Genetic, immunologic, and immunohistochemical analysis of the programmed death 1/programmed death ligand 1 pathway in human systemic lupus erythematosus
| Autor: | Amalia Raptopoulou, Christianna Choulaki, Clio Mamalaki, Eva D. Papadimitraki, Herakles Kritikos, George Bertsias, Magda Nakou, Dimitris Kardassis, Maria Tzardi, Dimitrios T. Boumpas, Prodromos Sidiropoulos, George N. Goulielmos |
|---|---|
| Rok vydání: | 2009 |
| Předmět: |
Adult
CD4-Positive T-Lymphocytes Male Heterozygote Genotype medicine.medical_treatment T cell Lymphocyte Biopsy Immunology Programmed Cell Death 1 Receptor Lupus nephritis Biology Kidney Ligands Lymphocyte Activation Jurkat cells Polymorphism Single Nucleotide B7-H1 Antigen Flow cytometry Rheumatology Antigens CD medicine Immunology and Allergy Humans Lupus Erythematosus Systemic Pharmacology (medical) Systemic lupus erythematosus medicine.diagnostic_test Homozygote Peripheral tolerance Middle Aged medicine.disease Immunohistochemistry Cytokine medicine.anatomical_structure Female Apoptosis Regulatory Proteins Cell Division |
| Zdroj: | Arthritis and rheumatism. 60(1) |
| ISSN: | 0004-3591 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|
Plný text