Genetic, Immunologic, and Immunohistochemical Analysis of the Programmed Death 1/Programmed Death Ligand 1 Pathway in Human Systemic Lupus Erythematosus

    loading  Checking for direct PDF access through Ovid

Abstract

Objective.

A putative regulatory intronic polymorphism (PD1.3) in the programmed death 1 (PD-1) gene, a negative regulator of T cells involved in peripheral tolerance, is associated with increased risk for systemic lupus erythematosus (SLE). We undertook this study to determine the expression and function of PD-1 in SLE patients.

Methods.

We genotyped 289 SLE patients and 256 matched healthy controls for PD1.3 by polymerase chain reaction–restriction fragment length polymorphism analysis. Expression of PD-1 and its ligand, PDL-1, was determined in peripheral blood lymphocytes and in renal biopsy samples by flow cytometry and immunohistochemistry. A crosslinker of PD-1 was used to assess its effects on anti-CD3/anti-CD28–induced T cell proliferation and cytokine production.

Results.

SLE patients had an increased frequency of the PD1.3 polymorphism (30.1%, versus 18.4% in controls;P= 0.006), with the risk A allele conferring decreased transcriptional activity in transfected Jurkat cells. Patients homozygous for PD1.3—but not patients heterozygous for PD1.3—had reduced basal and induced PD-1 expression on activated CD4+ T cells. In autologous mixed lymphocyte reactions (AMLRs), SLE patients had defective PD-1 induction on activated CD4+ cells; abnormalities were more pronounced among homozygotes. PD-1 was detected within the glomeruli and renal tubules of lupus nephritis patients, while PDL-1 was expressed by the renal tubules of both patients and controls. PD-1 crosslinking suppressed proliferation and cytokine production in both normal and lupus T cells; addition of serum from patients with active SLE significantly ameliorated this effect on proliferation.

Conclusion.

SLE patients display aberrant expression and function of PD-1 attributed to both direct and indirect effects. The expression of PD-1/PDL-1 in renal tissue and during AMLRs suggests an important role in regulating peripheral T cell tolerance.

Related Topics

    loading  Loading Related Articles