondary diversification of the B cell receptor. We immunized AID−/− mice with the extracellular domain (amino acids 1–120) of recombinant human MOG protein (rhMOG) and examined the incidence and severity of disease in AID−/− versus wild type mice. Corresponding with these clinical measurements, we also evaluated parameters of T cell activation in the periphery and the CNS as well as the generation of anti-MOG antibodies (Ab).ConclusionsAID−/− mice exhibit reduced severity and incidence of EAE. This suggests that the secondary diversification of the B cell receptor is required for B cells to exert their full encephalogenic potential during rhMOG-induced EAE, and possibly also during MS.
Highlights
It has been long recognized that B cells are present in the Multiple Sclerosis (MS) central nervous system (CNS) [1,2], including white matter lesions [3,4], the normal appearing white matter [5], the cerebrospinal fluid (CSF) [6,7], perivascular spaces in the Central Nervous System (CNS) [3], and the CNS meninges [8]
Activation-Induced Deaminase (AID)-deficient mice exhibit impaired EAE in response to recombinant human MOG protein (rhMOG) immunization To examine the role of B cell receptor (BCR) secondary diversification during
Compared to WT mice, the incidence and severity of disease provoked by rhMOG was significantly reduced in AID2/2 mice throughout the chronic stage of the disease (Fig. 1B, Table 1)
Summary
It has been long recognized that B cells are present in the MS central nervous system (CNS) [1,2], including white matter lesions [3,4], the normal appearing white matter [5], the cerebrospinal fluid (CSF) [6,7], perivascular spaces in the CNS [3], and the CNS meninges [8]. B cells have varying roles in Experimental Autoimmune Encephalomyelitis (EAE), an animal model of MS, depending on which EAE model is employed. An alternative model to MOG35-55 C57Bl/6 EAE is the induction of EAE with full-length myelin proteins that contain B cell conformational epitopes [14]. Experimental Autoimmune Encephalomyelitis (EAE) is an animal model of MS whereby myelin-specific T cells become activated and subsequently migrate to the Central Nervous System (CNS) where they perform pro-inflammatory functions such as cytokine secretion. Novel roles for B-lymphocytes in EAE may be explored by immunization with full-length myelin oligodendrocyte glycoprotein (MOG) that contains the B cell conformational epitope. We show that full length MOG immunization promotes a chronic disease in mice that depends on antigen-driven secondary diversification of the B cell receptor
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