The gene, CRTH2, encoding a receptor for prostaglandin D(2) (PGD(2)), is located within the peak linkage region for asthma on chromosome (Chr.) 11q reported in African American families. Family-based analysis of asthma and two common SNPs [G1544C and G1651A (rs545659)] in the 3'-untranslated region of CRTH2 showed significant evidence of linkage in the presence of disequilibrium for the 1651G allele (P = 0.003) of SNP rs545659. Haplotype analysis yielded additional evidence of linkage disequilibrium for the 1544G-1651G haplotype (P < 0.001). Population-based case-control analyses were conducted in two independent populations, and demonstrated significant association of the 1544G-1651G haplotype with asthma in an African American population (P = 0.004), and in a population of Chinese children (P < 0.001). Moreover, in the Chinese children the frequency of the 1651G allele in near-fatal asthmatics was significantly higher than mild-to-moderate asthmatics (P = 0.001) and normal controls (P < 0.001). The 1651G allele of SNP re545659 was also associated with a higher degree of bronchial hyperresponsiveness (P < 0.027). Transcriptional pulsing experiments showed that the 1544G-1651G haplotype confers a significantly higher level of reporter mRNA stability, when compared with a non-transmitted haplotype (1544C-1651A), suggesting that the CRTH2 gene on Chr. 11q is a strong candidate gene for asthma.
We propose that a C-type lectin receptor, SIGNR-1, plays a role in conditioning gastrointestinal lamina propria (LP) DC subset for the induction of oral tolerance in a model of food-induced anaphylaxis. Oral delivery of bovine serum albumin (BSA) bearing 51 mols of mannosides (Man51-BSA) significantly reduced the levels of BSA-induced anaphylactic response. Man51-BSA was found to, selectively, target the LPDC subset expressing a member of the CLRs, SIGNR1, and induce the expression of IL-10, but not IL-6 and IL-12p70. This was noted also in Man51-BSA-treated IL-10-GFPknockin (tiger) mice. The Man51-BSA–SIGNR1 axis in LPDCs, both in vitro and in vivo, promoted the generation of CD4+ Tr1-like cells expressing IL-10 and IFN-γ, in a SIGNR-1- and IL-10-dependent manner, but not of CD4+CD25+Foxp3+ Tregs. The in vivo-generated Tr1-like cells were capable of transferring tolerance. These results suggest the potential utility of sugar-modified antigen in oral tolerance through targeting of SIGNR1 and LPDCs.
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