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

Abstract

Structural polymorphisms (L263P, M313V, and S331P) in the third intracellular loop of the murine histamine receptor H(1) (H(1)R) 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 (H(1)R(S)) whereas the L-M-S haplotype is associated with less severe disease (H(1)R(R)). In this study, we show that selective re-expression of the H(1)R(S) allele in T cells fully complements experimental allergic encephalomyelitis susceptibility and the production of disease-associated cytokines while selective re-expression of the H(1)R(R) allele does not. Mechanistically, we show that the two H(1)R alleles exhibit differential cell surface expression and altered intracellular trafficking, with the H(1)R(R) allele being retained within the endoplasmic reticulum. Moreover, we show that all three residues (L-M-S) comprising the H(1)R(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.

• Authors: Rajkumar Noubade, Naresha Saligrama, Karen Spach, Roxana Del Rio, Elizabeth P Blankenhorn, Theodoros Kantidakis, Graeme Milligan, Mercedes Rincon, Cory Teuscher
• Journal: Journal of immunology (Baltimore, Md. : 1950) (J Immunol) Vol. 180 Issue 11 Pg. 7471-9 (Jun 01 2008) ISSN: 0022-1767 [Print] United States
• PMID: 18490747 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• GTP-Binding Protein alpha Subunits
• Receptors, Histamine H1

Topics

• Alleles
• Animals
• Autoimmune Diseases (genetics, immunology)
• Cell Line
• Cell Membrane (metabolism)
• Encephalomyelitis, Autoimmune, Experimental (genetics, immunology)
• Endoplasmic Reticulum (metabolism)
• GTP-Binding Protein alpha Subunits (metabolism)
• Genetic Predisposition to Disease
• Haplotypes
• Male
• Mice
• Mice, Inbred C57BL
• Mice, Transgenic
• Orchitis (genetics, immunology)
• Polymorphism, Genetic
• Protein Transport
• Receptors, Histamine H1 (deficiency, genetics, immunology, metabolism)
• T-Lymphocytes (metabolism)