Complement drives Th17 cell differentiation and triggers autoimmune arthritis

Abstract

Activation of serum complement triggers Th17 cell–dependent spontaneous autoimmune disease in an animal model. In genetically autoimmune-prone SKG mice, administration of mannan or β-glucan, both of which activate serum complement, evoked Th17 cell–mediated chronic autoimmune arthritis. C5a, a chief component of complement activation produced via all three complement pathways (i.e., lectin, classical, and alternative), stimulated tissue-resident macrophages, but not dendritic cells, to produce inflammatory cytokines including IL-6, in synergy with Toll-like receptor signaling or, notably, granulocyte/macrophage colony-stimulating factor (GM-CSF). GM-CSF secreted by activated T cells indeed enhanced in vitro IL-6 production by C5a-stimulated macrophages. In vivo, C5a receptor (C5aR) deficiency in SKG mice inhibited the differentiation/expansion of Th17 cells after mannan or β-glucan treatment, and consequently suppressed the development of arthritis. Transfer of SKG T cells induced Th17 cell differentiation/expansion and produced arthritis in C5aR-sufficient recombination activating gene (RAG)−/− mice but not in C5aR-deficient RAG−/− recipients. In vivo macrophage depletion also inhibited disease development in SKG mice. Collectively, the data suggest that complement activation by exogenous or endogenous stimulation can initiate Th17 cell differentiation and expansion in certain autoimmune diseases and presumably in microbial infections. Blockade of C5aR may thus be beneficial for controlling Th17-mediated inflammation and autoimmune disease.

Pathogenic conversion of Foxp3+ T cells into TH17 cells in autoimmune arthritis

“…1f). These findings suggest that under arthritic conditions, CD25 lo Foxp3 + CD4 + T cells are prone to differentiate into T H 17 cells that are known to have a key pathological role in arthritis [13][14][15][16][17][18] .…”

Sexual Dimorphism in the Th17 Signature of Ankylosing Spondylitis

“…We further detected a reduction in a number of T cell receptor (TCR) signaling-related molecules, including CD81, TARP (CD3g), and CD247 (CD3z), and TCR signal strengthmodulating IL-2R (IL2RB) (31). Altered TCR signaling can affect the skewing of T cell polarization and selection, as seen in SKG mice, in which signaling defects associated with CD3z result in an increase in autoreactive T cells, including Th17 cells (32,33). It is thus tempting to hypothesize that altered TCR signaling in AS patients may be affecting T cell polarization and self-reactivity.…”

Treatment with anti-C5aR mAb leads to early-onset clinical and mechanistic effects in the murine delayed-type hypersensitivity arthritis model

“…A vaccine that induces generation of anti-C5a antibodies has been shown to be effective in murine collagen-induced arthritis (CIA) in mice [16], and oral treatment with a small molecule C5a antagonist reduced joint damage in the rat antigen-induced arthritis model [17]. In several mouse models of arthritis C5aR-deficient mice show reduced disease development [18][19][20][21]. In human C5aR knockin mice, a mouse anti-human C5aR monoclonal antibody effectively ameliorated neutrophil-dependent K/B Â N serum transfer-induced arthritis [22], and it has been shown that antimouse C5aR mAb lowers disease activity when administered in the early stages of murine CIA [23].…”