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 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 ₁R^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 encephalomyeiitis 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.