• Contact Us
  • Indexing
  • Submit Manuscript
  • Open Access
  • Journals
  • Home
  • ISSN: 2333-6714
    J Immunol Clin Res 2(1): 1011.
    Submitted: 02 December 2013; Accepted: 03 January 2014; Published: 20 January 2014
    Research Article
    PD1 Gene Promoter Polymorphism in Thymoma and Myasthenia Gravis
    Hidefumi Sasaki1*, Tsutomu Tatematsu1, Masayuki Shitara1, Yu Hikosaka1, Katsuhiro Okuda1, Satoru Moriyama1, Motoki Yano1, Masayuki Tanahashi2, Kotaro Mizuno3, Katsuhiko Endo4 and Yoshitaka Fujii1
    1Department of Oncology, Immunology and Surgery, Nagoya City University Graduate School of Medical Sciences, Japan
    2Department of Chest Surgery, Seirei Mikatahara General Hospital, Japan
    3Department of Chest Surgery, Kariya Toyota General Hospital, Japan
    4Department of Surgery, Nagoya City East Medical Center, Japan
    *Corresponding author: Hidefumi Sasaki, Department of Oncology Immunology and Surgery, Nagoya City University Graduate School of Medical Sciences, 1 Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya 467-8601, Japan, Tel: +81-52-853-8231; Fax: +81-52-853-6440; Email: hisasaki @med.nagoya-cu.ac.jp
    Abstract
    Imbalance of immune regulation affects tumor-specific T-cell immunity in the cancer microenvironment and reshapes tumor progression and metastasis. Recent studies demonstrated that blockade of interactions of immune function mediates antitumor activity in preclinical models. Myasthenia gravis (MG) in thymoma patients depends critically on intratumorous generation and export of mature autoreactive T cells. On the other hands, the programmed death 1 (PD-1) molecule plays a role for negative regulator of T cells. Thus we investigated PD1 and cytotoxic T lymphocyte associated antigen-4 (CTLA4) gene polymorphism by genotyping assay using TaqMan PCR methods in surgically treated thymoma cases and myasthenia gravis cases. In this study included 148 surgically removed thymoma cases and 32 myasthenia gravis cases for PD-1 and CTLA4 genotyping analyses. The PD1 polymorphism at promoter -606 position (rs36084323) or at intron 2 (rs34819629) was not significantly different between myasthenia gravis patients (MG) and not with MG patients (non MG) within thymoma cases. PD-1 polymorphism (GG) at promoter -606 position (rs36084323) was tendency towards lower in MG cases without thymoma when compared to MG with thymoma cases (p=0.1003). CTLA4 gene polymorphism (rs231775) was not different within age, stage and MG statuses. AA genotype (3.1%) in MG without thymoma was tendency towards lower when compared to anti-acetylcholine antibody negative thymoma patients (p=0.0928). Thus PD-1 or CTLA4 low activity might favor the development of non-thymomatous MG.
    Keywords: PD-1; Promoter; Thymoma; Polymorphism; Myasthenia gravis; CTLA4
    Introduction
    Myasthenia gravis (MG) is considered a phenotype for antibody-mediated neuromuscular disorder and autoimmune diseases, directed against the nicotinic acetylcholine receptor. Among MG patients, those with thymoma differ from the other groups by a lack of significant human leukocyte antigen (HLA) association, absence of sex preponderance, and a poor response to thymectomy [1]. There is also good evidence that paraneoplastic MG has a different pathogenesis from the common thymic lymphofollicular hyperplasia-associated MG [2]. MG [3] or thymoma is associated with the +49A/G single nucleotide polymporphism (SNP) of the cytotoxic T-lymphocyte-associated antigen 4 (CTLA4) gene.
    An imbalance of immune regulation affects tumor-specific T-cell immunity in the cancer microenvironment and reshapes tumor progression and metastasis [4]. The lack of immuno-stimulatory activation can be harmful if it impairs immune responses against cancer [5]. Many receptor-ligand interactions are known to trigger anti-apoptotic pathways that prevent activation-induced T-cell death [6,7]. Programmed death 1 (PD-1) protein, a T-cell coinhibitory receptor plays a central role in the ability of tumor cells to escape the host’s immune system. Blockade of interactions between PD-1 and PD-1 ligands enhances immune function in vitro and mediates antitumor activity in preclinical models [8,9]. Recent reports suggested that antibody-mediated blockade of PD-1 [10,11] induced durable tumor regression and prolonged stabilization of disease in some patients with advanced cancers. The PD-1 molecule is a negative regulator of T cells. One of the SNP of PD-1 (PD1.3 G/A), a regulatory SNP located in intron 4, showed to be involved in susceptibility to SLE in Caucasian [12], however, Asian populations are not polymorphic at this SNP [13]. In addition, the PD-1 SNP statuses were not correlated with MG in Caucasians [14]. The polymorphism at PD-1 promoter was reported by Chinese, but vary rare in Caucasians [15]. The PD-1 promoter SNP statuses in tumors are not well investigated.
    In this paper, we have investigated the PD-1 gene polymorphisms in Japanese thymoma with or without MG using real-time polymerase chain reaction (PCR) using TaqMan PCR in surgically treated cases. The findings were compared to the clinicopathologic features of thymoma/MG and PD-1 gene status.
    Patients and Methods
    Patients
    The study group included thymoma patients (54.8±14.7 years old) and MG patients (38.4±18.9 years old) who had undergone surgery at the Department of Surgery, Nagoya City University Hospital between 1995 to 2013. All thymus tissue samples were immediately frozen and stored at -80 °C until assayed. Patient consent was obtained from the patients. The study was approved by the ethics committee of the University. The clinical and pathological characteristics of the 148 thymoma patients for PD-1 gene genotyping analyses were as follows; 65(43.9%) were male 83 were female. 30(20.2%) were less than 40 years old. 40(27.0%) were with MG (male; 15, female; 25) and 84 were anti-acecyhlcholine receptor negative (male 43, female; 41). 49 (34.5%) were pathological stage I, 51 were stage II, 22 were stage III, 25 were stage IV and 1 unknown.
    PCR assay for PD-1 and CTLA4 gene
    Genomic DNA was extracted from thymus tissues using Wizard SV Genomic DNA Purification System (Promega. Madison, WI, USA) according to the manufactures’ instructions. DNA concentration was determined by Nano Drop ND-1000 Spectrophotometer (Nano Drop Technologies Inc., Rockland, DE, USA). The primers and TaqMan probes for PD-1(-606 G/A; codon -606 of intron; rs36084323, +6371G/A; inton 2; rs34819629) and CTLA4; +49A/G, codon 17 of exon1; rs231775) were designed at Applied Biosystems (Foster City, CA, USA). For SNP genotyping, one pair of TaqMan probes and one pair of PCR primers were used. Two TaqMan probes differ at the polymorphic site, with one probe complementary to the wild-type allele and the other to the variant allele. TaqMan PCR and genotyping analysis were performed on Applied Biosystems 7500 Real Time PCR System. The reaction mixtures were amplified in 1 µl of template DNA (10ng/µl), 12.5 µl of 2X TaqMan Universal Master Mix, 0.625 µl of 20X primer/probe mix, 10.875 µl of ddH2O in a volume of 25 µl. The cycling conditions were as follows: initial denaturation at 95°C for 10 minutes, followed by 40 cycles at 95°C for 15 seconds and 58°C for 1 minutes. The results were analyzed on Applied Biosystems 7500 Real Time PCR System using alleic discrimination assay program.
    Statistical analysis
    Statistical analyses were done using the Student’s t-test for unpaired samples and T2 test for paired samples. All analysis was done using the Stat-View software package (Abacus Concepts Inc. Berkeley, CA), and was considered significant when the p -value was less than 0.05.
    Results
    PD-1 polymorphisn status in Japanese thymoma and mg
    We have investigated PD-1 gene status for 148 thymoma samples tissues. The PD-1 SNPs at promoter region (rs 36084323) were 35 AA, 71 GA and 42 GG in thymomas. The ratio was very similar to the Asian healthy control as previously reported [15]. The ratio of GG genotype was not different between MG patients (32.5%), anti-acetylcholine antibody positive patients but not with MG patients (29.2%), and anti-antibody negative patients (26.2%) within thymoma cases. The GG ratio was not significantly different between male (30.8%) and female (26.5%, p=0.5680). The GG ratio was not different whether higher than 40 years old (27.1%) or lower than 40 years old (33.3%). The GG ratio was not correlated with pathological stages, if we compared stage I-III (20.4%) vs. IV (9.5%, p=0.1214), and GG was even smaller population in stage IV (Table 1). The PD-1 SNPs at promoter region were 10 AA, 17 GA and 5 GG (15.6%) in MG without thymoma patients. GG genotype was tendency towards lower when compared to the MG with thymoma patients (p=0.1003) (Table 2).
    Table 1 Clinico-pathological data of 148 thymoma patients.
    * MG: Myasthenia Gravis; AchR: Acetylcholine Receptor; Ab; antibody. N.S.: not significant

     PD-1

     

    No. of AA+GA

    No. of GG

    p-value

    Factors

    patients

              patients

     

    Mean age (years)

    54.8±14.7

    106

    55.1±14.5

    42

    54.7±15.7

    0.9078

    Stage

     I

    II

    III

    IV

    35(33.7%)

    33(31.7%)

    15(14.4%)

    21(20.2%)

    14(33.3%)

    18(42.9%)

    7(16.7%)

    4(9.5%)

        I-III vs. IV

          0.1212

    MG status

    MG+

    27(25.5%)

    13(31.0%)

    N. S.

    AchR Ab+

    17(16.0%)

    7(16.7%)

     

    Negative

    62(58.5%)

    22(52.4%)

     

    Gender

    Male

     45(42.5%)

    20(47.6%)

    0.5680

    Female

    61(57.5%)

    22(52.4%)

     

    Age

    40

         20(18.9%)

    10(23.8%)

    0.5002

    >40

      86(81.1%)

    32(76.2%)

     

    Table 1 Clinico-pathological data of 148 thymoma patients.
    * MG: Myasthenia Gravis; AchR: Acetylcholine Receptor; Ab; antibody. N.S.: not significant

    ×
    Table 2 Comparison of -606G/A genotype.
    *Kong et al. 2005 Arthritis Rheum

     

    AA

    AG

    GG

    Thymoma (n=148)

    23.60%

    48.00%

    28.40%

    MG (Non-thymoma; n=32)

    31.30%

    53.10%

    15.60%

    *RA

    13.90%

    51.10%

    35.00%

    *Control  (Chinese; n=647)     

    24.90%

    47.80%

    27.30%

    Table 2 Comparison of -606G/A genotype.
    *Kong et al. 2005 Arthritis Rheum

    ×
    PD-1 gene SNP status at intron 2 (rs 34819629) was very similar to the status for rs 36084323, and 93.9% identical. The PD-1 rs 34819629 SNPs were 35 AA, 67 GA and 46 GG in thymomas. GG genotype was not different between MG patients (35.0%), anti-antibody positive but not with MG patients (33.3%), and anti-acetylcholine antibody negative patients (28.5%). The GG ratio was not significantly different between male (33.8%) and female (28.9%, p=0.5201). The GG ratio was not different whether higher than 40 years old (29.7%) or lower than 40 years old (36.7%, p=0.4591). The GG ratio was tendency towards lower in pathological stages IV (8.7%) when compared to stage I-III (21%, p=0.0667) (Table 3). The PD-1 SNPs at intron 2 region were 10 AA, 16 GA and 6 GG (18.8%) in MG without thymoma patients. GG genotype was not significantly different with the MG with thymoma patients (p=0.1261).
    Table 3 Clinico-pathological data of 148 thymoma patients.

     PD-1

     

    No. of AA+GA

    No. of GG

    p-value

    Factors

    patients

              patients

     

    Mean age (years)

    102

    55.2±14.5

    46

    54.6±15.6

    0.8994

    Stage

    I

    II

    III

    IV

    34(34.0%)

    31(31.0%)

    14(14.0%)

    21(21.0%)

    15(32.6%)

    20(43.5%)

    7(15.2%)

    4(8.7%)

        I-III vs. IV

          0.1345

    MG status

     

    MG+

    26(25.5%)

    14(30.4%)

    N. S.

    AchR Ab+

              16(15.7%)

    8(17.4%)

     

    Negative

    60(58.8%)

    24(52.2%)

     

    Gender

     

     

     

    Male

     43(42.2%)

    22(47.8%)

    0.5201

    Female

              59(57.8%)

    24(52.2%)

     

    Age   

    40

         19(18.6%)

    11(23.9%)

    0.4591

    >40

       83(81.4%)

    35(76.1%)

     

    Table 3 Clinico-pathological data of 148 thymoma patients.

    ×
    CTLA4 polymorphisn status in Japanese thymoma and MG
    CTLA4 gene SNP status at exon1 (+49A/G, rs 231775) was 17 AA, 65 GA and 66 GG in thymomas. AA genotype was not different between MG patients (5%), anti-antibody positive but not with MG patients (20.8%), and anti-acetylcholine antibody negative patients (11.9%), and the ratio was lower in MG patients. The AA phenotype was significantly higher in male (20%) than in female (7.2%, p=0.0254). CTLA-4 +49 SNP statuses was not different whether higher than 40 or lower than 40 (p=0.3190). CTLA4 +49 SNP was not correlated with pathological stages (I-III vs IV, p=0.8548) (Table 4). The CTLA4 SNPs at +49 were 1 AA, 13 GA and 18 GG in MG without thymoma patients. AA genotype (3.1%) was tendency towards lower when compared to anti-acetylcholine antibody negative thymoma patients (p=0.0928). Within 10 AA -606 PD-1 patients with non-thymomataous MG, 5 were GG at +49 CTLA4. Within 5 GG -606 PD-1 patients with non-thymomatous MG, no AA at +49 CTLA4. Thus, PD-1 and CTLA4 SNP was independent.
    Table 4 Clinico-pathological data of 148 thymoma patients.

    CTLA-4

     

    No. of GG+GA

    No. of AA

    p-value

    Factors

    patients

    patients

     

    Mean age (years)

    131

    55.4±14.5

    17

    52.1±17.2

    0.3896

    Stage

     

     

     

    I

    II

    III

    IV

    45(34.6%)

    44(33.8%)

    19(14.6%)

    22(16.9%)

    4(25.0%)

    7(43.8%)

    2(12.5%)

    3(18.8%)

    I-III vs. IV

    0.8584

    MG status

     

     

     

    MG+

    38(29.0%)

    2(11.8%)

    N. S.

    AchR Ab+

    74(56.5%)

    5(29.4%)

     

    Negative

    19(14.5%)

    10(58.8%)

     

    Gender

     

     

     

    Male

    54(41.2%)

    11(64.7%)

    0.0254

    Female

    77(58.8%)

    6(35.3%)

     

    Age

     

     

     

    40

    25(19.1%)

    5(29.4%)

    0.319

    >40

    106(80.9%)

    12(70.6%)

     

    Table 4 Clinico-pathological data of 148 thymoma patients.

    ×
    Discussion
    In this study, we focused on one of the programmed death 1, PD-1 gene SNP to know whether it might be new molecular mechanism for thymoma. We have found that PD-1 gene SNP was tendency towards lower in MG patients (without thymoma) when correlated to MG with thymoma patients.
    Human cancers harbor numerous genetic and epigenetic changes, generating neoantigens that are potentially recognizable by immune system [16]. Tumors develop multistep resistance systems, including local immuno-suppression, induction of tolerance, and systemic dysfunction in T-cell signaling [17-20]. In addition, tumors utilize several pathways to escape immune destruction. PD1 is a key immune-checkpoint receptor expressed by activated T-cells and mediates immuno-suppressions. Thus PD-1 might also act as a molecule target for tumor progression in cancers. In in vitro, inhibition of the interaction between PD-1 and PD-L1 could enhance T-cell responses and mediate preclinical antitumor activity [8, 9]. These observations made us our intensive efforts to develop immunotherapeutic approaches for cancer, including immune-checkpoint-pathway inhibitors such as anti-CTLA-4 antibody [21,22] and anti-PD-L1 therapy [11,12]. Anti-PD-1 antibody study has been started in advances solid tumors [23]. The recent studies by Brahmer et al. [11] and Topalian et al. [12] have been reporting the safety and activity of anti-PD1 or PD-L1 immunotherapy in cancers. However, in our analysis, PD-1 or CTLA-4 polymorphism did not correlate with thymoma progression. PD-1 polymorphSNPs at thymoma patients were very similar to Asian healthy controls. These molecules might not have a role in thymoma itself.
    The PD-1 belongs to the immunoglobulin receptor superfamily, encodes a 55-kd type 1 transmembrane inhibitory immunoreceptor, and is responsible for the negative regulation in T-cell activation and peripheral torelance [24]. Expression of PD-1 was observed only in activated T and B cells and early lymphoid precursors [25]. Previous reports indicate that PD-1 is markedly upregulated on surface of exhausted virus-specific CD8+ T cells in mice with lymphocytic choriomeningitis virus infection [26], and in humans with human immunodeficiency virus (HIV) infection [27,28]. PD-1 -606G allele showed a significant association with Japanese subacute sclerosing panencephalitis (SSPE) [29]. A haplotype having -606G allele with high promoter activity was associated with the development of SSPE [29]. Relative PD1 expression was higher in SSPE patients than in control [29]. PD-1 pathway might play a central role for the T cell dysfunction. Previous report demonstrated that -606G/A (previously called PD-1.1 at -531G/A) was associated with rheumatoid arthritis (RA) in Chinese [30]. However, this PD-1 SNP is rare in Europeans (1%) and Africans (4%) [15]. Other PD-1 SNP statuses were not significantly associated with MG in Sweden [14]. There is large variation in the frequencies of PD-1 SNP among different ethnic groups.
    Studies on PD-1 deficient mice in different genetic backgrounds showed the development of lupus-like autoimmune diseases [30] and autoimmune cardio myopathy [31]. Various studies indicated that PD-1 gene SNP polymorphisms were associated with autoimmune diseases such as SLE [32], multiple sclerosis [33], rheumatoid arthritis (RA) [34] and type 1 diabetes [35], although most of the SNPs were Caucasian specific. Some reports on transcriptional levels have shown decreased expression in Japanese DM 1 patients [36]. We have found the tendency towards lower GG phenotype at PD-1 promoter in MG without thymoma when compared to MG with thymoma patients. Thus PD1 low activity might favor the development of non-thymomatous MG. We could not demonstrate any significant association of the PD-1 gene SNP to MG, the possible reason could be sample size, fewer number of SNPs analyzed.
    CTLA4 is a receptor mainly displayed on activated T-cells. CTLA4 plays a critical role in down regulating immune responses. Mice who lack the CTLA4 gene develop a lethal phenotype with massive T-cell activation and T-cell infiltrates in virtually all organs [37]. SNP of the CTLA4 gene. +49A/G in exon 1 has been shown to affect gene expression [38]. The frequency of allele G and genotype G/G at position +49 was increased in MG thymoma patients than healthy controls in Sweden [3]. In contrast, +49 A/A genotype were reported to be higher in MG thymomas than non-MG thymomas from German [1]. Our results were similar to the results from Wang et al. [3]. There might be also a large variation in the frequencies of CTLA4 SNP among different ethnic groups. AA might be lower in Asian [40]. Our AA ratio in thymomas is very similar to the previous Asian report [40].
    In summary, PD-1 might have no role in thymomas. However, lower GG phenotype at promoter region of PD-1, as well as lower AA phenotype at CTLA4 +49 provided a candidate of its function as the autoimmune process. PD1 or CTLA4 low activity might favor the development of non-thymomatous MG. Larger cohort may be needed to determine the exact role of PD-1 and CTLA4 in MG.
    Acknowledgement
    The authors thank Miss. Yuka Toda and Ito Yamamoto for their excellent technical assistances. This work was supported by Grants-in-Aid for Scientific Research, Japan Society for the Promotion of Science (JSPS) (Nos, 25293303, 24592097, 23659674) and the Health and Labour Sciences Research Grant on Intractable Diseases (Nueroimmunological Diseases) from the Ministry of Health, Labour and Welfare of Japan.
    References
    1. Chuang WY, Ströbel P, Gold R, Nix W, Schalke B, Kiefer R, et al. A CTLA4high genotype is associated with myasthenia gravis in thymoma patients. Ann Neurol. 2005; 58: 644-648.
    2. Wang XB, Kakoulidou M, Qiu Q, Giscombe R, Huang D, Pirskanen R, et al. CDS1 and promoter single nucleotide polymorphisms of the CTLA-4 gene in human myasthenia gravis. Genes Immun. 2002; 3: 46-49.
    3. Zou W. Immunosuppressive networks in the tumour environment and their therapeutic relevance. Nat Rev Cancer. 2005; 5: 263-274.
    4. Chen L, Linsley PS, Hellström KE. Costimulation of T cells for tumor immunity. Immunol Today. 1993; 14: 483-486.
    5. Boise LH, Noel PJ, Thompson CB. CD28 and apoptosis. Curr Opin Immunol. 1995; 7: 620-625.
    6. Watts TH, DeBenedette MA. T cell co-stimulatory molecules other than CD28. Curr Opin Immunol. 1999; 11: 286-293.
    7. Dong H, Strome SE, Salomao DR, Tamura H, Hirano F, Flies DB, et al. Tumor-associated B7-H1 promotes T-cell apoptosis: a potential mechanism of immune evasion. Nat Med. 2002; 8: 793-800.
    8. 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 U S A. 2002; 99: 12293-12297.
    9. Brahmer JR, Tykodi SS, Chow LQ, Hwu WJ, Topalian SL, Hwu P, et al. Safety and activity of anti-PD-L1 antibody in patients with advanced cancer. N Engl J Med. 2012; 366: 2455-2465.
    10. Topalian SL, Hodi FS, Brahmer JR, Gettinger SN, Smith DC, McDermott DF, et al. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med. 2012; 366: 2443-2454.
    11. Prokunina L, Castillejo-López C, Oberg F, Gunnarsson I, Berg L, Magnusson V, et al. A regulatory polymorphism in PDCD1 is associated with susceptibility to systemic lupus erythematosus in humans. Nat Genet. 2002; 32: 666-669.
    12. Mori M, Yamada R, Kobayashi K, Kawaida R, Yamamoto K. Ethnic differences in allele frequency of autoimmune-disease-associated SNPs. J Hum Genet. 2005; 50: 264-266.
    13. Sakthivel P, Ramanujam R, Wang XB, Pirskanen R, Lefvert AK. Programmed Death-1: from gene to protein in autoimmune human myasthenia gravis. J Neuroimmunol. 2008; 193: 149-155.
    14. Kong EK, Prokunina-Olsson L, Wong WH, Lau CS, Chan TM, Alarcón-Riquelme M, et al. A new haplotype of PDCD1 is associated with rheumatoid arthritis in Hong Kong Chinese. Arthritis Rheum. 2005; 52: 1058-1062.
    15. Sjöblom T, Jones S, Wood LD, Parsons DW, Lin J, Barber TD, et al. The consensus coding sequences of human breast and colorectal cancers. Science. 2006; 314: 268-274.
    16. Topalian SL, Weiner GJ, Pardoll DM. Cancer immunotherapy comes of age. J Clin Oncol. 2011; 29: 4828-4836.
    17. Mellman I, Coukos G, Dranoff G. Cancer immunotherapy comes of age. Nature. 2011; 480: 480-489.
    18. Drake CG, Jaffee E, Pardoll DM. Mechanisms of immune evasion by tumors. Adv Immunol. 2006; 90: 51-81.
    19. Mizoguchi H, O'Shea JJ, Longo DL, Loeffler CM, McVicar DW, Ochoa AC. Alterations in signal transduction molecules in T lymphocytes from tumor-bearing mice. Science. 1992; 258: 1795-1798.
    20. Hodi FS, O'Day SJ, McDermott DF, Weber RW, Sosman JA, Haanen JB, et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med. 2010; 363: 711-723.
    21. Robert C, Thomas L, Bondarenko I, O'Day S, M D JW, Garbe C, et al. Ipilimumab plus dacarbazine for previously untreated metastatic melanoma. N Engl J Med. 2011; 364: 2517-2526.
    22. Brahmer JR, Drake CG, Wollner I, Powderly JD, Picus J, Sharfman WH, et al. Phase I study of single-agent anti-programmed death-1 (MDX-1106) in refractory solid tumors: safety, clinical activity, pharmacodynamics, and immunologic correlates. J Clin Oncol. 2010; 28: 3167-3175.
    23. Freeman GJ, Long AJ, Iwai Y, Bourque K, Chernova T, Nishimura H, et al. 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: 1027-1034.
    24. Nishimura H, Honjo T. PD-1: an inhibitory immunoreceptor involved in peripheral tolerance. Trends Immunol. 2001; 22: 265-268.
    25. Barber DL, Wherry EJ, Masopust D, Zhu B, Allison JP, Sharpe AH, et al. Restoring function in exhausted CD8 T cells during chronic viral infection. Nature. 2006; 439: 682-687.
    26. Day CL, Kaufmann DE, Kiepiela P, Brown JA, Moodley ES, Reddy S, et al. PD-1 expression on HIV-specific T cells is associated with T-cell exhaustion and disease progression. Nature. 2006; 443: 350-354.
    27. Petrovas C, Casazza JP, Brenchley JM, Price DA, Gostick E, Adams WC, et al. PD-1 is a regulator of virus-specific CD8+ T cell survival in HIV infection. J Exp Med. 2006; 203: 2281-2292.
    28. Ishizaki Y, Yukaya N, Kusuhara K, Kira R, Torisu H, Ihara K, et al. PD1 as a common candidate susceptibility gene of subacute sclerosing panencephalitis. Hum Genet. 2010; 127: 411-419.
    29. Nishimura H, Nose M, Hiai H, Minato N, Honjo T. Development of lupus-like autoimmune diseases by disruption of the PD-1 gene encoding an ITIM motif-carrying immunoreceptor. Immunity. 1999; 11: 141-151.
    30. Nishimura H, Okazaki T, Tanaka Y, Nakatani K, Hara M, Matsumori A, et al. Autoimmune dilated cardiomyopathy in PD-1 receptor-deficient mice. Science. 2001; 291: 319-322.
    31. Prokunina L, Castillejo-López C, Oberg F, Gunnarsson I, Berg L, Magnusson V, et al. A regulatory polymorphism in PDCD1 is associated with susceptibility to systemic lupus erythematosus in humans. Nat Genet. 2002; 32: 666-669.
    32. Kroner A, Mehling M, Hemmer B, Rieckmann P, Toyka KV, Mäurer M, et al. A PD-1 polymorphism is associated with disease progression in multiple sclerosis. Ann Neurol. 2005; 58: 50-57.
    33. Prokunina L, Padyukov L, Bennet A, de Faire U, Wiman B, Prince J, et al. Association of the PD-1.3A allele of the PDCD1 gene in patients with rheumatoid arthritis negative for rheumatoid factor and the shared epitope. Arthritis Rheum. 2004; 50: 1770-1773.
    34. Nielsen C, Hansen D, Husby S, Jacobsen BB, Lillevang ST. Association of a putative regulatory polymorphism in the PD-1 gene with susceptibility to type 1 diabetes. Tissue Antigens. 2003; 62: 492-497.
    35. Tsutsumi Y, Jie X, Ihara K, Nomura A, Kanemitsu S, Takada H, et al. Phenotypic and genetic analyses of T-cell-mediated immunoregulation in patients with Type 1 diabetes. Diabet Med. 2006; 23: 1145-1150.
    36. Tivol EA, Borriello F, Schweitzer AN, Lynch WP, Bluestone JA, Sharpe AH. Loss of CTLA-4 leads to massive lymphoproliferation and fatal multiorgan tissue destruction, revealing a critical negative regulatory role of CTLA-4. Immunity. 1995; 3: 541-547.
    37. Anjos S, Ngyyen A, Ounissi-Benkalha H, Tessier MC, Polychronakos C. A common autoimmunity predisposing signal peptide variant of the cytotoxic T-lymphocyte antigen 4 results in inefficient glycosylation of the susceptibility allele. J Biol Chem. 2002; 277: 46478-46486.
    38. Song B, Liu Y, Liu J, Song X, Wang Z, Wang M, et al. CTLA-4 +49A>G polymorphism is associated with advanced non-small cell lung cancer prognosis. Respiration. 2011; 82: 439-444.
    Cite this article: Sasaki H, Tatematsu T, Shitara M, Hikosaka Y, Okuda K, et al. (2014) PD1 Gene Promoter Polymorphism in Thymoma and Myasthenia Gravis. J Immunol Clin Res 2(1): 1011.
  • Current Issue Highlights
  • JSciMed Central welcomes back astronaut Scott Kelly and cosmonaut Mikhail Kornienko.
    Readmore...

    Wonder Women Tech not only disrupted the traditional conference model but innovatively changed the way conferences should be held.
    Readmore...

    JSciMed Central Peer-reviewed Open Access Journals
    About      |      Journals      |      Open Access      |      Special Issue Proposals      |      Guidelines      |      Submit Manuscript      |      Contacts
    Copyright © 2016 JSciMed Central All Rights Reserved
    Creative Commons Licence Open Access Publication by JSciMed Central is licensed under a Creative Commons Attribution 4.0 International License.
    Based on a work at https://jscimedcentral.com/. Permissions beyond the scope of this license may be available at https://creativecommons.org/.