A B Cell-Driven Autoimmune Pathway Leading to Pathological Hallmarks of Progressive Multiple Sclerosis in the Marmoset Experimental Autoimmune Encephalomyelitis Model.

Bert A ’T Hart,Jordon Dunham,Jon D Laman,Jan Bauer,Jack Van Horssen,Yolanda S Kap,Bart W Faber

doi:10.3389/fimmu.2017.00804

Abstract

The absence of pathological hallmarks of progressive multiple sclerosis (MS) in commonly used rodent models of experimental autoimmune encephalomyelitis (EAE) hinders the development of adequate treatments for progressive disease. Work reviewed here shows that such hallmarks are present in the EAE model in marmoset monkeys (Callithrix jacchus). The minimal requirement for induction of progressive MS pathology is immunization with a synthetic peptide representing residues 34–56 from human myelin oligodendrocyte glycoprotein (MOG) formulated with a mineral oil [incomplete Freund’s adjuvant (IFA)]. Pathological aspects include demyelination of cortical gray matter with microglia activation, oxidative stress, and redistribution of iron. When the peptide is formulated in complete Freund’s adjuvant, which contains mycobacteria that relay strong activation signals to myeloid cells, oxidative damage pathways are strongly boosted leading to more intensive pathology. The proven absence of immune potentiating danger signals in the MOG34–56/IFA formulation implies that a narrow population of antigen-experienced T cells present in the monkey’s immune repertoire is activated. This novel pathway involves the interplay of lymphocryptovirus-infected B cells with MHC class Ib/Caja-E restricted CD8+ CD56+ cytotoxic T lymphocytes.

Highlights

Multiple sclerosis (MS) is a devastating autoimmune neurological disease that damages the human central nervous system (CNS) through inflammation and tissue injury [1, 2]
In a model based on selective activation of the cytotoxic T lymphocytes (CTL), we found demyelination in the white as well as the gray matter (GM) of brain and spinal cord in the absence of myelinbinding antibodies, suggesting that demyelination may have been caused by a cytotoxic process that leads to the death of ODC [33]
Stys et al posited the intriguing concept that PPMS is the real multiple sclerosis (MS), which is putatively caused by degenerative events [110]

Summary

INTRODUCTION

Multiple sclerosis (MS) is a devastating autoimmune neurological disease that damages the human central nervous system (CNS) through inflammation and tissue injury [1, 2]. The collective data (reviewed in subsequent paragraphs) indicate that the initiation phase of the model involves a combined autoimmune attack of pro-inflammatory CD4+ T cells, antibodies, macro phages (Mfs), and complement factors on CNS WM myelin [36] Via this pathway, which recapitulates the immunology of mouse EAE models, MS-like lesions are induced in the WM. Gray matter pathology was substantially more robust and present in a higher number of monkeys in the model induced with MOG34–56/CFA, indicating that GM pathology in low responder marmosets can be amplified by innate immune stimulation of myeloid cells by the mycobacteria present in CFA Lesions in this model are characterized by the activation of oxidative damage pathways, including the redistribution of iron [37]. Treatment with ustekinumab at a late disease stage only delayed the onset of clinically evident EAE, indicating that Th1/Th17 cells have a less prominent pathogenic role than in the initiation phase of the disease [47]

B Cell Involvement

A CRITICAL ROLE OF MEMORY B CELLS IN MS

Findings

CONCLUDING REMARKS