721 Wang, et al: PD-L gene in SLE Ligands for Programmed Cell Death 1 Gene in Patients with Systemic Lupus Erythematosus SHU-CHEN WANG, CHIA-HUI LIN, TSAN-TENG OU, CHENG-CHIN WU, WEN-CHAN TSAI, CHAUR-JONG HU, HONG-WEN LIU, and JENG-HSIEN YEN ABSTRACT. Objective. To investigate the role of ligands for programmed cell death 1 (PD-L) in the pathogenesis of systemic lupus erythematosus (SLE). Methods. One hundred sixty-four patients with SLE and 160 healthy controls were enrolled in our study. The PD-L1 and PD-L2 polymorphisms were determined by polymerase chain reaction (PCR)/direct sequencing or restriction fragment length polymorphism (RFLP)-PCR. Results. The genotype distributions of PD-L2 47103 C/T polymorphisms in patients with SLE were sig- nificantly different from those of the controls (p = 0.003). The genotype frequency of PD-L2 47103 T/T, in comparison with 47103 C/C, was significantly increased in patients with SLE when compared with that of the controls (odds ratio 2.5, 95% confidence interval 1.4–4.4, p = 0.001). A similar finding could also be found in the allele frequency of PD-L2 47103 T (SLE vs control, OR 1.7, 95% CI 1.3–2.4, p = 0.001). There were no significant differences in the genotype and allele frequencies of PD-L1 poly- morphisms between the patients and controls. Conclusion. PD-L2 47103 T may be associated with susceptibility to SLE in Taiwan. (First Release Mar 1 2007; J Rheumatol 2007;34:721–5) Key Indexing Terms: PROGRAMMED CELL DEATH 1 LIGAND PROGRAMMED CELL DEATH 2 LIGAND SYSTEMIC LUPUS ERYTHEMATOSUS PROGRAMMED CELL DEATH 1 From the Department of Laboratory Medicine and Division of Rheumatology, Department of Internal Medicine, Kaohsiung Medical University Hospital; College of Medicine and Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung; and the Department of Neurology, Taipei Medical University Hospital, Taipei, Taiwan. S-C. Wang, MSc, Department of Laboratory Medicine; C-H. Lin, MSc; T-T. Ou, MD, Attending Physician; C-C. Wu, MD, Attending Physician, Division of Rheumatology, Department of Internal Medicine, Kaohsiung Medical University Hospital; W-C. Tsai, MD, PhD, Associate Professor; H-W. Liu, MD, Professor, Division of Rheumatology, Department of Internal Medicine and College of Medicine, Kaohsiung Medical University; C-J. Hu, MD, Assistant Professor, Department of Neurology, Taipei Medical University Hospital; J-H. Yen, MD, PhD, MSc, Professor, Division of Rheumatology, Department of Internal Medicine and Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University. Address reprint requests to Dr. J-H. Yen, Division of Rheumatology, Department of Internal Medicine, Kaohsiung Medical University Hospital, No. 100 Zih-You 1st Road, Kaohsiung City 807, Taiwan. E-mail: jehsye@kmu.edu.tw Accepted for publication December 28, 2006. Systemic lupus erythematosus (SLE) is a prototype of autoim- mune diseases, which frequently involves multiple organs. The detailed pathogenesis is still obscure. Many genes such as human leukocyte antigen, complement, FcrR, mannose bind- ing lectin, protein tyrosine phosphatase N22, cytokines, and chemokine genes have been described to be associated with the development of SLE 1-5 . Programmed cell death 1 (PD-1) is an immunoinhibitory receptor expressed by activated T cells, B cells, and myeloid cells 6 . The ligands for PD-1 (PD-L1 and PD-L2, also known as B7-H1 and B7-DC) are type I transmembrane proteins structurally related to the B7 family. They can be induced in monocytes, dendritic cells, endothelial cells, keratinocytes, and B cells 6-10 . However, PD-L1 expression is different from that of PD-L2. PD-L1 is also expressed on activated T cells, placental trophoblasts, myocardial endothelium, and cortical thymic epithelial cells. In contrast, PD-L2 can also be pre- sented on placental endothelium and medullary thymic epithe- lial cells 10 . The interactions of PD-1 with PD-L1 and PD-L2 result in the inhibition of T cell receptor-mediated lymphocyte proliferation and cytokine secretion, and they also inhibit CD28-mediated costimulation. The relative levels of inhibito- ry PD-L1 and costimulatory CD80/CD86 signals on antigen- presenting cells determine the extent of T cell activation and the threshold between tolerance and autoimmunity. Therefore, PD-L1 expression on nonlymphoid tissues and its interaction with PD-1 may determine the extent of immune responses at sites of inflammation 6 . Recent studies using anti-PD-L1 monoclonal antibodies have suggested a role for PD-L1 in regulating autoimmune diseases. Blockade of the PD-L during experimental autoim- mune encephalomyelitis (EAE) or diabetes exacerbates the diseases 11,12 . PD-L1 blockade rapidly precipitated diabetes in prediabetic female non-obese diabetic (NOD) mice. PD-L2 blockade in animals also resulted in augmentation of EAE. These studies showed that PD-1–PD-L blockade was related to the development of autoimmune disease. The polymorphisms in exons of PD-L1 and PD-L2 may result in amino acid substitution, structural changes, and expression of PD-L1 and PD-L2. The consequent interactions Personal non-commercial use only. The Journal of Rheumatology Copyright © 2007. All rights reserved. www.jrheum.org Downloaded on January 22, 2022 from