Mast Cells and Innate Lymphoid Cells: Underappreciated Players in CNS Autoimmune Demyelinating Disease.

Melissa A Brown,Rebecca B Weinberg

doi:10.3389/fimmu.2018.00514

Abstract

Multiple sclerosis (MS) and its mouse model, experimental autoimmune encephalomyelitis, are autoimmune CNS inflammatory diseases. As a result of a breakdown in the relatively impermeable blood–brain barrier (BBB) in affected individuals, myelin-specific CD4+ and CD8+ T cells gain entry into the immune privileged CNS and initiate myelin, oligodendrocyte, and nerve axon destruction. However, despite the absolute requirement for T cells, there is increasing evidence that innate immune cells also play critical amplifying roles in disease pathogenesis. By modulating the character and magnitude of the myelin-reactive T cell response and regulating BBB integrity, innate cells affect both disease initiation and progression. Two classes of innate cells, mast cells and innate lymphoid cells (ILCs), have been best studied in models of allergic and gastrointestinal inflammatory diseases. Yet, there is emerging evidence that these cell types also exert a profound influence in CNS inflammatory disease. Both cell types are residents within the meninges and can be activated early in disease to express a wide variety of disease-modifying cytokines and chemokines. In this review, we discuss how mast cells and ILCs can have either disease-promoting or -protecting effects on MS and other CNS inflammatory diseases and how sex hormones may influence this outcome. These observations suggest that targeting these cells and their unique mediators can be exploited therapeutically.

Highlights

TO MULTIPLE SCLEROSIS (MS) AND EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS (EAE)MS: A Sex-Dimorphic Autoimmune Disease With a Variable CourseMultiple sclerosis is a CNS demyelinating disease of unknown etiology [reviewed in Ref. [1]]
Our work revealed that interactions between resident mast cells and autoreactive T cells in the meninges induce caspase-1-dependent IL-1β production by mast cells, which in turn elicits T cell production of GM-cerebrospinal fluid (CSF) [50]
The realization that neutrophils, mast cells, and innate lymphoid cells (ILCs) can exert profound influences on T cell polarization, effector function, and immune cell infiltration to the CNS suggests that new therapeutic strategies should be considered that target these cells and their mediators

Summary

INTRODUCTION

Multiple sclerosis is a CNS demyelinating disease of unknown etiology [reviewed in Ref. [1]]. Differences in a phenotype between wild type and KitW/Wv mice indicate a possible role for mast cells and this mouse model has provided an invaluable tool for defining mast cell contributions to protective and pathologic immunity [reviewed in Ref. Disease induction conditions that elicit early and strong T cell responses in EAE models, conditions that do not recapitulate the normal evolution of MS in humans, can mask the contributions of mast cells In support of this idea, Piconese et al showed that altering disease inducing conditions in KitW/Wv mice changed the apparent mast cell dependence on severe disease development [82]. Antibody blockade of IL-33 abolishes EAE protection in males

A CONTEXT-DEPENDENT PROTECTIVE FUNCTION OF MAST CELLS IN EAE

Findings

CONCLUDING REMARKS