We have previously demonstrated that Bordetella pertussis toxin-induced HA sensitization (Bphs) is a shared autoimmune disease susceptibility gene in EAE and experimental allergic orchitis, and positional candidate gene cloning identified Bphs to be Hrh1 [[27]]. In addition, gene targeting ABC294640 in vivo studies from our lab and other groups demonstrated that HA, H1R, H2R, H3R, and H4R play important roles in EAE susceptibility and pathogenesis, either by regulating

encephalitogenic T-cell responses, cytokine production by antigen-presenting cells (APCs), BBB permeability, or T regulatory (Treg)-cell activity [[27, 30-34]]. The current therapeutic mainstays for MS include IFN-β and glatiramer acetate; however, in most instances, these Selleck Decitabine drugs are of limited efficacy [[35]]. Consequently, research efforts have been increasingly directed toward identifying new therapeutic modalities and disease-modifying therapies (DMTs). Previously, using individual H1R-H4RKO mice, we showed that H1R and H2R are propathogenic, whereas H3R and H4R are antipathogenic. This

suggests that combinatorial pharmacological targeting of HRs may be an effective DMT in MS. To test this hypothesis, we generated H1H2RKO and H3H4RKO mice on the C57BL/6J (B6) background and studied them for susceptibility to EAE elicited by immunization with myelin oligodendrocyte glycoprotein peptide 35–55 (MOG35–55). The results of our study show that compared to B6 mice, H1H2RKO

mice exhibit decreased susceptibility to EAE, whereas H3H4RKO mice develop more severe disease. The findings of our study support the concept that combined pharmacological targeting of HRs may be an appropriate DMT in the treatment of MS and other immunopathologic diseases, particularly given the recent development of highly selective agonists and antagonists for H3R and H4R [[36]]. EAE was induced in B6, H1H2RKO, and H3H4RKO mice by immunization using a 2× MOG35–55-CFA protocol [[37, 38]]. The severity of the clinical disease courses differed significantly among the three strains (F = 28.5; p < 0.0001) (Fig. 1A), with H1H2RKO mice exhibiting significantly less severe disease than both B6 (F = 17.3; p < 0.0001) and H3H4RKO ADAMTS5 (F = 57.3; p < 0.0001) mice. In contrast, the severity of the clinical disease course of H3H4RKO mice was significantly greater than B6 (F = 8.2; p < 0.0001) and H1H2RKO (F = 57.3; p < 0.0001) mice. Analysis of EAE-associated clinical quantitative trait variables [[31]] revealed that the percentage of animals affected, cumulative disease score, and days affected were significantly greater in H3H4RKO compared with B6 mice. In contrast, percentage of animals affected, cumulative disease score, and days affected were significantly less in H1H2RKO compared with B6 mice (Table 1).