The PD-1/PD-L1 Inhibitory Pathway is Altered in Primary Glomerulonephritides

Abstract

The pathogenesis of primary proliferative and non-proliferative glomerulonephritides (PGN and NPGN) is still not fully understood, however, current evidence suggests that most cases of PGN and NPGN are the results of immunologic response to different etiologic agents that activates various biological processes leading to glomerular inflammation and injury. Programmed cell death protein 1 (PD-1) is the major inhibitory receptor regulating T cell exhaustion. The aim of this study was to evaluate the frequencies of PD-1-positive and PD-ligand 1 (PD-L1)-positive T and B lymphocytes in patients with NPGN and PGN in relation to clinical parameters for the first time. The study included peripheral blood (PB) samples from 20 newly diagnosed PGN and NPGN patients. The control group comprised of 20 healthy age- and sex-matched subjects. The viable PB lymphocytes underwent labelling with fluorochrome-conjugated monoclonal antibodies anti-PD-1 and anti-PD-L1, and were analyzed using a flow cytometer. The frequencies of CD4+/PD1+ T lymphocytes, CD8+/PD1+ T lymphocytes, and CD19+/PD-1+ B lymphocytes in the PGN group exceeded values obtained both in the NPGN group, and the control group. Alteration of PD-1/PD-L1 pathway may be involved in poorer prognosis, as patients with PGN are characterized by higher frequencies of PD-1-positive and PD-L1-positive T and B lymphocytes than patients with NPGN. Our results suggest that deregulation of PD-1/PD-L1 axis may contribute to the PGN and NPGN pathogenesis. High percentages of lymphocytes with PD-1 and PD-L1 expression may be related to the continuous T-cell activation and development of glomerular inflammation and injury.

PD-1 and PD-L1 Expression on Circulating Lymphocytes as a Marker of Epstein-Barr Virus Reactivation-Associated Proliferative Glomerulonephritis

“…Since complications may appear up to 8h after the procedure, an overnight hospitalization is required after a kidney biopsy, particularly if moderate-to-advanced chronic kidney disease occurs [35]. Therefore, there is an urgent need for identification of novel, non-invasive markers to diagnose primary GN [25,30]. Our study suggest that PD-1 and PD-L1 antigen expression on the surface of circulating lymphocytes may be a sensitive marker of PGN.…”

“…Although the immunopathogenesis of these disorders is not fully understood, many researchers have observed a link between infections and the development of primary GN [27][28][29]. Moreover, in a cohort of 20 patients with primary GN, we previously showed that the frequencies of PD-1-positive and PD-L1-positive T and B lymphocytes were higher among patients suffering from PGN than in those diagnosed with NPGN or in the control group [30]. Therefore, in the current study, we aimed to examine a potential involvement of infectious agents in the upregulation of the PD-1/PD-L1 axis in patients with primary GN and to determine whether these proteins could serve as non-invasive markers to distinguish PGN from NPGN.…”

“…Plasma was stored at −80 • C until use. Only PBMCs with a viability of ≥95% (determined using 0.4% trypan blue solution; Sigma Aldrich, Hamburg, Germany) were used in subsequent experiments [25,30].…”

“…Immunophenotyping was performed using a FACSCalibur flow cytometer (BD Biosciences, San Jose, CA, USA) equipped with a 488 nm argon laser, as previously described [30,40,43]. Briefly, cells were stained with monoclonal antibodies (purchased from BD Biosciences, San Jose, CA, USA) conjugated with different fluorochromes to determine the proportion of the specific cell types and the surface expression of PD-1 and PD-L1.…”

The Increase of Circulating PD-1- and PD-L1-Expressing Lymphocytes in Endometriosis: Correlation with Clinical and Laboratory Parameters

“…Expression of PD-1 causes several changes; among others, it decreases the induction of cell survival protein Bcl-xL and expression of IFN- γ and IL-2. Blocking of the PD-1/PD-L1 pathway increases the response against antigen presented by DCs [28–31].…”