Combinatorial roles for histamine H ₁-H ₂ and H ₃-H ₄ receptors in autoimmune inflammatory disease of the central nervous system

Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system in which histamine (HA) and its receptors have been implicated in disease pathogenesis. HA exerts its effects through four different G protein-coupled receptors designated H ₁-H ₄. We previously examined the effects of traditional single HA receptor (HR) knockouts (KOs) in experimental allergic encephalomyelitis (EAE), the autoimmune model of MS. Our results revealed that H ₁R and H ₂R are propathogenic, while H ₃R and H ₄R are antipathogenic. This suggests that combinatorial targeting of HRs may be an effective disease-modifying therapy (DMT) in MS. To test this hypothesis, we generated H ₁H ₂RKO and H ₃H ₄RKO mice and studied them for susceptibility to EAE. Compared with wild-type (WT) mice, H ₁H ₂RKO mice developed a less severe clinical disease course, whereas the disease course of H ₃H ₄RKO mice was more severe. H ₁H ₂RKO mice also developed less neuropathology and disrupted blood brain barrier permeability compared with WT and H ₃H ₄RKO mice. Additionally, splenocytes from immunized H ₁H ₂RKO mice produced less interferon(IFN)-γ and interleukin(IL)-17. These findings support the concept that combined pharmacological targeting of HRs may be an appropriate ancillary DMT in MS and other immunopathologic diseases.