Polymorphisms in murine histamine receptor H1 leading to differential cell surface expression influence autoimmune disease progression

Abstract

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 (EAE) and experimental allergic orchitis (EAO). The P‐V‐P haplotype is associated with increased disease susceptibility (H1RS) whereas the L‐M‐S haplotype is associated with less severe disease (H1RR). Here we show that selective reexpression of the H1RS allele in T cells fully complements EAE susceptibility and production of disease associated cytokines while selective reexpression 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 (ER). 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 couple receptor in T cells regulates immune functions and autoimmune disease susceptibility.