A C-type lectin receptor, SIGNR-1, helps dendritic cells in the gut induce oral tolerance. Sugar-modified antigens might therefore be used to induce oral tolerance to food-induced anaphylaxis. We propose that a C-type lectin receptor, SIGNR-1 (also called Cd209b), helps to condition dendritic cells (DCs) in the gastrointestinal lamina propria (LPDCs) for the induction of oral tolerance in a model of food-induced anaphylaxis. Oral delivery of BSA bearing 51 molecules of mannoside (Man51-BSA) substantially reduced the BSA-induced anaphylactic response. Man51-BSA selectively targeted LPDCs that expressed SIGNR1 and induced the expression of interleukin-10 (IL-10), but not IL-6 or IL-12 p70. We found the same effects in IL-10–GFP knock-in (tiger) mice treated with Man51-BSA. The Man51-BSA–SIGNR1 axis in LPDCs, both in vitro and in vivo, promoted the generation of CD4+ type 1 regulatory T (Tr1)-like cells that expressed IL-10 and interferon-γ (IFN-γ), in a SIGNR-1– and IL-10–dependent manner, but not of CD4+CD25+Foxp3+ regulatory T cells. The Tr1-like cells could transfer tolerance. These results suggest that sugar-modified antigens might be used to induce oral tolerance by targeting SIGNR1 and LPDCs.

Key Points: AhR ligands result in calcium- and ROS-dependent enhancement of mast cell activation. AhR is critical in controlling mast cell homeostasis.

The gene, CRTH2, encoding a receptor for prostaglandin D₂ (PGD₂), 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.

Fucosylated glycans on pathogens are known to shape the immune response through their interaction with pattern recognition receptors, such as C-type lectin receptors (CLRs), on dendritic cells (DCs). Similar fucosylated structures are also commonly found in a variety of allergens, but their functional significance remains unclear. To test a hypothesis that allergen-associated glycans serve as the molecular patterns in functional interaction with CLRs, an enzyme-linked immunosorbent assay-based binding assay was performed to determine the binding activity of purified allergens and allergen extracts. THP-1 cells and monocyte-derived DCs (MDDCs) were investigated as a model for testing the functional effects of allergen-CLR interaction using enzyme-linked immunosorbent assay, Western blotting, and flow cytometry. Significant and saturable bindings of allergens and allergen extracts with variable binding activities to DC-specific ICAM3-grabbing non-integrin (DC-SIGN) and its related receptor, L-SIGN, were found. These include bovine serum albumin coupled with a common glycoform (fucosylated glycan lacking the α1,3-linked mannose) of allergens and a panel of purified allergens, including BG60 (Cyn dBG-60; Bermuda grass pollen) and Der p2 (house dust mite). The binding activity was calcium-dependent and inhibitable by fucose and Lewis-x trisaccharides (Le^x). In THP-1 cells and human MDDCs, BG60-DC-SIGN interaction led to the activation of Raf-1 and ERK kinases and the induction of tumor necrosis factor-α expression. This effect could be blocked, in part, by Raf-1 inhibitor or anti-DC-SIGN antibodies and was significantly reduced in cells with DC-SIGN knockdown. These results suggest that allergens are able to interact with DC-SIGN and induce tumor necrosis factor-α expression in MDDCs via, in part, Raf-1 signaling pathways.

The burden of chronic liver disease (CLD) deaths attributable to the hepatitis B virus (HBV) and hepatitis C virus (HCV) remains unknown. Further research is required to elucidate the extent of this burden in the eventual elimination of these diseases. Data on liver cancer, cirrhosis, and other CLD among 204 countries and territories between 1990 and 2019 was extracted from the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) published in 2019. The Bayesian age-period-cohort model was used to analyze the temporal trend and predict the disease burden by 2030. The number of HCV-related CLD deaths surpassed that of CLD deaths caused by HBV in 2019 (536833 deaths versus 523003 deaths) and is expected to be maintained until 2030 (689124 deaths versus 628824 deaths). East Asia had the highest burden of chronic HBV and HCV infections during the study period. In 2019, the largest age-standardized death rates (ASDR) of CLD deaths caused by HBV and HCV were mainly observed in Western Sub-Saharan Africa (18.75%) and Eastern Sub-Saharan Africa (16.42%), respectively. South Asia and East Asia are predicted to have the highest number of CLD deaths related to HCV and HBV by 2030. Eastern Europe and South Asia show the largest expected increase in disease burden caused by HCV or HBV between 2019 and 2030. No GBD region is projected to achieve the WHO target of a 65% reduction in mortality from chronic HBV and HCV infections by 2030. Although the mortality of CLD caused by HBV and HCV decreased in the last three decades (from 1990 to 2019), the number of deaths will continue to increase until 2030. Therefore, governments and international organizations need to strengthen the effectiveness of vaccines, screening, and treatment, especially in potential emerging hotspot regions.