Targeting immune checkpoints in anti-neutrophil cytoplasmic antibodies associated vasculitis: the potential therapeutic targets in the future

Abstract

Anti-neutrophil cytoplasmic autoantibodies (ANCA) associated vasculitis (AAV) is a necrotizing vasculitis mainly involving small blood vessels. It is demonstrated that T cells are important in the pathogenesis of AAV, including regulatory T cells (Treg) and helper T cells (Th), especially Th2, Th17, and follicular Th cells (Tfh). In addition, the exhaustion of T cells predicted the favorable prognosis of AAV. The immune checkpoints (ICs) consist of a group of co-stimulatory and co-inhibitory molecules expressed on the surface of T cells, which maintains a balance between the activation and exhaustion of T cells. CD28, inducible T-cell co-stimulator (ICOS), OX40, CD40L, glucocorticoid induced tumor necrosis factor receptor (GITR), and CD137 are the common co-stimulatory molecules, while the programmed cell death 1 (PD-1), cytotoxic T lymphocyte-associated molecule 4 (CTLA-4), T cell immunoglobulin (Ig) and mucin domain-containing protein 3 (TIM-3), B and T lymphocyte attenuator (BTLA), V-domain Ig suppressor of T cell activation (VISTA), T-cell Ig and ITIM domain (TIGIT), CD200, and lymphocyte activation gene 3 (LAG-3) belong to co-inhibitory molecules. If this balance was disrupted and the activation of T cells was increased, autoimmune diseases (AIDs) might be induced. Even in the treatment of malignant tumors, activation of T cells by immune checkpoint inhibitors (ICIs) may result in AIDs known as rheumatic immune-related adverse events (Rh-irAEs), suggesting the importance of ICs in AIDs. In this review, we summarized the features of AAV induced by immunotherapy using ICIs in patients with malignant tumors, and then reviewed the biological characteristics of different ICs. Our aim was to explore potential targets in ICs for future treatment of AAV.

Keywords: T cells; antineutrophil cytoplasmic autoantibody associated vasculitis; co-inhibitory signal pathway; co-stimulatory signal pathway; immune checkpoint; immunotherapy.

Figure 1

Pathogenesis of ANCA associated vasculitis. T cells, B cells, and neutrophils were activated by multiple stimulations in the background of genetic susceptibility. Th and Treg cells differentiated from T cells synergistically promote B cells to develop into plasma cells, and produce ANCA. ANCA then combined with PR3 or MPO expressed on neutrophils pre-activated by inflammatory cytokines. Also, C5a derived from activated cAP might combine with the C5a receptor on neutrophils. Neutrophils activated by ANCA, C5a and various cytokines might produce more NETs conducive for the inflammatory response and adaptive immunity, ultimately leading to clinical damages. Abbreviations: ANCA, anti-neutrophil cytoplasmic autoantibodies; C5a, fragment a of the fifth complement; cAP, complement alternative pathway; MPO, myeloperoxidase; NETs, neutrophil extracellular traps; PR3, proteinase-3; Th, helper T; Treg, regulatory T.

Figure 2

Co-stimulatory signal pathways in T cells. The activation and proliferation of T cells at least need two signals. The first signal is provided by the binding of TCR to MHC with antigenic polypeptide processed by APC. Co-stimulatory molecules bind to the ligand or receptor presented by APCs, transmitting the second signal. The molecules in the left box are members of IgSF, activating the signal pathways downstream by different motifs in the cytoplasmic tail. The members of TNFRSF are represented in the right box. They bind to TRAF to activate the signal pathways downstream. Abbreviations: APC, antigen-presenting cell; GITR, glucocorticoid induced tumor necrosis factor receptor; ICOS, inducible T-cell co-stimulator; IgSF, immunoglobulin superfamily; MHC, major histocompatibility complex; TCR, T cell receptor; TNFRSF, tumor necrosis factor receptor superfamily; TRAF, tumor necrosis factor receptor-associated factor.

Figure 3

Co-inhibitory signal pathways in T cells. The co-inhibitory signal pathways induced the exhaustion of T cells. HVEM is a member of TNFRSF. Other molecules belong to IgSF. Except for LAG-3, VISTA, TIM-3, and CD200, all of them have inhibitory signal motifs in the cytoplasmic tail. LAG-3 has a unique KIEELE motif whose role is unclear, while VISTA, TIM-3, and CD200 do not have any motifs in the cytoplasmic tail. Abbreviation: APC, antigen-presenting cell; BTLA, B and T lymphocyte attenuator; CTLA-4, cytotoxic T lymphocyte-associated molecule 4; Gal-9, galactin-9; HVEM, herpesvirus entry mediator; IgSF, immunoglobulin superfamily; LAG-3, lymphocyte activation gene 3; MHC, major histocompatibility complex; PD-1, programmed cell death 1; PD-L1, programmed death ligand 1; TCR, T cell receptor; TIGIT, T‐cell immunoglobulin and ITIM domain; TIM-3, T cell immunoglobulin and mucin domain-containing protein 3; TNFRSF, tumor necrosis factor receptor superfamily; VISTA, V-domain immunoglobulin suppressor of T cell activation; VSIG-3, V-set and immunoglobulin domain containing 3. .