Role of PTPN2/22 polymorphisms in pathophysiology of Crohn's disease
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摘要
AIM To establish the relationship of protein tyrosine phosphatase non-receptor type 2 and 22(PTPN2/22) polymorphisms and mycobacterial infections in Crohn's disease(CD). METHODS All 133 subjects' blood samples were genotyped for nine single nucleotide polymorphisms(SNPs) in PTPN2/22 using TaqMan~(?) genotyping, while the effect of the SNPs on PTPN2/22 and IFN-γ gene expression was determined using RT-PCR. Detection of Mycobacterium avium subspecies paratuberculosis(MAP) IS900 gene was done by nPCR after DNA extraction from the isolated leukocytes of each subjects' blood samples. T-cells isolated from the patient samples were tested for response to phytohematoagglutonin(PHA) mitogen or mycobacterial antigens by Brd U proliferation assays for T-cell activity. RESULTS Out of the nine SNPs examined, subjects with either heterozygous(TC)/minor(CC) alleles in PTPN2:rs478582 occurred in 83% of CD subjects compared to 61% healthy controls(P-values < 0.05; OR = 3.03). Subjects with either heterozygous(GA)/minor(AA) alleles in PTPN22:rs2476601 occurred in 16% of CD compared to 6% healthy controls(OR = 2.7). Gene expression in PTPN2/22 in CD subjects was significantly decreased by 2 folds compared to healthy controls(P-values < 0.05). IFN-γ expression levels were found to be significantly increased by approxiately 2 folds in subjects when either heterozygous or minor alleles in PTPN2:rs478582 and/or PTPN22:rs2476601 were found(P-values < 0.05). MAP DNA was detected in 61% of CD compared to only 8% of healthy controls(P-values < 0.05, OR = 17.52), where subjects with either heterozygous or minor alleles in PTPN2:rs478582 and/or PTPN22:rs2476601 had more MAPbacteremia presence than subjects without SNPs did. T h e average T-cell proliferation in CD treated with PHA or mycobacteria antigens was, respectively, 1.3 folds and 1.5 folds higher than healthy controls without any significant SNP. CONCLUSION The data suggests that SNPs in PTPN2/22 affect the negative regulation of the immune response in CD patients, thus leading to an increase in inflammation/apoptosis and susceptibility of mycobacteria.
AIM To establish the relationship of protein tyrosine phosphatase non-receptor type 2 and 22(PTPN2/22) polymorphisms and mycobacterial infections in Crohn's disease(CD). METHODS All 133 subjects' blood samples were genotyped for nine single nucleotide polymorphisms(SNPs) in PTPN2/22 using TaqMan~(?) genotyping, while the effect of the SNPs on PTPN2/22 and IFN-γ gene expression was determined using RT-PCR. Detection of Mycobacterium avium subspecies paratuberculosis(MAP) IS900 gene was done by nPCR after DNA extraction from the isolated leukocytes of each subjects' blood samples. T-cells isolated from the patient samples were tested for response to phytohematoagglutonin(PHA) mitogen or mycobacterial antigens by Brd U proliferation assays for T-cell activity. RESULTS Out of the nine SNPs examined, subjects with either heterozygous(TC)/minor(CC) alleles in PTPN2:rs478582 occurred in 83% of CD subjects compared to 61% healthy controls(P-values < 0.05; OR = 3.03). Subjects with either heterozygous(GA)/minor(AA) alleles in PTPN22:rs2476601 occurred in 16% of CD compared to 6% healthy controls(OR = 2.7). Gene expression in PTPN2/22 in CD subjects was significantly decreased by 2 folds compared to healthy controls(P-values < 0.05). IFN-γ expression levels were found to be significantly increased by approxiately 2 folds in subjects when either heterozygous or minor alleles in PTPN2:rs478582 and/or PTPN22:rs2476601 were found(P-values < 0.05). MAP DNA was detected in 61% of CD compared to only 8% of healthy controls(P-values < 0.05, OR = 17.52), where subjects with either heterozygous or minor alleles in PTPN2:rs478582 and/or PTPN22:rs2476601 had more MAPbacteremia presence than subjects without SNPs did. T h e average T-cell proliferation in CD treated with PHA or mycobacteria antigens was, respectively, 1.3 folds and 1.5 folds higher than healthy controls without any significant SNP. CONCLUSION The data suggests that SNPs in PTPN2/22 affect the negative regulation of the immune response in CD patients, thus leading to an increase in inflammation/apoptosis and susceptibility of mycobacteria.
AIM To establish the relationship of protein tyrosine phosphatase non-receptor type 2 and 22(PTPN2/22) polymorphisms and mycobacterial infections in Crohn's disease(CD). METHODS All 133 subjects' blood samples were genotyped for nine single nucleotide polymorphisms(SNPs) in PTPN2/22 using TaqMan~(?) genotyping, while the effect of the SNPs on PTPN2/22 and IFN-γ gene expression was determined using RT-PCR. Detection of Mycobacterium avium subspecies paratuberculosis(MAP) IS900 gene was done by nPCR after DNA extraction from the isolated leukocytes of each subjects' blood samples. T-cells isolated from the patient samples were tested for response to phytohematoagglutonin(PHA) mitogen or mycobacterial antigens by Brd U proliferation assays for T-cell activity. RESULTS Out of the nine SNPs examined, subjects with either heterozygous(TC)/minor(CC) alleles in PTPN2:rs478582 occurred in 83% of CD subjects compared to 61% healthy controls(P-values < 0.05; OR = 3.03). Subjects with either heterozygous(GA)/minor(AA) alleles in PTPN22:rs2476601 occurred in 16% of CD compared to 6% healthy controls(OR = 2.7). Gene expression in PTPN2/22 in CD subjects was significantly decreased by 2 folds compared to healthy controls(P-values < 0.05). IFN-γ expression levels were found to be significantly increased by approxiately 2 folds in subjects when either heterozygous or minor alleles in PTPN2:rs478582 and/or PTPN22:rs2476601 were found(P-values < 0.05). MAP DNA was detected in 61% of CD compared to only 8% of healthy controls(P-values < 0.05, OR = 17.52), where subjects with either heterozygous or minor alleles in PTPN2:rs478582 and/or PTPN22:rs2476601 had more MAPbacteremia presence than subjects without SNPs did. T h e average T-cell proliferation in CD treated with PHA or mycobacteria antigens was, respectively, 1.3 folds and 1.5 folds higher than healthy controls without any significant SNP. CONCLUSION The data suggests that SNPs in PTPN2/22 affect the negative regulation of the immune response in CD patients, thus leading to an increase in inflammation/apoptosis and susceptibility of mycobacteria.
引文
[1]Gutierrez-Arcelus M,Rich SS,Raychaudhuri S.Autoimmune diseases-connecting risk alleles with molecular traits of the immune system.Nat Rev Genet 2016;17:160-174[PMID:26907721 DOI:10.1038/nrg.2015.33]
2 Richard-Miceli C,Criswell LA.Emerging patterns of genetic overlap across autoimmune disorders.Genome Med 2012;4:6[PMID:22284131 DOI:10.1186/gm305]
3 Hewagama A,Richardson B.The genetics and epigenetics of autoimmune diseases.J Autoimmun 2009;33:3-11[PMID:19349147 DOI:10.1016/j.jaut.2009.03.007]
4 Sharp RC,Abdulrahim M,Naser ES,Naser SA.Genetic Variations of PTPN2 and PTPN22:Role in the Pathogenesis of Type 1 Diabetes and Crohn’s Disease.Front Cell Infect Microbiol2015;5:95[PMID:26734582 DOI:10.3389/fcimb.2015.00095]
5 Gurzov EN,Stanley WJ,Brodnicki TC,Thomas HE.Protein tyrosine phosphatases:molecular switches in metabolism and diabetes.Trends Endocrinol Metab 2015;26:30-39[PMID:25432462 DOI:10.1016/j.tem.2014.10.004]
6 Cheifetz AS,Feuerstein JD.Treatment of Inflammatory Bowel Disease with Biologics.Springer International Publishing,2017
7 Smolen JS,Aletaha D,Mc Innes IB.Rheumatoid arthritis.Lancet 2016;388:2023-2038[PMID:27156434 DOI:10.1016/S0140-6736(16)30173-8]
8 Kuek A,Hazleman BL,Ost?r AJ.Immune-mediated inflammatory diseases(IMIDs)and biologic therapy:a medical revolution.Postgrad Med J 2007;83:251-260[PMID:17403952 DOI:10.1136/pgmj.2006.052688]
9 Qasem A,Naser AE,Naser SA.The alternate effects of antiTNFαtherapeutics and their role in mycobacterial granulomatous infection in Crohn’s disease.Expert Rev Anti Infect Ther 2017;15:637-643[PMID:28481651 DOI:10.1080/14787210.2017.1328276]
10 Allen PB,Olivera P,Emery P,Moulin D,Jouzeau JY,Netter P,Danese S,Feagan B,Sandborn WJ,Peyrin-Biroulet L.Review article:moving towards common therapeutic goals in Crohn’s disease and rheumatoid arthritis.Aliment Pharmacol Ther 2017;45:1058-1072[PMID:28247573 DOI:10.1111/apt.13995]
11 Naser SA,Thanigachalam S,Dow CT,Collins MT.Exploring the role of Mycobacterium avium subspecies paratuberculosis in the pathogenesis of type 1 diabetes mellitus:a pilot study.Gut Pathog2013;5:14[PMID:23759115 DOI:10.1186/1757-4749-5-14]
12 Naser SA,Collins MT,Crawford JT,Valentine JF.Culture of Mycobacterium avium subspecies paratuberculosis(MAP)from the Blood of Patients with Crohn’s disease:A Follow-Up Blind Multi Center Investigation.Open Inflamm J 2010;3:22-23[DOI:10.2174/1875041900902010022]
13 Masala S,Paccagnini D,Cossu D,Brezar V,Pacifico A,Ahmed N,Mallone R,Sechi LA.Antibodies recognizing Mycobacterium avium paratuberculosis epitopes cross-react with the beta-cell antigen Zn T8 in Sardinian type 1 diabetic patients.PLo S One 2011;6:e26931[PMID:22046415 DOI:10.1371/journal.pone.0026931]
14 Sechi LA,Dow CT.Mycobacterium avium ss.paratuberculosis Zoonosis-The Hundred Year War-Beyond Crohn’s Disease.Front Immunol 2015;6:96[PMID:25788897 DOI:10.3389/fimmu.2015.00096]
15 Naser SA,Ghobrial G,Romero C,Valentine JF.Culture of Mycobacterium avium subspecies paratuberculosis from the blood of patients with Crohn’s disease.Lancet 2004;364:1039-1044[PMID:15380962 DOI:10.1016/S0140-6736(04)17058-X]
16 Naser SA,Romero C,Elwasila S,Ghonaim M,Naser N,Valentine JF.Functional Dysregulation of PBMC and PMN in Crohn’s Disease.Open Inflamm J 2009;2:24-33[DOI:10.2174/1875041900902010024]
17 Serrano A,Márquez A,Mackie SL,Carmona FD,Solans R,Miranda-Filloy JA,Hernández-Rodríguez J,Cid MC,Casta?eda S,Morado IC,Narváez J,Blanco R,Sope?a B,García-Villanueva MJ,Monfort J,Ortego-Centeno N,Unzurrunzaga A,Marí-Alfonso B,Sánchez Martín J,de Miguel E,Magro C,Raya E;UKGCA Consortium;Spanish GCA Consortium,Braun N,Latus J,Molberg O,Lie BA,Moosig F,Witte T,Morgan AW,GonzálezGay MA,Martín J.Identification of the PTPN22 functional variant R620W as susceptibility genetic factor for giant cell arteritis.Ann Rheum Dis 2013;72:1882-1886[PMID:23946333 DOI:10.1136/annrheumdis-2013-203641]
18 Spalinger MR,Lang S,Weber A,Frei P,Fried M,Rogler G,Scharl M.Loss of protein tyrosine phosphatase nonreceptor type22 regulates interferon-γ-induced signaling in human monocytes.Gastroenterology 2013;144:978-988.e10[PMID:23380085 DOI:10.1053/j.gastro.2013.048]
19 Qu H,Tessier MC,Hudson TJ,Polychronakos C.Confirmation of the association of the R620W polymorphism in the protein tyrosine phosphatase PTPN22 with type 1 diabetes in a family based study.J Med Genet 2005;42:266-270[PMID:15744042 DOI:10.1136/jmg.2004.026971]
20 Naser SA,Sagramsingh SR,Naser AS,Thanigachalam S.Mycobacterium avium subspecies paratuberculosis causes Crohn’s disease in some inflammatory bowel disease patients.World J Gastroenterol 2014;20:7403-7415[PMID:24966610 DOI:10.3748/wjg.v20.i23.7403]
21 Manuc TE,Manuc MM,Diculescu MM.Recent insights into the molecular pathogenesis of Crohn’s disease:a review of emerging therapeutic targets.Clin Exp Gastroenterol 2016;9:59-70[PMID:27042137 DOI:10.2147/CEG.S53381]
22 Glas J,Wagner J,Seiderer J,Olszak T,Wetzke M,Beigel F,Tillack C,Stallhofer J,Friedrich M,Steib C,G?ke B,Ochsenkühn T,Karbalai N,Diegelmann J,Czamara D,Brand S.PTPN2 gene variants are associated with susceptibility to both Crohn’s disease and ulcerative colitis supporting a common genetic disease background.PLo S One 2012;7:e33682[PMID:22457781 DOI:10.1371/journal.pone.0033682]
23 Barrett JC,Hansoul S,Nicolae DL,Cho JH,Duerr RH,Rioux JD,Brant SR,Silverberg MS,Taylor KD,Barmada MM,Bitton A,Dassopoulos T,Datta LW,Green T,Griffiths AM,Kistner EO,Murtha MT,Regueiro MD,Rotter JI,Schumm LP,Steinhart AH,Targan SR,Xavier RJ;NIDDK IBD Genetics Consortium,Libioulle C,Sandor C,Lathrop M,Belaiche J,Dewit O,Gut I,Heath S,Laukens D,Mni M,Rutgeerts P,Van Gossum A,Zelenika D,Franchimont D,Hugot JP,de Vos M,Vermeire S,Louis E;Belgian-French IBD Consortium;Wellcome Trust Case Control Consortium,Cardon LR,Anderson CA,Drummond H,Nimmo E,Ahmad T,Prescott NJ,Onnie CM,Fisher SA,Marchini J,Ghori J,Bumpstead S,Gwilliam R,Tremelling M,Deloukas P,Mansfield J,Jewell D,Satsangi J,Mathew CG,Parkes M,Georges M,Daly MJ.Genome-wide association defines more than 30distinct susceptibility loci for Crohn’s disease.Nat Genet 2008;40:955-962[PMID:18587394 DOI:10.1038/ng.175]
24 Waterman M,Xu W,Stempak JM,Milgrom R,Bernstein CN,Griffiths AM,Greenberg GR,Steinhart AH,Silverberg MS.Distinct and overlapping genetic loci in Crohn’s disease and ulcerative colitis:correlations with pathogenesis.Inflamm Bowel Dis 2011;17:1936-1942[PMID:21830272 DOI:10.1002/ibd.21579]
25 Espino-Paisan L,de la Calle H,Fernández-Arquero M,Figueredo MA,de la Concha EG,Urcelay E,Santiago JL.A polymorphism in PTPN2 gene is associated with an earlier onset of type 1 diabetes.Immunogenetics 2011;63:255-258[PMID:21246196 DOI:10.1007/s00251-010-0500-x]
26 Hendriks WJ,Pulido R.Protein tyrosine phosphatase variants in human hereditary disorders and disease susceptibilities.Biochim Biophys Acta 2013;1832:1673-1696[PMID:23707412 DOI:10.1016/j.bbadis.2013.05.022]
27 Vang T,Miletic AV,Bottini N,Mustelin T.Protein tyrosine phosphatase PTPN22 in human autoimmunity.Autoimmunity 2007;40:453-461[PMID:17729039 DOI:10.1080/08916930701464897]
28 Zikherman J,Weiss A.Unraveling the functional implications of GWAS:how T cell protein tyrosine phosphatase drives autoimmune disease.J Clin Invest 2011;121:4618-4621[PMID:22080861 DOI:10.1172/JCI60001]
29 Schoenborn JR,Wilson CB.Regulation of interferongamma during innate and adaptive immune responses.Adv Immunol 2007;96:41-101[PMID:17981204 DOI:10.1016/S0065-2776(07)96002-2]
30 Janeway Jr CA,Tr av ers P,Walp or t M,S hlo mch ik M J.Macrophage activation by armed CD4 TH1 cells.Immunobiology:The Immune System in Health and Disease,5th edition,2001
31 Prezzemolo T,Guggino G,La Manna MP,Di Liberto D,Dieli F,Caccamo N.Functional Signatures of Human CD4 and CD8 T Cell Responses to Mycobacterium tuberculosis.Front Immunol 2014;5:180[PMID:24795723 DOI:10.3389/fimmu.2014.00180]
32 Alberts B,Johnson A,Lewis J,Raff M,Roberts K,Walter P.Helper T Cells and lymphocyte activation.Molecular Biology of the Cell,4th edition,2002
33 Bermudez LE,Danelishvili L,Early J.Mycobacteria and macrophage apoptosis:complex struggle for survival.Microbe Wash DC 2006;1:372-375
34 Early J,Fischer K,Bermudez LE.Mycobacterium avium uses apoptotic macrophages as tools for spreading.Microb Pathog 2011;50:132-139[PMID:21167273 DOI:10.1016/j.micpath.2010.12.004]
2 Richard-Miceli C,Criswell LA.Emerging patterns of genetic overlap across autoimmune disorders.Genome Med 2012;4:6[PMID:22284131 DOI:10.1186/gm305]
3 Hewagama A,Richardson B.The genetics and epigenetics of autoimmune diseases.J Autoimmun 2009;33:3-11[PMID:19349147 DOI:10.1016/j.jaut.2009.03.007]
4 Sharp RC,Abdulrahim M,Naser ES,Naser SA.Genetic Variations of PTPN2 and PTPN22:Role in the Pathogenesis of Type 1 Diabetes and Crohn’s Disease.Front Cell Infect Microbiol2015;5:95[PMID:26734582 DOI:10.3389/fcimb.2015.00095]
5 Gurzov EN,Stanley WJ,Brodnicki TC,Thomas HE.Protein tyrosine phosphatases:molecular switches in metabolism and diabetes.Trends Endocrinol Metab 2015;26:30-39[PMID:25432462 DOI:10.1016/j.tem.2014.10.004]
6 Cheifetz AS,Feuerstein JD.Treatment of Inflammatory Bowel Disease with Biologics.Springer International Publishing,2017
7 Smolen JS,Aletaha D,Mc Innes IB.Rheumatoid arthritis.Lancet 2016;388:2023-2038[PMID:27156434 DOI:10.1016/S0140-6736(16)30173-8]
8 Kuek A,Hazleman BL,Ost?r AJ.Immune-mediated inflammatory diseases(IMIDs)and biologic therapy:a medical revolution.Postgrad Med J 2007;83:251-260[PMID:17403952 DOI:10.1136/pgmj.2006.052688]
9 Qasem A,Naser AE,Naser SA.The alternate effects of antiTNFαtherapeutics and their role in mycobacterial granulomatous infection in Crohn’s disease.Expert Rev Anti Infect Ther 2017;15:637-643[PMID:28481651 DOI:10.1080/14787210.2017.1328276]
10 Allen PB,Olivera P,Emery P,Moulin D,Jouzeau JY,Netter P,Danese S,Feagan B,Sandborn WJ,Peyrin-Biroulet L.Review article:moving towards common therapeutic goals in Crohn’s disease and rheumatoid arthritis.Aliment Pharmacol Ther 2017;45:1058-1072[PMID:28247573 DOI:10.1111/apt.13995]
11 Naser SA,Thanigachalam S,Dow CT,Collins MT.Exploring the role of Mycobacterium avium subspecies paratuberculosis in the pathogenesis of type 1 diabetes mellitus:a pilot study.Gut Pathog2013;5:14[PMID:23759115 DOI:10.1186/1757-4749-5-14]
12 Naser SA,Collins MT,Crawford JT,Valentine JF.Culture of Mycobacterium avium subspecies paratuberculosis(MAP)from the Blood of Patients with Crohn’s disease:A Follow-Up Blind Multi Center Investigation.Open Inflamm J 2010;3:22-23[DOI:10.2174/1875041900902010022]
13 Masala S,Paccagnini D,Cossu D,Brezar V,Pacifico A,Ahmed N,Mallone R,Sechi LA.Antibodies recognizing Mycobacterium avium paratuberculosis epitopes cross-react with the beta-cell antigen Zn T8 in Sardinian type 1 diabetic patients.PLo S One 2011;6:e26931[PMID:22046415 DOI:10.1371/journal.pone.0026931]
14 Sechi LA,Dow CT.Mycobacterium avium ss.paratuberculosis Zoonosis-The Hundred Year War-Beyond Crohn’s Disease.Front Immunol 2015;6:96[PMID:25788897 DOI:10.3389/fimmu.2015.00096]
15 Naser SA,Ghobrial G,Romero C,Valentine JF.Culture of Mycobacterium avium subspecies paratuberculosis from the blood of patients with Crohn’s disease.Lancet 2004;364:1039-1044[PMID:15380962 DOI:10.1016/S0140-6736(04)17058-X]
16 Naser SA,Romero C,Elwasila S,Ghonaim M,Naser N,Valentine JF.Functional Dysregulation of PBMC and PMN in Crohn’s Disease.Open Inflamm J 2009;2:24-33[DOI:10.2174/1875041900902010024]
17 Serrano A,Márquez A,Mackie SL,Carmona FD,Solans R,Miranda-Filloy JA,Hernández-Rodríguez J,Cid MC,Casta?eda S,Morado IC,Narváez J,Blanco R,Sope?a B,García-Villanueva MJ,Monfort J,Ortego-Centeno N,Unzurrunzaga A,Marí-Alfonso B,Sánchez Martín J,de Miguel E,Magro C,Raya E;UKGCA Consortium;Spanish GCA Consortium,Braun N,Latus J,Molberg O,Lie BA,Moosig F,Witte T,Morgan AW,GonzálezGay MA,Martín J.Identification of the PTPN22 functional variant R620W as susceptibility genetic factor for giant cell arteritis.Ann Rheum Dis 2013;72:1882-1886[PMID:23946333 DOI:10.1136/annrheumdis-2013-203641]
18 Spalinger MR,Lang S,Weber A,Frei P,Fried M,Rogler G,Scharl M.Loss of protein tyrosine phosphatase nonreceptor type22 regulates interferon-γ-induced signaling in human monocytes.Gastroenterology 2013;144:978-988.e10[PMID:23380085 DOI:10.1053/j.gastro.2013.048]
19 Qu H,Tessier MC,Hudson TJ,Polychronakos C.Confirmation of the association of the R620W polymorphism in the protein tyrosine phosphatase PTPN22 with type 1 diabetes in a family based study.J Med Genet 2005;42:266-270[PMID:15744042 DOI:10.1136/jmg.2004.026971]
20 Naser SA,Sagramsingh SR,Naser AS,Thanigachalam S.Mycobacterium avium subspecies paratuberculosis causes Crohn’s disease in some inflammatory bowel disease patients.World J Gastroenterol 2014;20:7403-7415[PMID:24966610 DOI:10.3748/wjg.v20.i23.7403]
21 Manuc TE,Manuc MM,Diculescu MM.Recent insights into the molecular pathogenesis of Crohn’s disease:a review of emerging therapeutic targets.Clin Exp Gastroenterol 2016;9:59-70[PMID:27042137 DOI:10.2147/CEG.S53381]
22 Glas J,Wagner J,Seiderer J,Olszak T,Wetzke M,Beigel F,Tillack C,Stallhofer J,Friedrich M,Steib C,G?ke B,Ochsenkühn T,Karbalai N,Diegelmann J,Czamara D,Brand S.PTPN2 gene variants are associated with susceptibility to both Crohn’s disease and ulcerative colitis supporting a common genetic disease background.PLo S One 2012;7:e33682[PMID:22457781 DOI:10.1371/journal.pone.0033682]
23 Barrett JC,Hansoul S,Nicolae DL,Cho JH,Duerr RH,Rioux JD,Brant SR,Silverberg MS,Taylor KD,Barmada MM,Bitton A,Dassopoulos T,Datta LW,Green T,Griffiths AM,Kistner EO,Murtha MT,Regueiro MD,Rotter JI,Schumm LP,Steinhart AH,Targan SR,Xavier RJ;NIDDK IBD Genetics Consortium,Libioulle C,Sandor C,Lathrop M,Belaiche J,Dewit O,Gut I,Heath S,Laukens D,Mni M,Rutgeerts P,Van Gossum A,Zelenika D,Franchimont D,Hugot JP,de Vos M,Vermeire S,Louis E;Belgian-French IBD Consortium;Wellcome Trust Case Control Consortium,Cardon LR,Anderson CA,Drummond H,Nimmo E,Ahmad T,Prescott NJ,Onnie CM,Fisher SA,Marchini J,Ghori J,Bumpstead S,Gwilliam R,Tremelling M,Deloukas P,Mansfield J,Jewell D,Satsangi J,Mathew CG,Parkes M,Georges M,Daly MJ.Genome-wide association defines more than 30distinct susceptibility loci for Crohn’s disease.Nat Genet 2008;40:955-962[PMID:18587394 DOI:10.1038/ng.175]
24 Waterman M,Xu W,Stempak JM,Milgrom R,Bernstein CN,Griffiths AM,Greenberg GR,Steinhart AH,Silverberg MS.Distinct and overlapping genetic loci in Crohn’s disease and ulcerative colitis:correlations with pathogenesis.Inflamm Bowel Dis 2011;17:1936-1942[PMID:21830272 DOI:10.1002/ibd.21579]
25 Espino-Paisan L,de la Calle H,Fernández-Arquero M,Figueredo MA,de la Concha EG,Urcelay E,Santiago JL.A polymorphism in PTPN2 gene is associated with an earlier onset of type 1 diabetes.Immunogenetics 2011;63:255-258[PMID:21246196 DOI:10.1007/s00251-010-0500-x]
26 Hendriks WJ,Pulido R.Protein tyrosine phosphatase variants in human hereditary disorders and disease susceptibilities.Biochim Biophys Acta 2013;1832:1673-1696[PMID:23707412 DOI:10.1016/j.bbadis.2013.05.022]
27 Vang T,Miletic AV,Bottini N,Mustelin T.Protein tyrosine phosphatase PTPN22 in human autoimmunity.Autoimmunity 2007;40:453-461[PMID:17729039 DOI:10.1080/08916930701464897]
28 Zikherman J,Weiss A.Unraveling the functional implications of GWAS:how T cell protein tyrosine phosphatase drives autoimmune disease.J Clin Invest 2011;121:4618-4621[PMID:22080861 DOI:10.1172/JCI60001]
29 Schoenborn JR,Wilson CB.Regulation of interferongamma during innate and adaptive immune responses.Adv Immunol 2007;96:41-101[PMID:17981204 DOI:10.1016/S0065-2776(07)96002-2]
30 Janeway Jr CA,Tr av ers P,Walp or t M,S hlo mch ik M J.Macrophage activation by armed CD4 TH1 cells.Immunobiology:The Immune System in Health and Disease,5th edition,2001
31 Prezzemolo T,Guggino G,La Manna MP,Di Liberto D,Dieli F,Caccamo N.Functional Signatures of Human CD4 and CD8 T Cell Responses to Mycobacterium tuberculosis.Front Immunol 2014;5:180[PMID:24795723 DOI:10.3389/fimmu.2014.00180]
32 Alberts B,Johnson A,Lewis J,Raff M,Roberts K,Walter P.Helper T Cells and lymphocyte activation.Molecular Biology of the Cell,4th edition,2002
33 Bermudez LE,Danelishvili L,Early J.Mycobacteria and macrophage apoptosis:complex struggle for survival.Microbe Wash DC 2006;1:372-375
34 Early J,Fischer K,Bermudez LE.Mycobacterium avium uses apoptotic macrophages as tools for spreading.Microb Pathog 2011;50:132-139[PMID:21167273 DOI:10.1016/j.micpath.2010.12.004]