Autoimmune Disease-Associated Histamine Receptor H1 Alleles Exhibit Differential Protein Trafficking and Cell Surface Expression

Noubade, Rajkumar; Saligrama, Naresha; Spach, Karen; Rio, Roxana del; Blankenhorn, Elizabeth P.; Kantidakis, Theodoros; Milligan, Graeme; Rincón, Mercedes; Teuscher, Cory

doi:10.4049/jimmunol.180.11.7471

Cited by 12 publications

(13 citation statements)

References 37 publications

(46 reference statements)

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“…The G293D substitution in H 3 R is analogous to the amino acid substitutions recently identified within the third IC domain of H 1 R underlying Bphs , a shared immunopathology disease gene controlling Bordetella pertussis -induced sensitivity to histamine, EAE, and autoimmune orchitis [28], [29], [30]. Importantly, a A280V missense mutation within the third IC loop of the human H 3 R gene has been reported in multiple system atrophy (Shy-Drager Syndrome), a rare neurodegenerative disease [31] and as a risk factor for migraine [32].…”

Section: Resultsmentioning

confidence: 87%

Histamine H3 Receptor Integrates Peripheral Inflammatory Signals in the Neurogenic Control of Immune Responses and Autoimmune Disease Susceptibility

et al. 2013

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Histamine H3 receptor (Hrh3/H3R) is primarily expressed by neurons in the central nervous system (CNS) where it functions as a presynaptic inhibitory autoreceptor and heteroreceptor. Previously, we identified an H3R-mediated central component in susceptibility to experimental allergic encephalomyelitis (EAE), the principal autoimmune model of multiple sclerosis (MS), related to neurogenic control of blood brain barrier permeability and peripheral T cell effector responses. Furthermore, we identified Hrh3 as a positional candidate for the EAE susceptibility locus Eae8. Here, we characterize Hrh3 polymorphisms between EAE-susceptible and resistant SJL and B10.S mice, respectively, and show that Hrh3 isoform expression in the CNS is differentially regulated by acute peripheral inflammatory stimuli in an allele-specific fashion. Next, we show that Hrh3 is not expressed in any subpopulations of the immune compartment, and that secondary lymphoid tissue is anatomically poised to be regulated by central H3R signaling. Accordingly, using transcriptome analysis, we show that, inflammatory stimuli elicit unique transcriptional profiles in the lymph nodes of H3RKO mice compared to WT mice, which is indicative of negative regulation of peripheral immune responses by central H3R signaling. These results further support a functional link between the neurogenic control of T cell responses and susceptibility to CNS autoimmune disease coincident with acute and/or chronic peripheral inflammation. Pharmacological targeting of H3R may therefore be useful in preventing the development and formation of new lesions in MS, thereby limiting disease progression.

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Section: Resultsmentioning

confidence: 87%

Histamine H3 Receptor Integrates Peripheral Inflammatory Signals in the Neurogenic Control of Immune Responses and Autoimmune Disease Susceptibility

et al. 2013

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“…Some misfolded receptors could be rescued by addition of a pharmacological chaperone (“pharmacoperone”) to enhance proper folding and ultimately lead to proper membrane expression and pharmacological function (Conn and Ulloa-Aguirre 2010). However, other GPCR polymorphisms have been shown to alter intracellular trafficking and/or plasma membrane expression without affecting receptor function, such as certain naturally occurring DOR and H1 receptor polymorphisms (Noubade et al 2008; Leskela et al 2009). Thus, intracellular misrouting of receptors may be responsible for dysfunction of some variant GPCRs.…”

Section: Discussionmentioning

confidence: 99%

“…For example, a polymorphic form of the human delta opiate receptor (DOR) occurring in the amino terminus retained pharmacological binding properties, but exhibited altered intracellular trafficking, glycosidic processing, and plasma membrane expression (Leskela et al 2009). Similarly, a naturally occurring third intracellular (iC3) loop mutation in the histamine type 1 (H1) receptor has been shown to alter intra-cellular trafficking and plasma membrane expression, without abolishing receptor function (Noubade et al 2008), possibly by altering protein/chaperone interactions. Therefore, altered plasma membrane trafficking alone can be a mechanism of GPCR variant dysfunction.…”

Section: Introductionmentioning

confidence: 99%

Common α2A and α2C adrenergic receptor polymorphisms do not affect plasma membrane trafficking

Hurt

Sorensen

Angelotti

2014

Naunyn-Schmiedeberg's Arch Pharmacol

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Various naturally occurring polymorphic forms of human G protein-coupled receptors (GPCRs) have been identified and linked to diverse pathological diseases, including receptors for vasopressin type 2 (nephrogenic diabetes insipidus) and gonadotropin releasing hormone (hypogonadotropic hypogonadism). In most cases, polymorphic amino acid mutations disrupt protein folding, altering receptor function as well as plasma membrane expression. Other pathological GPCR variants have been found that do not alter receptor function, but instead affect only plasma membrane trafficking (e.g., delta opiate and histamine type 1 receptors). Thus, altered membrane trafficking with retained receptor function may be another mechanism causing polymorphic GPCR dysfunction. Two common human α2A and α2C adrenergic receptor (AR) variants have been identified (α2A N251K and α2C Δ322-325 ARs), but pharmacological analysis of ligand binding and second messenger signaling has not consistently demonstrated altered receptor function. However, possible alterations in plasma membrane trafficking have not been investigated. We utilized a systematic approach previously developed for the study of GPCR trafficking motifs and accessory proteins to assess whether these α2 AR variants affected intracellular trafficking or plasma membrane expression. By combining immunofluorescent microscopy, glycosidic processing analysis, and quantitative fluorescent-activated cell sorting (FACS), we demonstrate that neither variant receptor had altered intracellular localization, glycosylation, nor plasma membrane expression compared to wild-type α2 ARs. Therefore, pathopharmacological properties of α2A N251K and α2C Δ322-325 ARs do not appear to be due to altered receptor pharmacology or plasma membrane trafficking, but may involve interactions with other intracellular signaling cascades or proteins.

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“…Consequently, H1R-deficient mice present with a decreased level of EAE as compared to wildtype mice [19; 20]. Published data also show that H1R is a susceptibility gene in both EAE [21] and experimental autoimmune orchitis [22], which are two classical T cell-mediated models of organ-specific autoimmune disease. There are two potential mechanisms by which treatment with an antihistamine antagonist decreases the level of disease severity in EAE.…”

Section: Introductionmentioning

confidence: 99%

Combination treatment of mice with crx-153 (nortriptyline and desloratadine) decreases the severity of experimental autoimmune encephalomyelitis

Podojil

Padval

Miller

2011

Cellular Immunology

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Pro-inflammatory CD4+ T cell mediated autoimmune diseases, such as multiple sclerosis, are hypothesized to be initiated and maintained by self-reactive interferon-gamma (IFN-γ) and interleukin-17 (IL-17) producing CD4+ T cells. Previous studies have shown moderate to significant alterations in inflammatory T cell responses and potentially treatment of autoimmune disease by administration of anti-histamine or tricyclic antidepressants alone. The goal of the present study was to determine if treatment of PLP139–151-induced relapsing-remitting experimental autoimmune encephalomyelitis (R-EAE) in SJL/J mice with a combination of two FDA approved drugs for other indications could decrease R-EAE disease. The findings show that combination treatment with desloratadine and nortriptyline decreases the mean clinical score, disease relapse frequency, and number of CD4+ T cells infiltrating into the CNS. In addition, combination treatment of PLP139–151 primed mice decreases the level of IFN-γ and IL-17 secreted via a decrease in both the number of cells secreting and the amount of cytokine secreted per cell following PLP139–151 reactivation ex vivo. This is in contrast to an increase in the level of IL-4 produced and the number of IL-4 secreting cells. The data also show that combination treatment with desloratadine and nortriptyline inhibits the production of IFN-γ and IL-17 produced by naive CD4+ T cells activated in the presence of Th1 cell- and Th17-cell promoting conditions, while increasing the level of IL-4 produced by naive CD4+ T cells activated in the presence of Th2 cell-promoting conditions. The present findings suggest a novel method for the development of a putative autoimmune therapy.

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Autoimmune Disease-Associated Histamine Receptor H1 Alleles Exhibit Differential Protein Trafficking and Cell Surface Expression

Cited by 12 publications

References 37 publications

Histamine H3 Receptor Integrates Peripheral Inflammatory Signals in the Neurogenic Control of Immune Responses and Autoimmune Disease Susceptibility

Histamine H3 Receptor Integrates Peripheral Inflammatory Signals in the Neurogenic Control of Immune Responses and Autoimmune Disease Susceptibility

Common α2A and α2C adrenergic receptor polymorphisms do not affect plasma membrane trafficking

Combination treatment of mice with crx-153 (nortriptyline and desloratadine) decreases the severity of experimental autoimmune encephalomyelitis

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