The Role of Th17 in Neuroimmune Disorders: Target for CAM Therapy. Part I

Abstract

CD4(+) effector cells, based on cytokine production, nuclear receptors and signaling pathways, have been categorized into four subsets. T-helper-1 cells produce IFN-γ, TNF-β, lymphotoxin and IL-10; T-helper-2 cells produce IL-4, IL-5, IL-10, IL-13, IL-21 and IL-31; T-helper-3, or regulatory T-cells, produce IL-10, TGF-β and IL-35; and the recently discovered T-helper-17 cell produces IL-17, IL-17A, IL-17F, IL-21, IL-26 and CCL20. By producing IL-17 and other signaling molecules, Th17 contributes to the pathogenesis of multiple autoimmune diseases including allergic inflammation, rheumatoid arthritis, autoimmune gastritis, inflammatory bowel disease, psoriasis and multiple sclerosis. In this article, we review the differential regulation of inflammation in different tissues with a major emphasis on enhancement of neuroinflammation by local production of IL-17 in the brain. By understanding the role of pathogenic factors in the induction of autoimmune diseases by Th17 cells, CAM practitioners will be able to design CAM therapies targeting Th17 and associated cytokine activities and signaling pathways to repair the intestinal and blood-brain barriers for their patients with autoimmunities, in particular, those with neuroinflammation and neurodegeneration.

Figure 1

General scheme of T-helper cell differentiation. Naive CD4⁺ T cells, after activation by T-cell receptor and co-stimulatory molecules, such as CD28 and inducible T-cell co-stimulator (ICOS), can differentiate into four effector T-helper cells: Th1, Th2, Th3 or Th17 cells. These cells produce different cytokines, which have specialized immunoregulatory functions. IFN-γ produced by Th1 cells is important in the regulation of antigen presentation and cellular immunity. IL-4, IL-5 and IL-13 produced by Th2 cells regulate B-cell responses, important mediators of allergic diseases. TGF-β and IL-10 are produced by Th3 cells to regulate Th1 and Th2 cells. Th17 cells regulate inflammatory responses by expressing IL-17, IL-21, IL-22 and IL-26. CAM protocols can be implemented to reduce the level of proinflammatory cytokine IL-6, thereby inhibiting the conversion of activated T cells into pathogenic Th17 cells.

Figure 2

Cytokine production by dendritic cells and macrophages induce development of TReg, Th17 or IL-17-producing cells from naive CD4 cells and regulation of Th17 cells by Th1 and Th2 cytokines.

Figure 3

Effects of bacterial toxins and allergens on dendritic cell activation of cAMP induction of transmembrane signaling and its receptor ligand. Binding of c-Kit to its ligand SCF stimulates dendritic cells to secrete IL-6. IL-6 acts as a key factor in differentiation of T lymphocytes into Th2 and Th17 cells, which contribute to the development of allergic and autoimmune diseases. By inhibiting enhanced IL-6 production, CAM practitioners may prevent, slow down or reverse the development of allergic and inflammatory disorders.