Open AccessGenetic, immunologic, and immunohistochemical analysis of the programmed death 1/programmed death ligand 1 pathway in human systemic lupus erythematosus
Author(s) -
Bertsias George K.,
Nakou Magda,
Choulaki Christianna,
Raptopoulou Amalia,
Papadimitraki Eva,
Goulielmos George,
Kritikos Herakles,
Sidiropoulos Prodromos,
Tzardi Maria,
Kardassis Dimitris,
Mamalaki Clio,
Boumpas Dimitrios T.
Publication year - 2009
Publication title -
arthritis & rheumatism
Language(s) - English
Resource type - Journals
eISSN - 1529-0131
pISSN - 0004-3591
DOI - 10.1002/art.24227
Subject(s) - lupus nephritis , immunology , medicine , cytokine , immunohistochemistry , lupus erythematosus , systemic lupus erythematosus , cd3 , endocrinology , biology , immune system , antibody , cd8 , disease
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.