Role of the innate immune system in the pathogenesis of multiple sclerosis

doi:10.1016/j.jneuroim.2009.10.015

Journal of Neuroimmunology

Volume 221, Issues 1–2, 15 April 2010, Pages 7-14

https://doi.org/10.1016/j.jneuroim.2009.10.015 Get rights and content

Abstract

Multiple sclerosis (MS) is a chronic inflammatory autoimmune disease with heterogeneous clinical presentations and course. MS is considered to be a T cell mediated disease but in recent years contribution of innate immune cells in mediating MS pathogenesis is being appreciated. In this review, we have discussed the role of various innate immune cells in mediating MS. In particular, we have provided an overview of potential anti-inflammatory or pro-inflammatory function of DCs, microglial Cells, NK cells, NK-T cells and gamma delta T cells along with their interaction among themselves and with myelin. Given the understanding of the role of the innate immune cells in MS, it is possible that immunotherapeutic intervention targeting these cells may provide a better and effective treatment.

Introduction

Being the earliest defense against pathogens, the innate immune system fights against infections and protects against self or innocuous antigens. Various cell types that compose the innate immune system share antigen recognition ability through their invariant receptors which do not undergo rearrangement and have no immunological memory. We might compare the components of the innate immune system not only to first line soldiers, but also to sentinels, who encounter the enemy and report to the “commanders”, the T and B lymphocytes, thus activating the adaptive immune response.

Multiple sclerosis (MS) is a chronic inflammatory demyelinating autoimmune disease of the central nervous system (CNS) of unknown etiology and heterogeneous clinical symptoms and course (Weiner, 2004). Depending upon clinical presentation and course, MS is classified either as relapsing remitting (RR), primary progressive (PP) or secondary progressive (SP). About 87% of MS patients exhibit a RR course of disease (Weiner, 2008), characterized by acute attack (relapse) followed by partial or full recovery (remission) occurring at variable intervals (Debouverie et al., 2008). Of these RR–MS patients, about two-thirds transition to the secondary progressive phase where neurologic disability progresses in the absence of attacks (Runmarker and Andersen, 1993, Weiner, 2008). About 10% of MS patients have a primary progressive course manifested by progressive worsening from onset (Weiner, 2009).

Much has been done to understand the etiology of MS, with a major focus on the role of the adaptive immune system. It has been suggested that myelin-specific auto-reactive lymphocytes, mainly IFN-γ secreting T helper 1 (“Th1”) cells (Baker et al., 1991, Bettelli et al., 2004) and/or IL-17 producing “Th17” cells (Bettelli et al., 2008, Korn et al., 2007) are primed in periphery by unknown factors, after which they migrate to CNS, leading to demyelination and axonal loss and subsequent neurological disability (Sospedra and Martin, 2005). Recent studies have suggested that the innate immune system also plays an important role both in the initiation and progression of MS by influencing the effector function of T and B cells (Weiner, 2008). The effector cells, in turn, express cytokines and activation markers that further activate innate immune cells (Monney et al., 2002). In this review, we will discuss the potential role of the innate immune system in the pathogenesis of MS and EAE (the murine model of MS); specifically, dendritic cells, microglial cells, natural killer cells, natural-killer T cells, mast cells and gamma-delta T cells.

Section snippets

Dendritic cells

Dendritic cells (DCs) are “professional antigen presenting cells” that play an important role in promoting activation and differentiation of naïve T cells. DCs are classified into different categories based on their surface markers. A widely accepted classification distinguishes human DCs into two categories: myeloid (Lin⁻CD11c⁺) and lymphoid/plasmacytoid (Lin⁻CD11cdimCD123⁺) (Lipscomb and Masten, 2002, MacDonald et al., 2002). The interaction of DCs with T cells is crucial in determining T

Microglial cells/macrophages

Microglial cells comprise 10–20% of glial cells and are the most common immune cells in the CNS. Microglial cells are considered resident macrophages of the nervous system, being involved in phagocytosis, antigen presentation and production of cytokines (Benveniste, 1997). Microglial cells are rapidly activated in response to injury, neuro-degeneration, infection, tumors and inflammation. Until now, there are no unique markers distinguishing microglial cells from blood-derived macrophages in

Natural killer cells

Natural killer (NK) cells contribute to both effector and regulatory functions of the innate immune system via their cytotoxic activity mainly against viral infected cells or tumor cells and through their ability to secrete different cytokines (Moretta et al., 2008). These two functions are differently implemented by the two main subsets of NK cells that have been identified in the human. The CD56dim NK cell subset has primarily cytotoxic function, whereas the CD56bright NK cell subset secretes

Mast cells

Mast cells are a crucial component of allergic responses through the release of large quantities of histamine from their cytoplasmic granules upon binding of IgE to their FcR1 receptor expressed on their cell surface. Their granules contain several molecules including histamine, that are involved in inflammatory and antimicrobial response and can secrete cytokines and other mediators through mechanisms independent from degranulation. Thus, their involvement in the immune response is not limited

Invariant NK-T cells

NK-T cells are a particular subset of T cells that share properties of NK cells and T cells and that recognize lipid antigen presented by CD1d, a lipid monomorphic glycoprotein, by a T cell receptor of limited diversity (Tupin and Kronenberg, 2006). These cells can be either CD4⁺ or CD8⁺ or can be CD4⁻ CD8⁻. These cells are considered part of the innate rather than adaptive immune system cells due to: 1) their limited TCR diversity; and 2) because these cells affect cytotoxicity and cytokine

Gamma-delta T cells

Gamma-delta T cells are a unique subset of lymphocytes that recognize non-MHC restricted antigens through invariant gamma-delta T-cell receptors. They are present in abundance in epithelium, particularly intestinal epithelium, rather than in peripheral blood (Hayday, 2000). A subset of gamma-delta T cells that express Fc-gamma receptor, CD16, has cytotoxic properties (Angelini et al., 2004). The exact role of gamma-delta T cells in MS pathology is not clear. In EAE, they have been shown to play

Acknowledgement

This work is supported in part by the National Multiple Sclerosis Society and the NIH (NS 038037-06A2).

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¹: These authors contributed equally to this review.

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Review articleRole of the innate immune system in the pathogenesis of multiple sclerosis

Abstract

Introduction

Section snippets

Dendritic cells

Microglial cells/macrophages

Natural killer cells

Mast cells

Invariant NK-T cells

Gamma-delta T cells

Acknowledgement

Blood

Cell Immunol.

J. Neuroimmunol.

Trends Immunol.

Blood

J. Neuroimmunol.

J. Neuroimmunol.

J. Neuroimmunol.

Brain Res

J. Neuroimmunol.

J. Neuroimmunol.

J. Neuroimmunol.

J. Neuroimmunol.

Semin. Immunol.

Immunity

Blood

Autoimmun. Rev.

J. Neuroimmunol.

Pharmacol. Res.

Neuroscience

Brain Res. Brain Res. Rev.

Immunoregulatory factors in multiple sclerosis patients during and after pregnancy: relevance of natural killer cells

Clin. Exp. Immunol.

Pivotal advance: HMGB1 expression in active lesions of human and experimental multiple sclerosis

J. Leukoc. Biol.

Th2 bias of CD4+ NKT cells derived from multiple sclerosis in remission

Int. Immunol.

Toll-like receptors in defense and damage of the central nervous system

J. Neuroimmune Pharmacol.

CNS myeloid DCs presenting endogenous myelin peptides ‘preferentially’ polarize CD4+ T(H)-17 cells in relapsing EAE

Nat. Immunol.

Phagocytic activity of macrophages and microglial cells during the course of acute and chronic relapsing experimental autoimmune encephalomyelitis

J. Neurosci. Res.

Bone marrow-derived mast cells accumulate in the central nervous system during inflammation but are dispensable for experimental autoimmune encephalomyelitis pathogenesis

J. Immunol.

Cytokines: influence on glial cell gene expression and function

Chem. Immunol.

Induction and effector functions of T(H)17 cells

Nature

Loss of T-bet, but not STAT1, prevents the development of experimental autoimmune encephalomyelitis

J. Exp. Med.

Regulatory CD56(bright) natural killer cells mediate immunomodulatory effects of IL-2Ralpha-targeted therapy (daclizumab) in multiple sclerosis

Proc. Natl. Acad. Sci. U. S. A.

Broad expression of Toll-like receptors in the human central nervous system

J. Neuropathol. Exp. Neurol.

The multitasking mast cell: positive and negative roles in the progression of autoimmunity

J. Immunol.

Innate immune-mediated neuronal injury consequent to loss of astrocytes

J. Neuropathol. Exp. Neurol.

Cytometric profiling in multiple sclerosis uncovers patient population structure and a reduction of CD8low cells

Brain

Natural history of multiple sclerosis in a population-based cohort

Eur. J. Neurol.

Multidirectional interactions are bridging human NK cells with plasmacytoid and monocyte-derived dendritic cells during innate immune responses

Blood

The natural killer cell-mediated killing of autologous dendritic cells is confined to a cell subset expressing CD94/NKG2A, but lacking inhibitory killer Ig-like receptors

Eur. J. Immunol.

Presentation of the self antigen myelin basic protein by dendritic cells leads to experimental autoimmune encephalomyelitis

J. Immunol.

New insights into cell responses involved in experimental autoimmune encephalomyelitis and multiple sclerosis

Immunol. Lett.

Human dendritic cells activate resting natural killer (NK) cells and are recognized via the NKp30 receptor by activated NK cells

J. Exp. Med.

Dendritic cells directly trigger NK cell functions: cross-talk relevant in innate anti-tumor immune responses in vivo

Nat. Med.

Peripheral blood gamma-delta T cells lyse fresh human brain-derived oligodendrocytes

Ann. Neurol.

Activation of invariant NKT cells by alphaGalCer administration protects mice from MOG35-55-induced EAE: critical roles for administration route and IFN-gamma

Eur. J. Immunol.

Review article
Role of the innate immune system in the pathogenesis of multiple sclerosis

Th2 bias of CD4⁺ NKT cells derived from multiple sclerosis in remission