Functional niche of inflamed synovium for Th17-cell expansion and activation in rheumatoid arthritis: Implication to clinical therapeutics

Th17 cells selectively produce the signature cytokines such as IL-17, IL-21 and IL-22, and play a critical role for the chronic inflammatory response and subsequent tissue damage in synovial joints of patients with rheumatoid arthritis (RA). The preliminary clinical study indicates that IL-17 neutralizing therapy can ameliorate inflammatory cascades within peripheral synovial joints in the major population of patients with active RA. Multiple cellular and molecular modulations for the Th17-cell-polarized responses could exist, however, in the inflamed synovium, possibly resulting in a functional niche for the generation and activation of pathogenic Th17 cells. This might establish a vicious cycle culminating in the striking marginal erosions of cartilage and bone in the RA joints, and at least partially abrogate the potential therapeutic benefits related to IL-17 antagonizing or Th17-cell depleting therapy. This article is aimed to discuss the cellular and molecular pathways critically involved in the expansion and activation of pathogenic Th17 cells in RA synovium, with emphasis on the potential therapeutic implications for targeting these pathways to the present and future RA clinics. (C) 2012 Elsevier B.V. All rights reserved.