Diminished PD-L1 regulation along with dysregulated T lymphocyte subsets and chemokine in ANCA-associated vasculitis

• Published in: Clinical and experimental medicine Vol. 23; no. 5; pp. 1801 - 1813
• Main Authors: Singh, Jagdeep, Minz, Ranjana Walker, Saikia, Biman, Nada, Ritambhra, Sharma, Aman, Jha, Saket, Anand, Shashi, Rathi, Manish, D’Cruz, Sanjay
• Format: Journal Article
• Language: English
• Published: Cham Springer International Publishing 01-09-2023; Springer Nature B.V
• Subjects: Antigen-antibody complexes; Antineutrophil cytoplasmic antibodies; Apoptosis; Autoimmune diseases; Biopsy; BLyS protein; CD4 antigen; Cell death; Chemokines; CXCR2 protein; Effector cells; Hematology; HMGB1 protein; Homeostasis; Immunological memory; Immunological tolerance; Immunomodulation; Inflammation; Internal Medicine; Leukocytes (neutrophilic); Ligands; Lymphocytes B; Lymphocytes T; Macrophages; Medicine; Medicine & Public Health; Memory cells; Microenvironments; Neutrophils; Oncology; Original Article; PD-1 protein; Vasculitis; Pauci-immune crescentic glomerulonephritis; Programmed death-ligand 1; ANCA-associated vasculitis; Sub-clinical inflammation
• ISSN: 1591-9528; 1591-8890; 1591-9528
• DOI: 10.1007/s10238-022-00908-y

ANCA-associated vasculitis (AAV) is a life-threatening disease characterized by small vessel inflammation and pathogenic self-directed antibodies. Programmed death-ligand 1 receptor (PD-1) and programmed cell death ligand-1 (PD-L1) are immune checkpoint molecules crucial for maintaining tolerance and immune homeostasis. After checkpoint inhibition therapy, development of various autoimmune diseases and immune-related adverse events (irAEs) have been observed. Here, we investigated the immunomodulatory roles of neutrophils through the expression of immune checkpoint molecule (PD-L1), migratory molecules (CXCR2), chemotactic chemokines (CXCL5) and other important molecules (BAFF and HMGB1) in development of AAV. We also scrutinized the immune mechanism responsible for development of pauci-immune crescentic GN (PICGN). We demonstrate for the first time that the frequency of PD-L1 expressing neutrophils was significantly reduced in AAV patients compared to healthy controls and correlated negatively with disease severity (BVASv3). Further, in renal biopsy, reduced PD-L1 immune checkpoint expression provides a microenvironment that unleashes uncontrolled activated CD4 + T cells, B cells, neutrophils and macrophages and ultimately causes engulfment of immune complexes leading to PICGN. Furthermore, during remission, reduced neutrophils PD-L1 and CXCR2 expression, increased neutrophils CXCL5 expression and increased peripheral effector memory T cells and increased HMGB1 and BAFF levels in serum, demonstrate the propensity for the persistence of sub-clinical inflammation, which could explain relapse, in this group of diseases.