IL-17 / TGFβ Levels In Rheumatoid Arthritis: An Imbalance in Th17/Treg Function

Abstract

RA is a complex; chronic autoimmune disease characterized by an inflammatory infiltrate of immune cells, in particular T-cells, which participate in a number of inflammatory and destructive events, such as synovial hyperplasia, pannus setting, cartilage and bone erosion, and joint destruction. Dysregulation in the immune system plays an important role in the pathogenesis of RA. Multiple studies have indicated that the imbalance of Th1/Th2 and Th-17/Treg cells may be responsible for the initiation and progression of RA. Treg cell lineage is composed of overlapping T-cell subsets whose role is to dampen the immune response to minimize tissue destruction. Tregs inhibited osteoclastogenesis in a cell-contact-dependent manner with a minor contribution by the signature cytokines IL-4, TGF β, and IL-10.Although TGF-β is well known for its immune-suppressive and anti-inflammatory properties, it is also capable of promoting inflammation.The presence of TGF-β at a high level in the RA synovium suggests that TGF-β perse or in combination with other cytokines plays an important role in the progression of RA. Differentiation of naive Th cells towards a Th17 phenotype is supported by several cytokines including TGF-β, IL-1β, IL-6, IL-21, and IL-23 in mice and humans. Indeed, ligation of TLR3, TLR4, or TLR9 induces secretion of TGF-β and IL-6 that subsequently supports de novo differentiation of naive CD4+ T cells to Th17 cells in vitro. Therefore, in this study we assessed the level of IL-17 and TGF-β in serum of RA patients as signature cytokines for Th-17 and Treg cells respectively to test for possible imbalance in their levels. Wefound increase serum levels of IL-17, TGF-β and ESR in RA patients as compared with healthy control.Also,we found that RF positive patients were 43.3% while 56.7% of the patients were RF negative. There was increase in ESR serum levels among the RF positive patientswhen compared with the RF negative. We demonstrated higher values in serum CRP, ESR and IL-17 levels among RA patients with high disease activity versus RA patients withmoderate disease activity. In our study, Correlation studies were done between serum levels of IL-17 and TGF-β and the other studied parameters among RA patients group. There was negative correlation between serum levels of IL-17 and Hb. Also such correlation was found between IL-17 and TGF-β serum levels. So, increased serum levels of IL-17 and TGF-β may have role in pathogenesis of RA. Also, IL17 may have role as proinflammatory cytokine in severity and prognosis of RA specially patients with highDAS. Pathogenesis of RA might be associated with Th17/Treg imbalance. With continuous increase of TGF-β that promote differentiation of naïve CD4+ to IL-17+Th-17 cells which have inflammatory response in RA, and according to this results, IL-17 and TGF-β may act as pro-inflammatory cytokines. Combined blockade of TGF-β and IL-17 could be a therapeutic approach for patients with RA who fail to respond, or who lose responsiveness and consider hope to decrease side effects of cortisone or methotrexate in treatment of RA.