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Autoimmune Disease-Associated Histamine Receptor H₁ Alleles Exhibit Differential Protein Trafficking and Cell Surface Expression¹

Rajkumar Noubade^*, Naresha Saligrama^*, Karen Spach^*, Roxana del Rio^*, Elizabeth P. Blankenhorn, Theodoros Kantidakis, Graeme Milligan, Mercedes Rincon^* and Cory Teuscher^2,*,

^* Department of Medicine, University of Vermont, Burlington, VT 05405; Department of Microbiology and Immunology, College of Medicine, Drexel University, Philadelphia, PA 19129; Molecular Pharmacology Group, Institute of Biomedical and Life Sciences, University of Glasgow, Glasgow, United Kingdom; and Department of Pathology, University of Vermont, Burlington, VT 05405

Structural polymorphisms (L263P, M313V, and S331P) in the third intracellular loop of the murine histamine receptor H₁ (H₁R) are candidates for Bphs, a shared autoimmune disease locus in experimental allergic encephalomyelitis and experimental allergic orchitis. The P-V-P haplotype is associated with increased disease susceptibility (H₁R^S) whereas the L-M-S haplotype is associated with less severe disease (H₁R^R). In this study, we show that selective re-expression of the H₁R^S allele in T cells fully complements experimental allergic encephalomyelitis susceptibility and the production of disease-associated cytokines while selective re-expression of the H₁R^R allele does not. Mechanistically, we show that the two H₁R alleles exhibit differential cell surface expression and altered intracellular trafficking, with the H₁R^R allele being retained within the endoplasmic reticulum. Moreover, we show that all three residues (L-M-S) comprising the H₁R^R haplotype are required for altered expression. These data are the first to demonstrate that structural polymorphisms influencing cell surface expression of a G protein-coupled receptor in T cells regulates immune functions and autoimmune disease susceptibility.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by National Institutes of Health Grants AI041747, AI058052, AI045666, NS036526, and AI051454 and by National Multiple Sclerosis Society Grant RG-3575.

² Address correspondence and reprint requests to Dr. Cory Teuscher, C317 Given Medical Building, University of Vermont, Burlington, VT 05405. E-mail address: C.Teuscher{at}uvm.edu

³ Abbreviations used in this paper: MS, multiple sclerosis; EAE, experimental allergic encephalomyelitis; GPCR, G protein-coupled receptor; WT, wild type; ER, endoplasmic reticulum; HA, hemagglutinin; PTX, pertussis toxin; DO, day of onset; CDS, cumulative disease score; SI, severity index; PS, peak score; MOG_35–55, myelin oligodendrocyte glycoprotein peptide 35–55; DLN, draining lymph node; SH3, Src homology 3; DTH, delayed-type hypersensitivity.

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The JI 2008 180: 7053-7054. [Full Text]