SHORT ANALYTICAL REVIEWBreaking old paradigms: Th17 cells in autoimmune arthritis☆
Introduction
Effective immunologic homeostasis relies on a continual balance between a number of factors, including helper T (Th) cell activation and regulatory T cell (Treg) suppression. When homeostasis is disrupted and the immune system tips in favor of activation, the host becomes susceptible to autoimmunity. Although it was originally believed that many autoimmune disorders, including rheumatoid arthritis (RA) and multiple sclerosis, partially resulted from an aberrant Th1 response, several studies in mice that demonstrated the deleterious effects of interferon-gamma (IFN-γ) deficiency called the role of the Th1 lineage in autoimmune pathogenesis into question [1], [2], [3]. The recent discovery of another subset of helper T cells, termed Th17, breaks the long-accepted paradigms about T cell subsets in autoimmunity and has the potential to resolve the contradictory evidence regarding the role of Th1 cells. (For a schematic of T cell subsets, see Fig. 1.) Identified originally by their expression of the pro-inflammatory cytokine IL-17A (henceforth referred to as IL-17), Th17 cells have gained wide acceptance as a distinct subset of CD4+ cells with expression of unique master regulatory transcription factors retinoic acid receptor-related orphan receptor-gamma-t (RORγt) and RORα [4], [5]. Th17 cells are induced by a number of pro-inflammatory cytokines including IL-1, IL-6, and IL-23, and in turn these cells secrete anti-microbial peptides and pro-inflammatory cytokines such as TNF, IL-21, and IL-22. Interest in the relationship between Th17 cells and Tregs is growing rapidly given evidence that the relative proportions of each in the joint is a potential indicator of disease progression [6]; however, this subject will be mentioned only briefly. This review will focus on the mechanisms by which Th17 cells drive three overlapping phases of autoimmune arthritis: inflammation, cartilage destruction, and bone erosion.
Section snippets
Identification of Th17 cells as a principal mediator of autoimmune arthritis
Early observations of the inflamed tissue of rheumatoid arthritis led researchers to hypothesize that the disease was mediated by Th1 cells [7], [8]. Reports that the infiltration of activated T cells enhances osteoclastogenesis in the joint, coupled with the identification of elevated Th1-associated factors (M-CSF, IL-10, and TNF) that induce osteoclastogenesis in synovial tissue, supported this notion [7], [8], [9], [10]. However, the mechanism by which Th1 cells induced osteoclastogenesis
Inflammation
Th17-driven inflammation during host defense markedly resembles the inflamed synovial tissue in RA and other forms of autoimmune arthritis. The RA synovium is characterized by elevated levels of IL-6, TNF, and IL-1β along with nitric oxide (NO) and prostaglandin E2 (PGE2) [38]. Th17 cells, and IL-17 in particular, have been shown to synergize with or upregulate each of these pro-inflammatory factors. IL-17 mediates the induction of IL-6 and IL-8 in both adult RA and juvenile idiopathic
Current and emerging therapies
Cytokines involved in the Th17 network, including IL-6, IL-1β and TNF, have been targeted in therapies for RA, although to date no clinical trials have tested the efficacy of anti-IL-17 treatment directly. The synergy between IL-17 and TNF may partially explain the efficacy of TNF inhibitors in attenuating the symptoms of RA (for review of TNF inhibition, see Feldmann et al.) [104]. Although two separate studies reported that infliximab does not lower the gene expression or serum levels of
Conclusion
The identification of IL-17 producing T cells as a distinct subset of pro-inflammatory helper T cells has broken down old paradigms concerning the role of Th1 cells in autoimmune disorders. Mounting evidence indicates a destructive role for IL-17 in various stages of rheumatoid arthritis: inflammation, along with the cartilage destruction and bone erosion that subsequently result. Furthermore, the efficacy of therapies that inhibit cytokines in the IL-17 network (IL-6, IL-1, and TNF) suggest
Acknowledgments
We would like to acknowledge the collaboration of Michael Kattah and the early contributions of Diana Milojevic to the dialogue surrounding this review.
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None of the authors has any potential financial conflict of interest related to this manuscript.