Although the etiology of MS remains ill-defined, susceptibility likely results from a combination of factors, including genetic/epigenetic, environmental, immunological, hormonal, and infectious agents. Experimental allergic encephalomyelitis (EAE) is the autoimmune model of MS, in which disease
pathogenesis is associated with major histocompatibility complex (MHC) class II-restricted CD4+ T cells capable of secreting either interferon(IFN)-γ (Th1) or interleukin(IL)-17 (Th17) [[2]]. Histamine (HA, 2-(4-imidazole) ethylamine) is a biogenic monoamine that mediates a variety of physiological processes Ruxolitinib ic50 including neurotransmission, gastrointestinal and circulatory functions, secretion of pituitary hormones, cell proliferation, and this website hematopoiesis [[3]]. In addition, HA is a potent mediator of inflammation and regulator of innate and adaptive immune responses [[4]]. HA is synthesized by decarboxylation of L-histidine by the rate-limiting enzyme histidine decarboxylase (HDC). Mast cells and basophils are the major sources of stored HA in the body [[5]]. However, induced or nascent secretion of HA can occur in other cell types including dendritic cells, T cells, neutrophils, macrophages, and immature myeloid cells [[6-13]]. HA exerts its effects by binding to four different G protein-coupled receptors designated H1-H4. H1R and H2R couple to second
messenger signaling pathways via stimulatory G proteins (Gαq/11 and Gs, respectively), whereas H3R and H4R couple via inhibitory G proteins (Gi/o) [[14-16]]. HA has a diverse effect on many cell types due to differential expression of HRs and signaling through distinct intracellular signaling pathways. H1R and H2R are expressed more widely, while H4R expression
is mostly restricted to hematopoietically derived cells. Recently, it has been shown that H4R is also expressed functionally in the CNS [17]. H3R is primarily expressed within the CNS presynaptically, where it is an inhibitory auto- and heteroreceptor [[18]]. The role of HA in the pathogenesis of MS and EAE has been well documented [[19]]. HA and agents causing its release from mast cells alter the permeability of the blood brain barrier (BBB) [[20, 21]]. The use of first-generation antihistamines, which can readily cross the BBB, is oxyclozanide associated with a decrease in MS risk [[22]]. Patients with relapsing-remitting or relapsing-progressive MS given the H1R antagonist hydroxyzine were reported to remain stable and improved neurologically [[23]]. In addition, microarray analysis on the chronic plaques of MS patients revealed increased levels of H1R transcripts [[24]]. In EAE, higher levels of HA within the cerebrospinal fluid (CSF) correlate with the onset of disease and mast cell granule stabilizers and H1R-specific antagonists reduce EAE severity [[25-27]]. Importantly, in EAE, Th1 and Th2 clones reactive to proteolipid protein 139–151 have increased levels of H1R and H2R transcripts, respectively.