56 Cellular and Molecular Biology Original Research Association between the cytotoxic T-lymphocyte antigen-4 mutations and the susceptibility to systemic lupus erythematosus; Contribution markers of inflammation and oxidative stress M. Tanhapour 1,2,3 , A. Vaisi-Raygani 1,2,3* , F. Bahrehmand 1,2,3 , M. Khazaei 1 , A. Kiani 2,4 , Z. Rahimi 3,5 , H. Nomani 1 , H. Tavilani 6 , T. Pourmotabbed 7 1 Fertility and Infertility Research Center, Kermanshah University of Medical Sciences, Kermanshah, Iran 2 Tissue Engineering and Regenerative Medicine (TERM) Research Center, Kermanshah University of Medical Sciences, Kermanshah, Iran 3 Department of Clinical Biochemistry, Kermanshah University of Medical Sciences, Kermanshah, Iran 4 Department of Toxicology and Pharmacology, Kermanshah University of Medical Sciences, Kermanshah, Iran 5 Medical Biology Research Center, Kermanshah University of Medical Sciences, Kermanshah, Iran 6 Urology and Nephrology Research Center, Hamadan University of Medical Sciences, Hamadan, Iran 7 Department of Microbiology, Immunology and Biochemistry, University of Tennessee, Health Science Center, USA Abstract: The cytotoxic T lymphocyte antigen-4 (CTLA-4) also known as CD152 (cluster of differentiation 152) is a crucial negative regu- lator of the immune system. This protein receptor provides negative signals in order to suppress T-cell activation and immune attack against self-antigens, although its role is unclear. The ability of CTLA-4 to limit T cell-mediated immune response has made it a major target in treat- ment of tumors and autoimmune diseases such as systemic lupus erythematosus (SLE). In this study, we investigated whether CTLA-4 G -1661 A and CTLA-4 T -1722 C mutations are associated with SLE. So one hundred nine SLE patients and 101 gender and age-matched unrelated healthy controls were recruited for this case-control study. The promoter mutations were detected by PCR-RFLP, neopterin, malondialdehyde (MDA) and serum lipid concentration were determined by HPLC and enzyme assay, respectively. Result: We found that both codominant (AA vs. GG) and recessive (AA vs. GA+GG) CTLA-4 G -1661 A mutation significantly decreased the risk of SLE by 1.7 and 3.7 times, respectively. Interestin- gly, SLE patients with AA genotypes of CTLA-4 G -1661 A have lower neopterin and MDA concentration compared with GA+GG genotypes. The overall distribution of CTLA-4 T -1722 C genotypes and alleles in SLE patients were similar to those in control group. In conclusion, our findings showed, that there is an association between systemic inflammatory markers, oxidative stress and the CTLA-4 G -1661 A GG+AG genotypes, MDA and neopterin which are the most convenonal risk factors for coronary heart disease, therefore these mutations may be consider as a risk factor for susceptibility to heart disease in SLE patients. Key words: CTLA-4, neopterin, MDA, SLE. Introduction Systemic lupus erythematosus (SLE) is a chronic autoimmune disease in which the body produces au- toantibodies against self-antigens (1). The etiology and pathogenesis of SLE are unknown, although various factors such as environmental factors, sibling, hormonal factors and genetics play a role in the onset of the di- sease (2,3). The gene encoding CTLA-4 on chromosome 2q33 is one of the potential regions associated with an increased risk of developing SLE (2,4). CTLA-4 is a glycoprotein that is expressed by both CD4 + and CD8 + T cells (5). Due to alternative splicing of CTLA-4 gene there are 2 isoforms of protein, a full-length (flCTLA-4) and a soluble (sCTLA-4) form lacking transmembrane domain (4). CTLA-4 is related to T cell receptor, CD28. Both molecules interact with CD80 and CD86 ligands found on antigen presenting cells. Despite structural similarities, the functions of CD28 and CTLA-4 are al- most completely opposite. CD28 enhances T cell proli- feration, cytokine production, survival and also enables T cells to provide help for B cells, while CTLA-4 acts as an inhibitor of T cell responses (5). CTLA-4 binds to CD80 and CD86 and blocks their interactions with CD28 and down-regulates T-cell activation, which may help to maintain peripheral tolerance and contribute to SLE treatment (4,6). Several CTLA-4 gene mutations have been reported but only few of them are associa- ted with SLE (6). Two of the most important CTLA-4 gene variations are G/A nucleotide transition at position -1661 and T/C change at −1722 within the promoter re- gion (4). T/C change at position −1722 affects binding sites of transcription factors, whereas G/A transition at position -1661 may alter the potential response element for myocyte enhancer factor 2 (MEF2) (7). Previous studies demonstrated that neopterin is ge- nerated following activation of cellular immune system (8). Neopterin is derived from guanosine triphosphate (GTP) in response to interferon-(IFN) γ secreted by ac- tivated T cells (9,10). Although other cell types can pro- duce neopterin but its amount is negligible (11). Neop- terin elevated in patients with infections, neoplastic and Received May 11, 2016; Accepted October 17, 2016; Published October 31, 2016 * Corresponding author: Asad Vaisi-Raygani, Fertility and Infertility Research Center, Department of Clinical Biochemistry, School of Medicine, Kermanshah University of Medical Sciences, Daneshgah Avenue, P.O. Box 6714869914, Kermanshah, Iran. Email: avaisiraygani@gmail.com and asadvaisiraygani@kums.ac.ir Copyright: © 2016 by the C.M.B. Association. All rights reserved. Tanhapour et al. Cell. Mol. Biol.2016, 62 (12): 56-61 ISSN: 1165-158X doi: 10.14715/cmb/2016.62.12.10