Association between Loss of Immune Checkpoint Programmed Cell Death Protein 1 and Active ANCA-Associated Renal Vasculitis

• Published in: International journal of molecular sciences 2023-02, Vol.24 (3), p.2975
• Main Authors: Hakroush, Samy, Tampe, Björn
• Format: Article
• Language: English
• Subjects: Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis - pathology; Antibodies, Antineutrophil Cytoplasmic; Antigens; Antineutrophil cytoplasmic antibodies; Apoptosis; Autoimmune diseases; Autoimmunity; B7-H1 Antigen; Biopsy; Cell death; Communication; Complement; Complement C5; Complement component C5; Complement component C5a; Complement Factor B; Correlation; CTLA-4 protein; Cytotoxicity; Disease; Humans; Immune checkpoint inhibitors; Immune system; Inflammation; Kidney - metabolism; Kidney Diseases - pathology; Kidneys; Lesions; Ligands; Lymphocytes; Lymphocytes T; Patients; PD-1 protein; PD-L1 protein; Pilot Projects; Programmed Cell Death 1 Receptor - genetics; programmed cell death protein 1; Proteins; Receptor, Anaphylatoxin C5a; renal vasculitis; Signal transduction; Steroids; Vasculitis
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms24032975

Immune checkpoint inhibitors (ICIs) have made an important contribution to the survival of patients with certain cancers. ICIs interrupt co-inhibitory signaling pathways mediated by programmed cell death protein 1 (PD-1), programmed cell death protein ligand 1 (PD-L1) and cytotoxic T lymphocyte-associated antigen (CTLA-4) that result in the elimination of cancer cells by stimulating the immune system. However, immune-related adverse events have also been described and attributed to an enhanced immune system activation. Recent observations have suggested a dysregulation of immune checkpoints in active antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). We here analyzed intrarenal PD-1 and PD-L1 by immunostaining in a total of 15 kidney biopsies with ANCA-associated renal vasculitis in correlation with glomerular and tubulointerstitial lesions. For independent validation, publicly available datasets were analyzed for PD-1 expression (encoded by ). We here observed a predominant tubulointerstitial expression of PD-1 that is decreased in ANCA-associated renal vasculitis. Moreover, loss of tubulointerstitial PD-1 correlated with active ANCA-associated renal vasculitis. Consistent with the observed association with active glomerular and tubulointerstitial lesions, we identified that interstitial PD-1 correlated with tubular and/or glomerular PD-L1 positivity. Finally, PD-1 was associated with decreased local synthesis of complement factor B. Interestingly, we did not observe a correlation between PD-1 and complement C5 or its C5a receptor. Combined with our observations, this may implicate a link between impaired PD-1/PD-L1 signaling, complement factor B and active ANCA-associated renal vasculitis. These findings could be of relevance because experimental data have already described that PD-1 agonism can be used therapeutically to attenuate autoimmunity in multiple disease models. Furthermore, targeted therapy against a complement C5/C5a receptor and factor B are both available and currently evolving in the treatment of AAV. Therefore, this pilot study expands our current knowledge and describes a potential interplay between immune checkpoints and the alternative complement pathway in active ANCA-associated renal vasculitis.