Systemic lack of canonical histamine receptor signaling results in increased resistance to autoimmune encephalomyelitis

Histamine (HA) is a key regulator of experimental allergic encephalomyelitis (EAE), the autoimmune model of multiple sclerosis. HA exerts its effects through four known G-protein-coupled receptors: H₁, H₂, H₃, and H₄ (histamine receptors; H _1-4R). Using HR-deficient mice, our laboratory has demonstrated that H₁R, H₂R, H₃R, and H₄R play important roles in EAE pathogenesis, by regulating encephalitogenic T cell responses, cytokine production by APCs, blood-brain barrier permeability, and T regulatory cell activity, respectively. Histidine decarboxylase-deficient mice (HDCKO), which lack systemic HA, exhibit more severe EAE and increased Th1 effector cytokine production by splenocytes in response to myelin oligodendrocyte gp35-55. In an inverse approach, we tested the effect of depleting systemic canonical HA signaling on susceptibility to EAE by generating mice lacking all four known G-protein-coupled-HRs (H_1-4RKO mice). In this article, we report that in contrast to HDCKO mice, H_1-4RKO mice develop less severe EAE compared with wild-type animals. Furthermore, splenocytes from immunized H_1-4RKO mice, compared with wild-type mice, produce a lower amount of Th1/Th17 effector cytokines. The opposing results seen between HDCKO and H_1-4RKO mice suggest that HA may signal independently of H_1-4R and support the existence of an alternative HAergic pathway in regulating EAE resistance. Understanding and exploiting this pathway has the potential to lead to new disease-modifying therapies in multiple sclerosis and other autoimmune and allergic diseases.