Investigation of the effect of pd1.1, pd1.5, and pd1.9 mutations on pd1 gene function with a system biology approach

Document Type : Research Paper


1 Department of Urology, Icahn School of Medicine, Mount Sinai Hospitals, NY, USA.

2 Department of Basic Science, College of Medicine, Hawler Medical University, Erbil, Iraq.

3 Pars Advanced and Minimally Invasive Medical Manners Research Center, Pars Hospital, Iran.


Programmed cell death 1 (pd1) is an immune-inhibitory receptor that is expressed in activated T cells. This gene may play a role in inhibition of actual anti- microbial and anti-tumor immunity. In human, this gene is located on the long arm of chromosome 2. This gene has many variations that three of which are more common. This study was aimed to investigate the influence of pd1.1, pd1.5, and pd1.9 variations on function of pd1gene based on a bioinformatics approach. In this study, the EPD and PROMO webserver was used to evaluate the pd1.1 variation as a promoter mutation. It has been detected in the promoter region by EPD, while the transcription factor arrangement was evaluated by the PROMO server. But, some bioinformatics tools such as ProtScale – ExPASy and Ramachandran plot assay web servers were used to evaluate the effects of codding polymorphisms. Obtained data from EPD showed that the promoter of pd1 contains 60 nucleotides. Evaluation of upstream of pd1 revealed that the number of transcription factors could alter the pd1.1 variation. With regard to the pd1.5 polymorphisms, the result showed that it is considered as a synonymous variation, but the pd1.9 was known as a nonsynonymous mutation. Thus, the pd1.9 could alter the hydrophobicity and Ramachandran plots of PD1. The pd1.5 mutation may impact the expression of the pd1gene because it changes the transcription factor arrangement on the upstream of pd1. Also, the pd1.9 substitution could alter the hydrophobicity and Ramachandran plots of protein.

Graphical Abstract

Investigation of the effect of pd1.1, pd1.5, and pd1.9 mutations on pd1 gene function with a system biology approach


  • Programmed cell death 1 gene plays a key role in development of some disorders such as various cancers.
  • The pd1.1 variation may change the gene expression of pd1by altering the transcription factor binding sites of the promoter region.
  • The pd1.5 gene mutation as a non-synonymous variation may alter the function and structure of the pd1.


Main Subjects

Ishida M, Iwai Y, Tanaka Y, Okazaki T, Freeman GJ, Minato N, Honjo T. Differential expression of PD-L1 and PD-L2, ligands for an inhibitory receptor PD-1, in the cells of lymphohematopoietic tissues. Immun lett 2002; 84(1): 57-62.
Jin HT, Ahmed R, Okazaki T. Role of PD-1 in regulating T-cell immunity. Negative co-receptors and ligands. 2010; 17-37.
Agata Y, Kawasaki A, Nishimura H, Ishida Y, Tsubat T, Yagita H, Honjo T. Expression of the PD-1 antigen on the surface of stimulated mouse T and B lymphocytes. Int Immun 1996; 8(5): 765-772.
Ivansson EL, Juko-Pecirep I, Gyllensten UB. Interaction of immunological genes on chromosome 2q33 and IFNG in susceptibility to cervical cancer. Gynecol Oncol 2010; 116(3): 544-548.
Nishimura H, Minato N, Nakano T, Honjo T. Immunological studies on PD-1 deficient mice: implication of PD-1 as a negative regulator for B cell responses. Int immunol 1998; 10(10): 1563-1572.
Dong H, Strome SE, Salomao DR, Tamura H, Hirano F, Flies DB, Roche PC, Lu J, Zhu G, Tamada K, Lennon VA. Tumor-associated B7-H1 promotes T-cell apoptosis: a potential mechanism of immune evasion. Nat Med 2002; 8(8): 793-800.
Freeman GJ, Long AJ, Iwai Y, Bourque K, Chernova T, Nishimura H, Fitz LJ, Malenkovich N, Okazaki T, Byrne MC, Horton HF. Engagement of the PD-1 immunoinhibitory receptor by a novel B7 family member leads to negative regulation of lymphocyte activation. J Exp Med 2000; 192(7): 1027-1034.
Blank C, Brown I, Peterson AC, Spiotto M, Iwai Y, Honjo T, Gajewski TF. PD-L1/B7H-1 inhibits the effector phase of tumor rejection by T cell receptor (TCR) transgenic CD8+ T cells. Cancer Res 2004; 64(3): 1140-1145.
Iwai Y, Ishida M, Tanaka Y, Okazaki T, Honjo T, Minato N. Involvement of PD-L1 on tumor cells in the escape from host immune system and tumor immunotherapy by PD-L1 blockade. Proc Natl Acad Sci 2002; 99(19): 12293-12307.
Strome SE, Dong H, Tamura H, Voss SG, Flies DB, Tamada K, Salomao D, Cheville J, Hirano F, Lin W, Kasperbauer JL. B7-H1 blockade augments adoptive T-cell immunotherapy for squamous cell carcinoma. Cancer Res 2003; 63(19): 6501-6505.
Shinohara T, Taniwaki M, Ishida Y, Kawaichi M, Honjo T. Structure and chromosomal localization of the human PD-1 gene (PDCD1). Genomics 1994; 23(3): 704-706.
Blank C, Brown I, Marks R, Nishimura H, Honjo T, Gajewski TF. Absence of programmed death receptor 1 alters thymic development and enhances generation of CD4/CD8 double-negative TCR-transgenic T cells. J Immunol 2003; 171(9): 4574-4581.
Nishimura H, Honjo T. PD-1: an inhibitory immunoreceptor involved in peripheral tolerance. Trends immunol 2001; 22(5): 265-268.
Latchman Y, Wood CR, Chernova T, Chaudhary D, Borde M, Chernova I, Iwai Y, Long AJ, Brown JA, Nunes R, Greenfield EA. PD-L2 is a second ligand for PD-1 and inhibits T cell activation. Nat Immunol 2001; 2(3): 261-268.
Brown JA, Dorfman DM, Ma FR, Sullivan EL, Munoz O, Wood CR, Greenfield EA, Freeman GJ. Blockade of programmed death-1 ligands on dendritic cells enhances T cell activation and cytokine production. J Immunol 2003; 170(3): 1257-1266.
Carter LL, Fouser LA, Jussif J, Fitz L, Deng B, Wood CR, Collins M, Honjo T, Freeman GJ, Carreno BM. PD‐1: PD‐L inhibitory pathway affects both CD4+ and CD8+ T cells and is overcome by IL‐2. Eur J Immunol 2002; 32(3): 634-643.
Özkaynak E, Wang L, Goodearl A, McDonald K, Qin S, O’Keefe T, Duong T, Smith T, Gutierrez-Ramos JC, Rottman JB, Coyle AJ. Programmed death-1 targeting can promote allograft survival. J Immunol 2002; 169(11): 6546-6553.
Curiel TJ, Wei S, Dong H, Alvarez X, Cheng P, Mottram P, Krzysiek R, Knutson KL, Daniel B, Zimmermann MC, David O. Blockade of B7-H1 improves myeloid dendritic cell–mediated antitumor immunity. Nat Med 2003; 9(5): 562-567.
Loke P, Allison JP. PD-L1 and PD-L2 are differentially regulated by Th1 and Th2 cells. Proc Natl Acad Sci 2003; 100(9): 5336-5341.
Trabattoni D, Saresella M, Biasin M, Boasso A, Piacentini L, Ferrante P, Dong H, Maserati R, Shearer GM, Chen L, Clerici M. B7-H1 is up-regulated in HIV infection and is a novel surrogate marker of disease progression. Blood 2003; 101(7): 2514-2520.
Yamazaki T, Akiba H, Iwai H, Matsuda H, Aoki M, Tanno Y, Shin T, Tsuchiya H, Pardoll DM, Okumura K, Azuma M. Expression of programmed death 1 ligands by murine T cells and APC. J Immunol 2002; 169(10): 5538-5545.
Kazemi E, Zargooshi J, Kaboudi M, Heidari P, Kahrizi D, Mahaki B, Mohammadian Y, Khazaei H, Ahmed K. A genome-wide association study to identify candidate genes for erectile dysfunction. Brief Bioinform 2020.
Ghaheri M, Kahrizi D, Yari K, Babaie A, Suthar RS, Kazemi E. A comparative evaluation of four DNA extraction protocols from whole blood sample. Cell Mol Biol 2016; 62(3): 120-124.
Rahimi A, Mirmoayedi A, Kahrizi D, Zarei L, Jamali S. Genetic diversity of Iranian honey bee (Apis mellifera meda Skorikow, 1829) populations based on ISSR markers. Cell Mol Biol 2016; 62(4): 53-58.