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Review
. 2018 Oct;194(1):1-8.
doi: 10.1111/cei.13188. Epub 2018 Sep 4.

Immune-bone Interplay in the Structural Damage in Rheumatoid Arthritis

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Free PMC article
Review

Immune-bone Interplay in the Structural Damage in Rheumatoid Arthritis

N Komatsu et al. Clin Exp Immunol. .
Free PMC article

Abstract

The immune and bone systems maintain homeostasis by interacting closely with each other. Rheumatoid arthritis is a pathological consequence of their interplay, as activated T cell immune responses result in osteoclast-mediated bone erosion. An imbalance between forkhead box protein 3 (Foxp3)+ regulatory T (Treg ) cells and T helper type 17 (Th17) cells is often linked with autoimmune diseases, including arthritis. Th17 cells contribute to the bone destruction in arthritis by up-regulating receptor activator of nuclear factor kappa-Β ligand (RANKL) on synovial fibroblasts as well as inducing local inflammation. Studies on the origin of Th17 cells in inflammation have shed light on the pathogenic conversion of Foxp3+ T cells. Th17 cells converted from Foxp3+ T cells (exFoxp3 Th17 cells) comprise the most potent osteoclastogenic T cell subset in inflammatory bone loss. It has been suggested that osteoclastogenic T cells may have developed originally to stop local infection in periodontitis by inducing tooth loss. In addition, Th17 cells also contribute to the pathogenesis of arthritis by modulating antibody function. Antibodies and immune complexes have attracted considerable attention for their direct role in osteoclastogenesis, and a specific T cell subset in joints was shown to be involved in B cell antibody production. Here we summarize the recent advances in our understanding of the immune-bone interplay in the context of the bone destruction in arthritis.

Keywords: Autoantibody; Osteoclast; RANKL; Th17; rheumatoid arthritis.

Figures

Figure 1
Figure 1
ex‐Forkhead box protein 3‐T helper type 17 (exFoxp3Th17) cells, the bone‐damaging T cells in rheumatoid arthritis (RA) and periodontitis. Foxp3+ T cells convert into exFoxp3Th17 cells, which are the most potent osteoclastogenic T cells in both arthritis and periodontitis. This conversion is promoted by mesenchymal cell‐derived interleukin (IL)‐6. exFoxp3Th17 cells induce osteoclastogenesis mainly by up‐regulating receptor activator of nuclear factor kappa‐Β ligand (RANKL) on mesenchymal cells. They evoke structural damage and are entirely pathogenic in the context of RA. While exFoxp3Th17 cells induce bone damage in periodontitis, they play a beneficial role in host defence against oral bacteria by ejecting the infected tooth and producing anti‐bacterial peptides.
Figure 2
Figure 2
Mechanism of bone destruction in rheumatoid arthritis (RA). The aetiology of RA is not elucidated completely, but it is assumed that both genetic and environmental factors are involved. Autoantigens are presented by dendritic cells to T cells, which undergo differentiation into T helper (Th) cells that mediate autoimmune inflammation. Presentation of autoantigens by dendritic cells leads to the generation of various Th cells. Th17 cells up‐regulate receptor activator of nuclear factor kappa‐Β ligand (RANKL) expression on synovial fibroblasts and activate innate immune cells to produce proinflammatory cytokines [interleukin (IL)‐6, tumour necrosis factor (TNF)‐α, IL‐1] that activate osteoclast precursors and up‐regulate RANKL further on fibroblasts, resulting in the induction of osteoclastogeneisis. exFoxp3Th17 cells comprise a pathogenic Th17 cell subset. Tfh and Tph help B cells produce antibodies that promote RANKL‐dependent osteoclastogenesis both directly and indirectly by activating innate immune cells. Thus, the Th17–synovial fibroblast–RANKL axis and the T cell–B cell–antibody axis co‐operatively induce structural damage in RA.

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