title: Systemic lack of canonical histamine receptor signaling results in increased resistance to autoimmune encephalomyelitis.
abstract: 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(1-4)R). 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(1-4)RKO mice). In this article, we report that in contrast to HDCKO mice, H(1-4)RKO mice develop less severe EAE compared with wild-type animals. Furthermore, splenocytes from immunized H(1-4)RKO mice, compared with wild-type mice, produce a lower amount of Th1/Th17 effector cytokines. The opposing results seen between HDCKO and H1-4RKO mice suggest that HA may signal independently of H1-4R 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.
authors.affiliation: Department of Medicine, University of Vermont, Burlington, VT 05405, USA.
authors.forename: Naresha
authors.initials: N
authors.lastname: Saligrama
authors.forename: Laure K
authors.initials: LK
authors.lastname: Case
authors.forename: Roxana
authors.initials: R
authors.lastname: del Rio
authors.forename: Rajkumar
authors.initials: R
authors.lastname: Noubade
authors.forename: Cory
authors.initials: C
authors.lastname: Teuscher
mesh_terms: D000818:Animals; D000938:Antigen-Presenting Cells; D001812:Blood-Brain Barrier / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D002454:Cell Differentiation; D002478:Cells, Cultured; D016207:Cytokines / Q000096:biosynthesis; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology* / Q000378:metabolism; D006632:Histamine / Q000378:metabolism*; D006640:Histidine Decarboxylase / Q000172:deficiency / Q000235:genetics* / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009103:Multiple Sclerosis / Q000276:immunology; D063308:Myelin-Oligodendrocyte Glycoprotein / Q000494:pharmacology; D010446:Peptide Fragments / Q000494:pharmacology; D011968:Receptors, Histamine / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D016207:Cytokines; D063308:Myelin-Oligodendrocyte Glycoprotein; D010446:Peptide Fragments; D011968:Receptors, Histamine; C445081:myelin oligodendrocyte glycoprotein (35-55); D006632:Histamine; D006640:Histidine Decarboxylase