Session Title: T-cell Biology and Targets in Autoimmune Disease
Session Type: Abstract Submissions (ACR)
Vitamin D has suppressive effects on autoimmune diseases, such as rheumatoid arthritis (RA). Within these diseases, T-helper-17 (Th17) cells have been implicated to play a crucial role in the development and progression of persistent inflammation. Recently, we have shown that Th17 cells are able to activate synovial fibroblasts of patients with RA (RASF) resulting in a pro-inflammatory feedback loop. This leads to increased production of pro-inflammatory cytokines and tissue-degrading enzymes. We have found that the active vitamin D compound, 1,25(OH)2D3, has direct suppressive effects on Th17 cells from patients with early RA. In addition 1,25(OH)2D3 is capable of inhibiting the pro-inflammatory feedback loop between Th17 cells and RASF. The objective of this study is to identify molecular targets of 1,25(OH)2D3 signaling underlying this suppressive action of 1,25(OH)2D3 in Th17 cells.
Primary Th17 cells were sorted from peripheral blood of treatment naïve patients with early RA. They were cultured with or without 1,25(OH)2D3 alone or together with RASF. From these cultures gene-expression profiles were generated. Expression of genes of interest was confirmed by Q-PCR and/or specific ELISA.
In the presence of 1,25(OH)2D3, protein expression of Th17 associated cytokines IL-17A and IL-22 was inhibited, while in contrast the anti-inflammatory cytokine IL-10 was induced. These findings were supported by the gene-expression profiles from these cultures. Furthermore, 1,25(OH)2D3 inhibited transcription of the cytokine receptors IL-23R and IL-7R, which are involved in Th17 survival and proliferation. Chemokines CCL20 and CXCL10 were down-regulated and chemokine receptors CCR2, CXCR6, CXCR3 and CCR10 were up-regulated. Importantly, Rorγt, which is critically involved in Th17 differentiation and function and the cell-size regulator and oncogene c-Myc were down-regulated by 1,25(OH)2D3.
From these findings, we concluded that 1,25(OH)2D3 modulates the expression of genes involved in cytokine production, proliferation, and migration of Th17 cells. These data indicate that 1,25(OH)2D3 not only suppresses Th17 cell activity but also regulates Th17 phenotype stability and migration of these cells to sites of tissue inflammation in RA.
J. P. van Hamburg,
P. S. Asmawidjaja,
A. M. Mus,
J. van Leeuwen,
J. M. W. Hazes,
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ACR Meeting Abstracts - http://acrabstracts.org/abstract/125oh2d3-modulates-the-migration-pattern-of-th17-cells-from-patients-with-rheumatoid-arthritis/