TACI-Ig Neutralizes Molecules Critical for B Cell Development and Autoimmune Disease Impaired B Cell Maturation in Mice Lacking BLyS

AbstractBLyS and APRIL have similar but distinct biological roles, mediated through two known TNF receptor family members, TACI and BCMA. We show that mice treated with TACI-Ig and TACI-Ig transgenic mice have fewer transitional T2 and mature B cells and reduced levels of circulating immunoglobulin. TACI-Ig treatment inhibits both the production of collagen-specific Abs and the progression of disease in a mouse model of rheumatoid arthritis. In BLyS-deficient mice, B cell development is blocked at the transitional T1 stage such that virtually no mature B cells are present, while B-1 cell numbers are relatively normal. These findings further elucidate the roles of BLyS and APRIL in modulating B cell development and suggest that BLyS is required for the development of most but not all mature B cell populations found in the periphery

Per- and polyfluoroalkyl substances, epigenetic age and DNA methylation: a cross-sectional study of firefighters

Background: Per- and polyfluoroalkyl substances (PFASs) are persistent chemicals that firefighters encounter. Epigenetic modifications, including DNA methylation, could serve as PFASs toxicity biomarkers. Methods: With a sample size of 197 firefighters, we quantified the serum concentrations of nine PFASs, blood leukocyte DNA methylation and epigenetic age indicators via the EPIC array. We examined the associations between PFASs with epigenetic age, site- and region-specific DNA methylation, adjusting for confounders. Results: Perfluorohexane sulfonate, perfluorooctanoate (PFOA) and the sum of branched isomers of perfluorooctane sulfonate (Sm-PFOS) were associated with accelerated epigenetic age. Branched PFOA, linear PFOS, perfluorononanoate, perfluorodecanoate and perfluoroundecanoate were associated with differentially methylated loci and regions. Conclusion: PFASs concentrations are associated with accelerated epigenetic age and locus-specific DNA methylation. The implications for PFASs toxicity merit further investigation. Lay abstract Per- and poly-fluoroalkyl substances (PFASs) are a group of toxic chemicals that populations around the world are widely exposed to through contaminated water and consumer products. Firefighters can also be exposed to PFASs from occupational practices. Epigenetic modifications, including DNA methylation, regulate gene expression. It can be modified by environmental exposures such as PFASs, which contribute to the development of diseases including cancer. We measured the concentrations of nine PFASs in samples from firefighters and profiled DNA methylation across the genome. Three PFASs were linked with accelerated epigenetic age, a marker associated with many diseases. Four PFASs were associated with altered DNA methylation levels at specific genes. These results may indicate how PFASs are harmful to health and merit further exploration