The immunoregulatory axis (programmed death‐1/programmed death ligand‐1) on CD4+ T cells in lupus nephritis: association with vitamin D and chemokine C‐X‐C motif ligand 12

Abstract

Lupus nephritis (LN) is one of the most serious complications of systemic lupus erythematosus (SLE). Multiple immunomodulatory mechanisms contribute to the pathogenesis of LN. A deep understanding of the immunopathogenesis of LN is essential to identify optimal molecular targets, as most immunotherapeutic algorithms are still based on unselective drugs. The study aimed to elucidate the possible association of vitamin D deficiency with the programmed death‐1 (PD‐1)/programmed death ligand‐1 (PD‐L1) axis and inflammatory response in patients with LN, as well as the relationship between the PD‐1/PD‐L1 axis and chemokine C‐X‐C motif ligand 12 (CXCL12). Flow cytometry was used to determine the frequencies of CD279 (PD‐1) and CD274 (PD‐L1) in the peripheral CD3+CD4+ cell population of persons with LN. Furthermore, ELISA was used to detect serum CXCL12 and vitamin D concentrations. A distinct decrease of PD‐1 and a significant increase of PD‐L1 was demonstrated in patients with LN compared with either SLE patients with no LN or healthy controls. The PD‐1/PD‐L1 axis was negatively correlated with different disease parameters. Vitamin D deficiency and insufficiency were more prevalent in patients with LN than in controls, being significantly associated with disease activity and inversely associated with the PD‐1/PD‐L1 expression. Moreover, CXCL12 was negatively correlated with the PD‐1/PD‐L1 axis and vitamin D concentration. The findings suggest an involvement of the PD‐1/PD‐L1 axis in lupus nephritis, which might serve as a potential highly selective therapeutic target that is more effective but less toxic. In addition, restoring adequate vitamin D levels in lupus nephritis could be a possible simple measure to control inflammatory immune responses.

Exhausted but Not Senescent T Lymphocytes Predominate in Lupus Nephritis Patients

“…Most investigators support a destructive effect of PD1 expression in LN as the frequency of CD4+PD1+ and CD4+CXCR5−PD1+ peripheral T cells has been correlated with increased levels of INF-gamma and IL-17, as well as with disease activity [27,28]. Meanwhile, others have shown that the PD1/PDL1 ratio is reduced in active LN, with vitamin D playing central role in the inflammatory immune process [29]. Moreover, exhausted CD8+PD1+ T cells exert a reduced cytotoxic function and a reduced capacity of IL-2, IFN-γ, and TNF production [30].…”

Relationship between CD274 gene polymorphism and systemic lupus erythematosus risk in a Chinese Han population

“…[27][28][29] As opposed to SLE patients without lupus nephritis (LN) and healthy controls, patients with LN exhibit higher levels of CD274. 30 When compared to healthy controls, SLE patients exhibit higher CD274 expression in peripheral blood neutrophils, which is correlated with disease activity and severity. 31 Dendritic cells (DCs) are important for the immune response and maintain the proper ratio of tolerance to immunity.…”

“…Studies have discussed CD274 in autoimmune disorders such as RA, SLE, and type I diabetes 27–29 . As opposed to SLE patients without lupus nephritis (LN) and healthy controls, patients with LN exhibit higher levels of CD274 30 . When compared to healthy controls, SLE patients exhibit higher CD274 expression in peripheral blood neutrophils, which is correlated with disease activity and severity 31 .…”