Type 2 Inflammatory Responses in Autoimmune Demyelination of the Central Nervous System: Recent Advances

Figure 1

Potential mechanisms of CNS autoimmune inflammation driven by type 2 immune cells and mediators. (1) Passive transfer of myelin-specific Th2 cells can trigger inflammation and demyelination in experimental models of central nervous system (CNS) autoimmunity [30, 31]. Of note, autoreactive Th2 cells have been found in pattern II plaques of secondary-progressive (SP)MS [24, 25]. Furthermore, increased concentrations of IL-13 have been detected in the cerebrospinal fluid (CSF) of NMO [11] and the opticospinal variant of MS, which shares several features with NMO [27]. Higher percentages of IFN-γ^- IL-4⁺ T cells have also been detected in the CSF of opticospinal MS compared to classical MS [27]. Th2 cells might amplify autoimmune responses through the secretion of IL-13 and IL-4, key cytokines for the induction of B cell proliferation and Ig isotype switch toward IgG1 and IgE production [1, 2]. IgG and complement deposition are key features of both pattern II MS and NMO lesions [9, 18], suggestive of complement-dependent cell cytotoxicity (CDCC) processes. Moreover, IgE without antigen binding can induce the activation and the release of inflammatory cytokines by mast cells (MCs) [33]. (2) Mast cells are CNS-resident immune cells and have been localized at the meningeal interface in both EAE and in a subset of MS patients [47, 56]. MCs have been proposed to sustain CNS autoimmunity through at least two mechanisms: (i) MC-derived TNF supports CNS infiltration of neutrophils [47], which have been suggested as first-line amplifiers of EAE and MS inflammatory lesions [57], by promoting blood-brain barrier (BBB) breach [47]; (ii) MC-release of IL-1β can enhance the encephalitogenic potential of CNS-infiltrating myelin-reactive Th17 cells that are restimulated by local antigen presenting cells (APC) [56]. (3) Th2 cytokines IL-4 and IL-5 are two crucial chemoattractants and growth factors of eosinophils, which infiltrate NMO lesions [9]. Eosinophils can bind aquaporin 4- (AQP4-) specific IgG through the Fcγ receptor (FcγR) and mediate antibody-dependent cell cytotoxicity (ADCC) of AQP4-expressing astrocytes [10].