CTLA4 and rheumatoid arthritis: Furthermore, the promoter region of its downstream gene Chemokine CxCL12 also shows high rates of hypomethylation in RA-FLS.315 Cribbs et al. revealed that the compromised function of Treg in RA patients is associated with the hypermethylation of a specific region in the promoter of the cytotoxic T-lymphocyte-associated protein 4 (CTLA-4;−658 CpG) as compared with healthy controls.316 DNA hypermethylation prevents the binding of NFATc2 to CTLA-4 and decreases CTLA-4 expression.