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

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Abstract

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.

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Availability of data and materials

The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.

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Acknowledgements

The manpower for this work was supported by the Indian Council of Medical Research (ICMR), New Delhi (Grant/Award no. 3/1/3/JRF-2015(2)/HRD).

Funding

This work was supported by Institutional Grant of PGIMER (Grant No. 71/2-Edu-16/142).

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Authors and Affiliations

  1. Department of Immunopathology, Postgraduate Institute of Medical Education and Research, Chandigarh, 160012, India

    Jagdeep Singh, Ranjana Walker Minz, Biman Saikia & Shashi Anand

  2. Department of Histopathology, Postgraduate Institute of Medical Education and Research, Chandigarh, 160012, India

    Ritambhra Nada

  3. Department of Internal Medicine, Postgraduate Institute of Medical Education and Research, Chandigarh, 160012, India

    Aman Sharma & Saket Jha

  4. Department of Nephrology, Postgraduate Institute of Medical Education and Research, Chandigarh, 160012, India

    Manish Rathi

  5. Department of General Medicine, Government Medical College and Hospital, Chandigarh, 160030, India

    Sanjay D’Cruz

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Contributions

JS executed the study, analysed the data, and wrote the manuscript. RWM designed and mentored the study, edited and corrected the manuscript. BS gave inputs, and played an active role in use of PCR-arrays for kidney biopsy gene expression. RN reported and provided the histopathological details of kidney biopsy. AS treated and managed the patients, and provided the clinical details of the patients. SJ helped in recruitment and patient treatment. SA contributed to execution and standardization of experiments, and helped in analysis of kidney biopsy gene expression data. MR treated the pauci-immune crescentic GN patients. SD treated patients of minimal change disease, lupus nephritis and pauci-immune crescentic GN. All authors approved the final version of the manuscript and concurred on its submission.

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Correspondence to Ranjana Walker Minz.

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The present study was approved by the Ethics Committee of Postgraduate Institute of Medical Education and Research (PGIMER), Chandigarh (IEC approval no: INT/IEC/2016/2515), and was performed in compliance with the Helsinki Declaration.

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Singh, J., Minz, R.W., Saikia, B. et al. Diminished PD-L1 regulation along with dysregulated T lymphocyte subsets and chemokine in ANCA-associated vasculitis. Clin Exp Med 23, 1801–1813 (2023). https://doi.org/10.1007/s10238-022-00908-y

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