No abstract

Genetics and environmental factors have important roles in autoimmune diseases but neither has given us sufficient understanding of these mysterious diseases. Therefore, we are now looking closer at epigenetics, an interface between genetics and environmental factors. Epigenetics can be defined as reversible heritable changes to chromatin that can alter gene expression without altering the gene's DNA sequence. Methylation of DNA and histones are primary means of epigenetic control. By adding methyl groups to DNA and histones, it can limit accessibility of the underlying gene thereby altering the amount of gene expression. The methyl group is derived from an essential molecule in the cell, S-adenosylmethionine (SAM). However, a group of small molecules called polyamines also require SAM for their synthesis. Polyamines are essential for many cellular functions and polyamine activity is increased in many autoimmune diseases. Presented here is the "polyamine hypothesis" in which increased polyamine synthesis competes with cellular methylation (epigenetic control) for SAM. It is proposed that increased polyamine activity can cause disruption of cellular methylation, which can lead to abnormal expression of previously sequestered genes and disruption of other methylation-dependent cellular processes.

Rheumatoid arthritis (RA) is an autoimmune disease characterized by synovial inflammation and joint destruction. previous studies have shown that natural killer (nK) cells may play an important role in the pathogenesis of RA. Interleukin (IL)-15, a pro-inflammatory cytokine which induces proliferation and differentiation of NK cells, is overexpressed in RA. In this present study, we examine various NKRs and adhesion molecule expression on NK cells from RA patients and their response to IL-15 stimulation. We also sought to study cytokine-induced memory-like (CIML) NK cells in RA patients. We established that 1. RA patients had higher NK cell percentages in peripheral blood and their serum IL-15 levels were higher compared to healthy volunteers; 2. NK cells from RA patients showed lower NKp46 expression and an impaired CD69 response to IL-15; 3. NK cells from RA patients showed higher CD158b and CD158e expression but lower CD62L expression; 4. exogenous IL-15 up-regulated CD69, CD158b, CD158e but down-regulated NKp46 and CD62L expression in RA; 5. As to CIML NK cells, restimulation-induced NK cytotoxicity and IFN-γ production was impaired in RA patients, 6. Reduced NKp46, perforin, and granzyme B expression on NK cells was found in RA patients with bone deformity and erosion, 7. RA disease activity (DAS28) showed inverse correlation with the percentages of CD56 + CD3 − NK cells, and NKp46 and perforin expression on NK cells, respectively. Taken together, our study demonstrated differential expression of various NK receptors in RA patients. NKp46, CD158e, and perforin expression on NK cells may serve as markers of RA severity.