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; H1–4R). 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.
Footnotes
This work was supported by National Institutes of Health Grants NS061014, AI041747, NS060901, NS036526, and NS069628 (to C.T) and by the Young Investigator Award (second prize) presented by the European Histamine Research Society (to N.S.).
The online version of this article contains supplemental material.
Abbreviations used in this article:
- B6
- C57BL/6J
- BBB
- blood–brain barrier
- DC
- dendritic cell
- DLN
- draining lymph node
- EAE
- experimental allergic encephalomyelitis
- GABA
- γ-aminobutyric acid
- GPCR
- G-protein–coupled receptor
- HA
- histamine
- HDC
- histidine decarboxylase
- HR
- histamine receptor
- MOG35–55
- myelin oligodendrocyte gp35–55
- MS
- multiple sclerosis
- OCT
- organic cation transporter
- P450
- cytochrome P450
- PTX
- pertussis toxin
- SNP
- single nucleotide polymorphism
- WT
- wild-type.
- Received November 14, 2012.
- Accepted May 18, 2013.
- Copyright © 2013 by The American Association of Immunologists, Inc.