TY - JOUR
T1 - Systemic lack of canonical histamine receptor signaling results in increased resistance to autoimmune encephalomyelitis
AU - Saligrama, Naresha
AU - Case, Laure K.
AU - Del Rio, Roxana
AU - Noubade, Rajkumar
AU - Teuscher, Cory
PY - 2013/7/15
Y1 - 2013/7/15
N2 - 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 (H1-4RKO mice). In this article, we report that in contrast to HDCKO mice, H1-4RKO mice develop less severe EAE compared with wild-type animals. Furthermore, splenocytes from immunized H1-4RKO 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.
AB - 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 (H1-4RKO mice). In this article, we report that in contrast to HDCKO mice, H1-4RKO mice develop less severe EAE compared with wild-type animals. Furthermore, splenocytes from immunized H1-4RKO 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.
UR - http://www.scopus.com/inward/record.url?scp=84880099354&partnerID=8YFLogxK
U2 - 10.4049/jimmunol.1203137
DO - 10.4049/jimmunol.1203137
M3 - Article
C2 - 23772030
AN - SCOPUS:84880099354
SN - 0022-1767
VL - 191
SP - 614
EP - 622
JO - Journal of Immunology
JF - Journal of Immunology
IS - 2
ER -