CCL2 recruitment of IL‐6‐producing CD11b⁺ monocytes to the draining lymph nodes during the initiation of Th17‐dependent B cell‐mediated autoimmunity

Abstract

The development and function of Th17 cells are influenced in part by the cytokines TGF-b, IL-23 and IL-6, but the mechanisms that govern recruitment and activity of Th17 cells during initiation of autoimmunity remain poorly defined. We show here that the development of autoreactive Th17 cells in secondary lymphoid organs in experimental autoimmune myasthenia gravis -an animal model of human myasthenia gravis -is modulated by IL-6-producing CD11b + cells via the CC chemokine ligand 2 (CCL2). Notably, acetylcholine receptor (AChR)-reactive Th17 cells provide help for the B cells to produce anti-AChR antibodies, which are responsible for the impairment of the neuromuscular transmission that contributes to the clinical manifestations of autoimmunity, as indicated by a lack of disease induction in IL-17-deficient mice. Thus, Th17 cells can promote humoral autoimmunity via a novel mechanism that involves CCL2.

Decreased microRNA miR-181c expression in peripheral blood mononuclear cells correlates with elevated serum levels of IL-7 and IL-17 in patients with myasthenia gravis

“…In this study, we focused on IL-7 as a target gene of miR-181c in view of its role in promoting differentiation and function of multiple effector T cell subsets, especially IFN-c or IL-17-producing T cells [16,21,22]. Experiments with gene-deficient mice indicate that Th17 cells and IL-17 play a crucial role in the pathogenesis of EAMG [23,24]. Moreover, previous studies have shown that serum IL-17 concentrations were higher in MG patients compared with controls and correlated with antiAchR antibody titers [25,26].…”

Lineages of human T-cell clones, including T helper 17/T helper 1 cells, isolated at different stages of anti–factor VIII immune responses

“…[22][23][24][25][26][27] In various mouse models of allergy and autoimmunity, IL-17 deficiency decreases germinal center B-cell development and antigen-specific antibody production, whereas high levels of IL-17 promote germinal center and antigen-specific antibody production. [22][23][24]26,27 Human T H 17 and T H 17/T H 1 clones have been shown to induce CD19 ϩ B cells to produce IgM, IgG, and IgA, but not IgE when stimulated with anti-CD3 antibody. 25 Human T H 17 cells, but not T H 1 and T H 2 cells, secrete high levels of the B-cell chemoattractant CXC chemokine ligand 13.…”

Suppression of ongoing experimental autoimmune myasthenia gravis by transfer of RelB-silenced bone marrow dentritic cells is associated with a change from a T helper Th17/Th1 to a Th2 and FoxP3+ regulatory T-cell profile

“…The Th17 population, which is characterized by production of IL-17, is important in mediating autoimmune diseases such as rheumatoid arthritis and EAE in animals [43,44]. A very recent study reported that TAChR-immunized IL-17 -/-mice exhibited significantly milder EAMG and reduced anti-AChR IgG2b compared to control B6 mice [10], indicating that Th17 plays a central role in humoral immunity in EAMG. In fact, using mice genetically deficient in IL-12/IL-23 and IFN-k (dKO mice) to examine the effects of IL-12 and IFN-k on EAMG susceptibility, Wang et al provided evidence that Th1 cytokines are not the exclusive players in EAMG-pathogenic Th17 cells and reduced CD4 ?…”

“…Recent studies indicate that Th17, Th1, Th2, and Treg cells play a very important role in the development and progression of EAMG via a complex network of interactions among the cells and their cytokines [9,10]. Thus, modulation of the differentiation of the four T-cell subsets in vivo would be an alternative to treatment of this autoimmune disorder.…”