Histamine (HA), a biogenic amine with a broad spectrum of activities in both physiological and pathological settings, plays a key regulatory role in experimental allergic encephalomyelitis, the autoimmune model of multiple sclerosis. HA exerts its effect through four G protein-coupled receptors designated HA receptor H 1, H2, H3, and H4. We report here that, compared with wild-type animals, mice with a disrupted HA H 3 receptor (H3RKO), the expression of which is normally confined to cells of the nervous system, develop more severe disease and neuroinflammation. We show that this effect is associated with dysregulation of bloodbrain barrier permeability and increased expression of MIP-2, IP-10, and CXCR3 by peripheral T cells. Our data suggest that pharmacological targeting of the H 3R may be useful in preventing the development and formation of new lesions in multiple sclerosis, thereby significantly limiting the progression of the disease.blood-brain barrier ͉ experimental allergic encephalomyelitis ͉ multiple sclerosis H istamine [2-(4-imidazole) ethylamine] (HA) is a ubiquitous mediator of diverse physiological processes including neurotransmission, secretion of pituitary hormones, and regulation of the gastrointestinal and circulatory systems (1). HA is a potent mediator of inflammation and a regulator of innate and adaptive immunity (2). HA exerts its effect through four G proteincoupled receptors [H 1 , H 2 , H 3 , and H 4 receptor, designated according to the chronological order of their discovery (1)].HA is implicated in the pathophysiology of multiple sclerosis (MS) and its animal models, collectively termed experimental allergic encephalomyelitis (EAE). HA and agents causing the release of HA from mast cells, the primary source of HA in the body (3), alter blood-brain barrier (BBB) permeability. Tissue levels of HA correlate with the onset of EAE (4-6). Inhibitors of mast cell degranulation and H 1 R and H 2 R antagonists modify EAE severity (7)(8)(9)(10)(11)(12). Epidemiological data indicate that use of sedating H 1 R antagonists is associated with decreased MS risk (13). In a small pilot study, patients with relapsing-remitting or relapsing-progressive MS given the H 1 R antagonist hydroxyzine remained stable or improved neurologically (14). Microarray analysis revealed that the H 1 R was overexpressed in the chronic plaques of MS patients (15). Moreover, mouse genetic studies have shown that HA, H 1 R, and H 2 R play an important role in regulating encephalitogenic T cell responses and susceptibility to EAE (16-18). The role of H 3 R and H 4 R in EAE and MS has not been studied.H 3 R is not normally expressed by hematopoietic cells; rather, it is expressed presynaptically where it is an inhibitory autoreceptor (inhibits release of HA from histaminergic neurons) and heteroreceptor (inhibits release of other neurotransmitters such as acetylcholine, noradrenaline, dopamine, and 5-HT from nonhistaminergic neurons) (19). Absence of presynaptic inhibition results in failure to limit neurotransmitter rel...

In vivo intoxication with Bordetella pertussis toxin (PTX) elicits a variety of physiological responses including a marked leukocytosis, disruption of glucose regulation, adjuvant activity, alterations in vascular function, hypersensitivity to vasoactive agents, and death. We recently identified Bphs, the locus controlling PTX-induced hypersensitivity to the vasoactive amine histamine, as the histamine H 1 receptor (Hrh1). In this study Bphs congenic mice and mice with a disrupted Hrh1 gene were used to examine the role of Bphs/Hrh1 in the genetic control of susceptibility to a number of phenotypes elicited following in vivo intoxication. We report that the contribution of Bphs/Hrh1 to the overall genetic control of responsiveness to PTX is restricted to susceptibility to histamine hypersensitivity and enhancement of antigen-specific delayed-type hypersensitivity responses. Furthermore, the genetic contribution of Bphs/Hrh1 to vasoactive amine sensitization is specific for histamine, since hypersensitivity to serotonin was unaffected by Bphs/Hrh1. Bphs/Hrh1 also did not significantly influence susceptibility to the lethal effects, the leukocytosis response, disruption of glucose regulation, and histamineindependent increases in vascular permeability associated with in vivo intoxication. Nevertheless, significant interstrain differences in susceptibility to the lethal effects of PTX and leukocytosis response were observed. These results indicate that the phenotypic variation in responsiveness to PTX reflects the genetic control of distinct intermediate phenotypes rather than allelic variation in genes controlling overall susceptibility to intoxication.Pertussis toxin (PTX) is a major virulence factor of Bordetella pertussis, the causative agent of whooping cough (9). The holotoxin is a hexameric protein that conforms to the A/B model of bacterial exotoxins (31). The A subunit is an ADPribosyltransferase which affects signal transduction by ribosylation of the ␣ subunit of trimeric Gi proteins while the B oligomer binds cell surface receptors on a variety of mammalian cells (19,31). PTX, when administered in vivo, elicits a large number of physiological responses including disruption of glucose regulation, leukocytosis, adjuvant activity, increased vascular permeability associated with alteration of blood-tissue barrier functions, sensitization to vasoactive agents, and death (12,24,27,29,44).Inbred strains of mice differ in susceptibility to vasoactive amine challenge following PTX sensitization in that genetically susceptible strains die from hypotensive and hypovolemic shock whereas resistant strains do not (29,43). Bphs, the gene controlling susceptibility to PTX-induced hypersensitivity to histamine, was previously mapped to the central region of mouse chromosome 6 (39) and recently identified as being the histamine H 1 receptor (Hrh1) (25). As the first step in positionally cloning Bphs, we generated a panel of interval-specific recombinant congenic lines by using marker-assisted selection to introgress the ...

Histamine is a ubiquitous regulator of diverse physiologic processes including inflammation, immune modulation and neurotransmission. Four subtypes of histamine receptors are currently recognized and genetic and pharmacological studies have shown that the H1 and H2 receptors play a role in susceptibility to experimental allergic encephalomyelitis (EAE), the primary autoimmune model of multiple sclerosis. Histamine H3 receptor (H3R), which is not expressed in hematopoietic cells, is a presynaptic auto- and hetero-receptor. Here we show that H3RKO mice develop significantly more severe acute phase clinical disease and neuropathology compared to wild-type controls. In H3RKO mice this is preceded by disruption of the blood brain barrier and increased chemokine/chemokine receptor expression in peripheral T-cells. These data are consistent with inhibition of H3R-mediated neurogenic control of cerebrovascular tone and T-cell function. Additionally, genetic studies indicate that an H3R polymorphism leading to differential expression of H3R isoforms underlies eae8, a locus controlling disease associated weight loss, a phenotype known to be regulated by central H3R activity.