Anti-CD1C monoclonal antibody, clone 6B9

CD1 is a family of atypical MHC class I molecules that present various endogenous and exogenous lipid antigens to CD1-restricted T cells. While little is known about the function of CD1a-, CD1b-, and CD1c- restricted lipid-reactive T cells due to their absence in mice, CD1d-restricted natural killer T (NKT) cells have been extensively studied since their description almost 20 years ago. NKT cells, effector memory cells that share characteristics of innate and adaptive lymphocytes, are among the earliest responders in immune reactions and have broad effects on the activation of other immune cell lineages, including NK cells, T cells, and B cells. Accordingly, studies in mice have revealed critical roles of NKT cells in infectious, malignant, and autoimmune diseases. The recent description of primary immunodeficiencies associated with defects in CD1 and CD1-restricted T cells has provided a unique opportunity to study the biological role of lipid antigen presentation in human disease. Intriguingly, these studies revealed that defects in lipid immunity are associated with susceptibility to selected infectious and malignant diseases but not with broad immunodeficiency.

Epigenetic regulation of immune cell types could be critical for the development and maintenance of autoimmune diseases like rheumatoid arthritis (RA). B cells are highly relevant in RA, since patients express autoantibodies and depleting this cell type is a successful therapeutic approach. Epigenetic variation, such as DNA methylation, may mediate the pathogenic activity of B cells. In this study, we performed an epigenome-wide association study (EWAS) for RA with three different replication cohorts, to identify disease-specific alterations in DNA methylation in B cells. CpG methylation in isolated B lymphocytes was assayed on the Illumina HumanMethylation450 BeadChip in a discovery cohort of RA patients (N = 50) and controls (N = 75). Differential methylation was observed in 64 CpG sites (q<0.05). Six biological pathways were also differentially methylated in RA B cells. Analysis in an independent cohort of patients (N = 15) and controls (N = 15) validated the association of 10 CpG sites located on 8 genes CD1C, TNFSF10, PARVG, NID1, DHRS12, ITPK1, ACSF3 and TNFRSF13C, and 2 intergenic regions. Differential methylation at the CBL signaling pathway was replicated. Using an additional case-control cohort (N - 24), the association between RA risk and CpGs cg18972751 at CD1C (P = 2.26 x 10(-9)) and cg03055671 at TNFSF10 (P = 1.67 x 10(-8)) genes was further validated. Differential methylation at genes CD1C, TNFSF10, PARVG, NID1, DHRS12, ITPK1, ACSF3, TNFRSF13C and intergenic region chr10p12.31 was replicated in a cohort of systemic lupus erythematosus (SLE) patients (N = 47) and controls (N = 56). Our results highlight genes that may drive the pathogenic activity of B cells in RA and suggest shared methylation patterns with SLE.