Noubade Rajkumar, Saligrama Naresha, Spach Karen, Del Rio Roxana, Blankenhorn Elizabeth P, Kantidakis Theodoros, Milligan Graeme, Rincon Mercedes, Teuscher Cory
Department of Medicine, University of Vermont, Burlington, VT 05405, USA.
J Immunol. 2008 Jun 1;180(11):7471-9. doi: 10.4049/jimmunol.180.11.7471.
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.
小鼠组胺受体H(1)（H(1)R）第三个细胞内环中的结构多态性（L263P、M313V和S331P）是Bphs的候选因素，Bphs是实验性变应性脑脊髓炎和实验性变应性睾丸炎中的一个共享自身免疫疾病位点。P-V-P单倍型与疾病易感性增加相关（H(1)R(S)），而L-M-S单倍型与病情较轻相关（H(1)R(R)）。在本研究中，我们发现T细胞中H(1)R(S)等位基因的选择性重新表达完全补充了实验性变应性脑脊髓炎的易感性以及疾病相关细胞因子的产生，而H(1)R(R)等位基因的选择性重新表达则没有。从机制上讲，我们发现这两个H(1)R等位基因表现出不同的细胞表面表达和改变的细胞内运输，H(1)R(R)等位基因保留在内质网中。此外，我们表明构成H(1)R(R)单倍型的所有三个残基（L-M-S）对于表达改变都是必需的。这些数据首次证明影响T细胞中G蛋白偶联受体细胞表面表达的结构多态性调节免疫功能和自身免疫疾病易感性。
