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

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.

Keywords: experimental autoimmune encephalomyelitis; innate immunity; innate lymphoid cells; mast cells; meninges; multiple sclerosis; sex-dimorphic autoimmunity; testosterone.

Figure 1

The meninges are sites of active immunity. The meninges are tripartite structures that surround the brain and spinal cord. Multiple innate immune cells reside here. T cells normally transit through the meninges during immunosurveillance and can encounter antigens presented on resident dendritic cells (DCs) or macrophages. Of note, compared to many tissues surveyed, mast cells and innate lymphoid cells are most prevalent in the meninges. These sites serve as first-line protection against infections that threaten the CNS, but are also gateways that can promote chronic CNS inflammation. The inflammatory milieu that is established in the meninges in experimental autoimmune encephalomyelitis/multiple sclerosis is proposed to allow mediator and immune cell infiltration that directly or indirectly damages myelin, olgodendrocytes, and nerves.

Figure 2

Pathogenic actions of mast cells in experimental autoimmune encephalomyelitis. Mast cells are activated in early disease and express mediators that affect blood–brain barrier (BBB) integrity and license T cells for pathogenicity.

Figure 3

Sex-specific protective actions of mast cells and innate lymphoid cells (ILCs) in male SJL mice. In the sex-dimorphic model of multiple sclerosis in SJL mice, males are protected. Testosterone activates mast cells [and perhaps other androgen receptor (AR)⁺ cells] inducing IL-33, which in turn activates the Th2-promoting action of ST2 + ILC2s. These cells limit the Th17-dominated response characteristic of susceptible females and drive a non-pathogenic Th2 anti-myelin response.

Figure 4

Pathogenic actions of innate lymphoid cells (ILCs) in experimental autoimmune encephalomyelitis. ILC1s and ILC3s express a number of cell surface receptors and mediators that can sustain memory T cells, cause local loss of blood–brain barrier (BBB) integrity, and recruit neutrophils, T cells, and myeloid cells to the meninges and CNS.