T-helper cells as new players in ANCA-associated vasculitides

Abstract

In anti-neutrophil cytoplasmic autoantibody-associated vasculitides (AAV), several observations support a key role of T-helper cells (CD4(+) T cells) in disease pathophysiology. An expanded population of effector memory CD4(+) T cells in AAV patients may contribute to tissue injury and disease progression. In addition, functional impairment of regulatory T cells (T(Regs)) is reported in AAV patients. A fraction of T(Regs) have the capacity to differentiate into Th17 cells in the context of a proinflammatory environment. Therefore, nonfunctionality of T(Regs) described in AAV patients may be caused by their conversion into IL-17-producing cells that may contribute to granulomatous vasculitis. Further investigations directed at the plasticity of T(Regs) in AAV patients are warranted.

Figure 1

Proposed pathophysiological mechanisms of anti-neutrophil cytoplasmic autoantibody-associated vasculitides. Inflammatory cytokines (IL-1β, IL-6, transforming growth factor beta (TGFβ)) released due to bacterial or viral infections can promote skewing of a subset of functional regulatory T cells (T_Regs) towards IL-17-producing nonfunctional T_Regs. These IL-17-producing cells play a key role in disease onset through their cytokine IL-17. This cytokine induces CXC chemokine release from the target tissue that will attract neutrophils to the site of inflammation. In addition, IL-17 stimulates the release of IL-1β and TNFα from macrophages, which causes upregulation of the expression of endothelial adhesion molecules and induces translocation of proteinase-3 (PR3) and myeloperoxidase (MPO) to the neutrophil membrane (priming). Released PR3 and MPO can be processed and presented by antigen-presenting cells (APC) to T-helper cells. Since T_Regs are converted into nonfunctional IL-17-producing cells that fail to inhibit this autoimmune response, autoreactive T cells may undergo repeated stimulation by PR3-pulsed or MPO-pulsed APC, resulting in a pool of effector memory T cells (T_EM). In addition, PR3-stimulated T-helper cells act on B cells. The presence of IL-17 can enhance the production of anti-neutrophil cytoplasmic autoantibody (ANCA) by autoreactive B cells. Subsequently, ANCA binds to PR3 or MPO on primed neutrophils that adhere to endothelial cells, which enhances neutrophil activation resulting in degranulation and release of reactive oxygen species (ROS) and proteolytic enzymes that can damage vascular endothelial cells. Moreover, persistent activation of T-helper cells by PR3 or MPO, together with the breakdown of T_Reg-mediated self-tolerance mechanisms, will induce autoreactive CD4⁺ T_EM expansion. Expanded CD4⁺ T_EM upregulate their killer immunoglobulin-like receptor (NKG2D) and interact with their ligand (major histocompatibility complex class-I chain-related molecule A (MICA)) on vascular endothelial cells, which in turn enhances their cytotoxic function and kills target cells in a perforin-dependent and granzyme-dependent way, ending up in vasculitis.