Autoimmune disease-associated histamine receptor H1 alleles exhibit differential protein trafficking and cell surface expression.
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.
Noubade
Rajkumar
R
Department of Medicine, University of Vermont, Burlington, VT 05405, USA.
Saligrama
Naresha
N
Spach
Karen
K
Del Rio
Roxana
R
Blankenhorn
Elizabeth P
EP
Kantidakis
Theodoros
T
Milligan
Graeme
G
Rincon
Mercedes
M
Teuscher
Cory
C
D000483:Alleles; D000818:Animals; D001327:Autoimmune Diseases / Q000235:genetics* / Q000276:immunology; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000235:genetics* / Q000276:immunology; D004721:Endoplasmic Reticulum / Q000378:metabolism; D044385:GTP-Binding Protein alpha Subunits / Q000378:metabolism; D020022:Genetic Predisposition to Disease; D006239:Haplotypes; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009920:Orchitis / Q000235:genetics* / Q000276:immunology; D011110:Polymorphism, Genetic; D021381:Protein Transport; D011969:Receptors, Histamine H1 / Q000172:deficiency / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D013601:T-Lymphocytes / Q000378:metabolism
D044385:GTP-Binding Protein alpha Subunits; D011969:Receptors, Histamine H1