Immune responses in the CNS are common, despite its perception as a site of immune privilege. These responses can be mediated by resident microglia and astrocytes, which are innate immune cells without direct counterparts in the periphery. Furthermore, CNS immune reactions often take place in virtual isolation from the innate/adaptive immune interplay that characterizes peripheral immunity. However, microglia and astrocytes also engage in significant cross-talk with CNS-infiltrating T cells and other components of the innate immune system. Here we review the cellular and molecular basis of innate immunity in the CNS and discuss what is known about how outcomes of these interactions can lead to resolution of infection, neurodegeneration, or neural repair depending on the context.

In addition to their well characterized role in allergic inflammation, recent data confirm that mast cells play a more extensive role in a variety of immune responses. However, their contribution to autoimmune and neurologic disease processes has not been investigated. Experimental allergic encephalomyelitis (EAE) and its human disease counterpart, multiple sclerosis, are considered to be CD4+ T cell–mediated autoimmune diseases affecting the central nervous system. Several lines of indirect evidence suggest that mast cells could also play a role in the pathogenesis of both the human and murine disease. Using a myelin oligodendrocyte glycoprotein (MOG)-induced model of acute EAE, we show that mast cell–deficient W/Wv mice exhibit significantly reduced disease incidence, delayed disease onset, and decreased mean clinical scores when compared with their wild-type congenic littermates. No differences were observed in MOG-specific T and B cell responses between the two groups, indicating that a global T or B cell defect is not present in W/Wv animals. Reconstitution of the mast cell population in W/Wv mice restores induction of early and severe disease to wild-type levels, suggesting that mast cells are critical for the full manifestation of disease. These data provide a new mechanism for immune destruction in EAE and indicate that mast cells play a broader role in neurologic inflammation.

There are many parallels between allergic and autoimmune responses. Both are considered hypersensitivity responses: pathologies that are elicited by an exuberant reaction to antigens that do not pose any inherent danger to the organism. Although mast cells have long been recognized as central players in allergy, only recently has their role in autoimmunity become apparent. Because of the commonalities of these responses, much of what we have learned about the underlying mast cell-dependent mechanisms of inflammatory damage in allergy and asthma can be used to understand autoimmunity. Here we review mast cell biology in the context of autoimmune disease. We discuss the huge diversity in mast cell responses that can exert either proinflammatory or antiinflammatory activity. We also consider the myriad factors that cause one response to predominate over another in a particular immune setting.

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Mast cells contribute to the pathogenesis of experimental autoimmune encephalomyelitis, a rodent model of the human demyelinating disease multiple sclerosis. Yet their site and mode of action is unknown. In both diseases, myelin-specific T cells are initially activated in peripheral lymphoid organs. However, for disease to occur, these cells must enter the immunologically privileged CNS through a breach in the relatively impermeable blood-brain barrier. In this study, we demonstrate that a dense population of resident mast cells in the meninges, structures surrounding the brain and spinal cord, regulate basal CNS barrier function, facilitating initial T cell CNS entry. Through the expression of TNF, mast cells recruit an early wave of neutrophils to the CNS. We propose that neutrophils in turn promote the blood-brain barrier breach and together with T cells lead to further inflammatory cell influx and myelin damage. These findings provide specific targets for intervention in multiple sclerosis as well as other immune-mediated CNS diseases.