title: Histamine H₂ receptor signaling × environment interactions determine susceptibility to experimental allergic encephalomyelitis.
abstract: Histamine and its receptors are important in both multiple sclerosis and experimental allergic encephalomyelitis (EAE). C57BL/6J (B6) mice deficient for the histamine H2 receptor (H2RKO) are less susceptible to EAE and exhibit blunted Th1 responses. However, whether decreased antigen-specific T-cell effector responses in H2RKO mice were due to a lack of H2R signaling in CD4(+) T cells or antigen-presenting cells has remained unclear. We generated transgenic mice expressing H2R specifically in T cells on the H2RKO background, and, using wild-type B6 and H2RKO mice as controls, induced EAE either in the presence or absence of the ancillary adjuvant pertussis toxin (PTX), which models the effects of infectious inflammatory stimuli on autoimmune disease. We monitored the mice for clinical signs of EAE and neuropathology, as well as effector T-cell responses using flow cytometry. EAE severity and neuropathology in H2RKO mice expressing H2R exclusively in T cells become equal to those in wild-type B6 mice only when PTX is used to elicit disease. EAE complementation was associated with frequencies of CD4(+)IFN-γ(+) and CD4(+)IL-17(+) cells that are equal to or greater than those in wild-type B6, respectively. Thus, the regulation of encephalitogenic T-cell responses and EAE susceptibility by H2R signaling in CD4(+) T cells is dependent on gene × environment interactions.
authors.affiliation: 1Immunobiology Program, C331 Given Medical Building, University of Vermont, Burlington, VT 05405, USA. c.teuscher@uvm.edu.
authors.forename: Naresha
authors.initials: N
authors.lastname: Saligrama
authors.forename: Laure K
authors.initials: LK
authors.lastname: Case
authors.forename: Dimitry N
authors.initials: DN
authors.lastname: Krementsov
authors.forename: Cory
authors.initials: C
authors.lastname: Teuscher
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D005434:Flow Cytometry; D015870:Gene Expression / Q000276:immunology; D020022:Genetic Predisposition to Disease; D057809:HEK293 Cells; D006801:Humans; D007371:Interferon-gamma / Q000276:immunology / Q000378:metabolism; D020381:Interleukin-17 / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D063308:Myelin-Oligodendrocyte Glycoprotein / Q000008:administration & dosage / Q000276:immunology / Q000633:toxicity; D010446:Peptide Fragments / Q000008:administration & dosage / Q000276:immunology / Q000633:toxicity; D037342:Pertussis Toxin / Q000008:administration & dosage / Q000276:immunology; D011970:Receptors, Histamine H2 / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012720:Severity of Illness Index; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism
chemical_list: D020381:Interleukin-17; D063308:Myelin-Oligodendrocyte Glycoprotein; D010446:Peptide Fragments; D011970:Receptors, Histamine H2; C445081:myelin oligodendrocyte glycoprotein (35-55); D007371:Interferon-gamma; D037342:Pertussis Toxin
keywords: CD4 T cells; effector T-cell response; multiple sclerosis; pertussis toxin