Anti-neutrophil cytoplasmic antibody (ANCA)–associated vasculitis (AAV) is a systemic autoimmune disease characterized by necrotizing small-vessel inflammation, in which dysregulated adaptive immune responses play a central pathogenic role. Beyond the well-established contribution of ANCAs and innate immune activation, increasing evidence highlights profound alterations in T-cell regulation that drive persistent inflammation, autoantibody production, and organ damage. Immune checkpoints (ICs)—a network of co-stimulatory and co-inhibitory pathways that fine-tune lymphocyte activation and maintain peripheral tolerance—have emerged as key regulators in this process. In this review, we summarize current experimental and clinical evidence demonstrating imbalance across multiple immune checkpoint pathways in AAV, including the PD-1/PD-L1/PD-L2 axis, CD28/CTLA-4, ICOS, CD40–CD40L, OX40, LAG-3, TIM-3, BTLA, and CD27. We discuss how impaired inhibitory signaling combined with enhanced co-stimulatory activity promotes sustained T-cell activation, aberrant T–B cell collaboration, and pathogenic ANCA production, contributing to vascular and renal injury. Importantly, both membrane-bound and soluble checkpoint molecules show disease-specific alterations in blood, urine, and renal tissue, correlating with disease activity, renal involvement, treatment response, and relapse risk. These findings position immune checkpoint components as promising biomarkers that may complement conventional clinical and serological markers. Finally, we review the current therapeutic landscape of checkpoint modulation in AAV, including clinical experience with abatacept and emerging evidence supporting PD-1 agonism and other pathway-targeted strategies derived from related autoimmune diseases. Collectively, this work highlights immune checkpoint dysregulation as a central feature of AAV pathophysiology and underscores its potential for advancing precision biomarkers and immune-targeted therapies.
García-Serrano et al. (Mon,) studied this question.