ReviewAutoimmune inflammation from the Th17 perspective
Introduction
The classical T helper (Th)1 and Th2 CD4+ T cell effector paradigm has recently been challenged. Studies from various laboratories have shown the existence of a T cell subpopulation, dubbed Th17, not only distinct from Th1 and Th2, but a different pro-inflammatory Th-cell lineage [1]. Here, we highlight the animal studies that led to the discovery of the Th17 T cell lineage and examine its link with the IL-17/IL-23 axis, particularly in the pathogenesis of collagen-induced arthritis (CIA) and experimental autoimmune encephalomyelitis (EAE). We focus our discussion on the role of the IL-17/IL-23 axis in the pathogenesis of human rheumatoid arthritis (RA). Taken together, these data promise to change our understanding of immune regulation and pathogenesis and maybe our approach to treat some human autoimmune diseases.
Section snippets
The Th1/Th2 paradigm
Two decades ago, Mosmann et al. proposed that Th cells could be subdivided in two subpopulations, Th1 and Th2, based upon their cytokine expression profiles [2]. Th1 cells produce IL-2 and interferon-γ (IFN-γ), while Th2 cells synthesize IL-4, IL-5 and IL-10 [2] (Fig. 1). These mutually inhibitory cytokine-function profiles are mediated by lineage-specific transcription mechanisms. Following receptor linking, IL-12 activates the transcription factor signal transducer and activator of
The Th17 lineage
The Th1/Th2 paradigm is paradoxical because anti-IFN-γ-treated mice, IFN-γ- or IFNR-deficient mice indeed develop CIA [3], [4], [5], [6] or EAE [7], [8], [9], two classical Th1 associated-diseases [2]. Similarly, Infante-Duran et al. recently demonstrated that Th cells primed with a synthetic peptide in the presence of Borrelia burgdorferi, the causative agent of Lyme disease, primarily express mRNA encoding IL-17 (IL-17A) at significantly higher levels than Th cells primed with IL-12, while
IL-17, IL-12 and IL-23
Interleukin-17 (IL-17A) is the prototypic IL-17 family member that is comprised of four other relatives: IL-17B–E. The IL-17F isoforms 1 and 2 (ML-1) have the highest degree of homology with IL-17A (55 and 40%, respectively), IL-17E is the most distant (17%). IL-17A is co-expressed with TNF-α and GM-CSF [16], [17] by Th17 cells [16], [17], and to a lesser extent by neutrophils, eosinophils, and CD8+ memory CD45RO+ T cells (reviewed in Ref. [27]).
The IL-17 receptor (IL-17RA), a type I
IL-17 in human rheumatoid arthritis
IL-17 and IL-23p19 are present in the sera, synovial fluids and synovial biopsies of most RA patients, while both are absent in osteoarthritis (OA) [29], [30], [31], [32], [33]. Similarly, IL-17 is produced by T cell clones developed from RA patients [34] and human RA T cells primed in vitro with type II collagen, stimulate IL-15, TNF-α and IL-18 production by RA synovial fibroblasts, in turn, T cells respond to fibroblasts by secreting high levels of IL-17 and IFN-γ [30]. It is also known that
Concluding remarks
Recent studies have demonstrated that the classical Th1/Th2 CD4+ T cell effector model needs reinterpretation. It is now known that the IL-17-producer T cell, heretofore thought of as a Th1 subset, is a distinct T cell lineage on its own right. This newly discovered T cell, termed Th17, has a defined cytokine profile, it has its own set of lineage-specific developmental genes and is the main pro-inflammatory CD4+ effector T cell involved in murine models of CIA and EAE. Th17 cells are feasible
Take-home messages
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Th17 cell is a recently discovered CD4+ effector T cell lineage, distinct from Th1, Th2 and Treg cells. Its master regulator is the orphan nuclear receptor RORγt.
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IL-17 is a marker molecule for Th17 cells rather than a unique cytokine of this helper cell lineage.
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The Th17 cytokine effector molecules are IL-17 A/F, TNF-α, IL-6 and GM-CSF.
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Murine Th17 cells play a major role in the pathogenesis of the human equivalent of multiple sclerosis and rheumatoid arthritis.
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Rheumatoid arthritis and multiple
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