Autoimmune disease-associated histamine receptor H1 alleles exhibit differential protein trafficking and cell surface expression

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

*Corresponding author for this work

Research output: Contribution to journalArticle

Abstract

Structural polymorphisms (L263P, M313V, and S331P) in the third intracellular loop of the murine histamine receptor H1 (H 1R) are candidates for Bphs, a shared autoimmune disease locus in experimental allergic encephalomyeiitis and experimental allergic orchitis. The P-V-P haplotype is associated with increased disease susceptibility (H 1RS) whereas the L-M-S haplotype is associated with less severe disease (H1RR). In this study, we show that selective re-expression of the H1RS allele in T cells fully complements experimental allergic encephalomyeiitis susceptibility and the production of disease-associated cytokines while selective re-expression of the H1RR allele does not. Mechanistically, we show that the two H1R alleles exhibit differential cell surface expression and altered intracellular trafficking, with the H1RR allele being retained within the endoplasmic reticulum. Moreover, we show that all three residues (L-M-S) comprising the H1RR 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.

Original languageEnglish
Pages (from-to)7471-7479
Number of pages9
JournalJournal of Immunology
Volume180
Issue number11
DOIs
Publication statusPublished - 1 Jan 2008

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Histamine Receptors
Protein Transport
Autoimmune Diseases
Disease Susceptibility
Alleles
Haplotypes
Orchitis
T-Lymphocytes
Immune System Diseases
G-Protein-Coupled Receptors
Endoplasmic Reticulum
Cytokines

Bibliographical note

Copyright © 2008 by The American Association of Immunologists

Cite this

Noubade, Rajkumar ; Saligrama, Naresha ; Spach, Karen ; Del Rio, Roxana ; Blankenhorn, Elizabeth P. ; Kantidakis, Theodoros ; Milligan, Graeme ; Rincon, Mercedes ; Teuscher, Cory. / Autoimmune disease-associated histamine receptor H1 alleles exhibit differential protein trafficking and cell surface expression. In: Journal of Immunology. 2008 ; Vol. 180, No. 11. pp. 7471-7479.
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abstract = "Structural polymorphisms (L263P, M313V, and S331P) in the third intracellular loop of the murine histamine receptor H1 (H 1R) are candidates for Bphs, a shared autoimmune disease locus in experimental allergic encephalomyeiitis and experimental allergic orchitis. The P-V-P haplotype is associated with increased disease susceptibility (H 1RS) whereas the L-M-S haplotype is associated with less severe disease (H1RR). In this study, we show that selective re-expression of the H1RS allele in T cells fully complements experimental allergic encephalomyeiitis susceptibility and the production of disease-associated cytokines while selective re-expression of the H1RR allele does not. Mechanistically, we show that the two H1R alleles exhibit differential cell surface expression and altered intracellular trafficking, with the H1RR allele being retained within the endoplasmic reticulum. Moreover, we show that all three residues (L-M-S) comprising the H1RR 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.",
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Noubade, R, Saligrama, N, Spach, K, Del Rio, R, Blankenhorn, EP, Kantidakis, T, Milligan, G, Rincon, M & Teuscher, C 2008, 'Autoimmune disease-associated histamine receptor H1 alleles exhibit differential protein trafficking and cell surface expression', Journal of Immunology, vol. 180, no. 11, pp. 7471-7479. https://doi.org/10.4049/jimmunol.180.11.7471

Autoimmune disease-associated histamine receptor H1 alleles exhibit differential protein trafficking and cell surface expression. / Noubade, Rajkumar; Saligrama, Naresha; Spach, Karen; Del Rio, Roxana; Blankenhorn, Elizabeth P.; Kantidakis, Theodoros; Milligan, Graeme; Rincon, Mercedes; Teuscher, Cory.

In: Journal of Immunology, Vol. 180, No. 11, 01.01.2008, p. 7471-7479.

Research output: Contribution to journalArticle

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AU - Saligrama, Naresha

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AU - Del Rio, Roxana

AU - Blankenhorn, Elizabeth P.

AU - Kantidakis, Theodoros

AU - Milligan, Graeme

AU - Rincon, Mercedes

AU - Teuscher, Cory

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