Reduced CD4+ T cell activation in children with type 1 diabetes carrying the PTPN22/Lyp 620Trp variant

被引:62
作者
Aarnisalo, Johanna [1 ,2 ]
Tresz, Andras [3 ,4 ]
Svec, Peter [5 ]
Marttila, Jane [1 ,2 ]
Oling, Viveka [1 ,2 ]
Simell, Olli [6 ]
Knip, Mikael [7 ,8 ]
Korner, Anna [3 ,4 ]
Madacsy, Laszlo [3 ,4 ]
Vasarhelyi, Bama [3 ,4 ]
Ilonen, Jorma [1 ,9 ]
Hermann, Robert [1 ,10 ]
机构
[1] Univ Turku, Immunogenet Lab, MediCity Res Labs, FIN-20520 Turku, Finland
[2] Univ Turku, Dept Virol, FIN-20520 Turku, Finland
[3] Hungarian Acad Sci, Res Lab Pediat & Nephrol, Dept Pediat 1, H-1083 Budapest, Hungary
[4] Semmelweis Univ, H-1083 Budapest, Hungary
[5] Comenius Univ, Dept Pediat 2, Sch Med, Childrens Fac Hosp,Pediat Clin 2, Bratislava 83340, Slovakia
[6] Univ Turku, Dept Pediat, Turku 20521, Finland
[7] Tampere Univ Hosp, Dept Pediat, Tampere 33521, Finland
[8] Univ Helsinki, Hosp Children & Adolescents, Helsinki 00029, Finland
[9] Univ Kuopio, Dept Clin Microbiol, FIN-70211 Kuopio, Finland
[10] Semmelweis Univ, CellScreen Appl Biomed Res Ctr, Immunogenom Lab, H-1083 Budapest, Hungary
基金
匈牙利科学研究基金会;
关键词
autoimmunity; LYP; PTPN22; T cell activation; type; 1; diabetes;
D O I
10.1016/j.jaut.2008.01.001
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
The 620Trp variant of the LYP protein, encoded by the lymphoid tyrosine phosphatase 22 gene (PTPN22), is associated with autoimmunity. In this study we aimed at characterising the role of this variant on lymphocyte activation. We analysed cytokine secretion and proliferation of peripheral blood mononuclear cells (PBMCs) and CD4(+)T cells in a cohort of clinically non-diabetic, multiple autoantibody-positive children, healthy controls and in children with type 1 diabetes (T1D). We found a decreased proliferation and IL-2 production of CD4(+)T cells after antiCD3/anti-CD28 stimulation (p = 0.04 for IL-2) among TID patients. In addition, a profoundly decreased intracellular calcium flux in CD4(+)T cells after PHA stimulus was detected among 620Trp carriers. In contrast, no effect of this polymorphism on tuberculin and tetanus toxoid induced PBMC proliferation and cytokine secretion was observed in autoantibody positive children, healthy controls and children with newly-diagnosed TID. In conclusion, the LYP 620Trp variant is associated with reduced activation, proliferation and IL-2 production in CD4(+)T cells among TID patients. In accordance with our previous findings on the key role of this variant on disease progression, this mechanism is likely to contribute to the development of beta-cell specific autoimmunity. (C) 2008 Elsevier Ltd. All rights reserved.
引用
收藏
页码:13 / 21
页数:9
相关论文
共 54 条
[1]   Balancing autoaggressive and protective T cell responses [J].
Abbas, Abul K. ;
Lohr, Jens ;
Knoechel, Birgit .
JOURNAL OF AUTOIMMUNITY, 2007, 28 (2-3) :59-61
[2]  
[Anonymous], 2006, R LANG ENV STAT COMP
[3]   Clinical review: Type 1 diabetes-associated autoimmunity: Natural history, genetic associations, and screening [J].
Barker, JM .
JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM, 2006, 91 (04) :1210-1217
[4]  
BARRATT BJ, DIABETES
[5]   A POLYMORPHIC LOCUS NEAR THE HUMAN INSULIN GENE IS ASSOCIATED WITH INSULIN-DEPENDENT DIABETES-MELLITUS [J].
BELL, GI ;
HORITA, S ;
KARAM, JH .
DIABETES, 1984, 33 (02) :176-183
[6]   SUSCEPTIBILITY TO HUMAN TYPE-1 DIABETES AT IDDM2 IS DETERMINED BY TANDEM REPEAT VARIATION AT THE INSULIN GENE MINISATELLITE LOCUS [J].
BENNETT, ST ;
LUCASSEN, AM ;
GOUGH, SCL ;
POWELL, EE ;
UNDLIEN, DE ;
PRITCHARD, LE ;
MERRIMAN, ME ;
KAWAGUCHI, Y ;
DRONSFIELD, MJ ;
POCIOT, F ;
NERUP, J ;
BOUZEKRI, N ;
CAMBONTHOMSEN, A ;
RONNINGEN, KS ;
BARNETT, AH ;
BAIN, SC ;
TODD, JA .
NATURE GENETICS, 1995, 9 (03) :284-292
[7]   A functional variant of lymphoid tyrosine phosphatase is associated with type I diabetes [J].
Bottini, N ;
Musumeci, L ;
Alonso, A ;
Rahmouni, S ;
Nika, K ;
Rostamkhani, M ;
MacMurray, J ;
Meloni, GF ;
Lucarelli, P ;
Pellecchia, M ;
Eisenbarth, GS ;
Comings, D ;
Mustelin, T .
NATURE GENETICS, 2004, 36 (04) :337-338
[8]   Association between protein tyrosine phosphatase 22 variant R620W in conjunction with the HLA-DRB1 shared epitope and humoral autoimmunity to an immunodominant epitope of cartilage-specific type II collagen in early rheumatoid arthritis [J].
Burkhardt, H ;
Hüffmeier, U ;
Spriewald, B ;
Böhm, B ;
Rau, R ;
Kallert, S ;
Engström, Å ;
Holmdahl, R ;
Reis, A .
ARTHRITIS AND RHEUMATISM, 2006, 54 (01) :82-89
[9]   PTPN22 and invasive bacterial disease [J].
Chapman, SJ ;
Khor, CC ;
O Vannberg, F ;
Maskell, NA ;
Davies, CW ;
Hedley, EL ;
Segal, S ;
Moore, CE ;
Knox, K ;
Day, NP ;
Gillespie, SH ;
Crook, DW ;
Davies, RJ ;
Hill, AV .
NATURE GENETICS, 2006, 38 (05) :499-500
[10]   Cooperative inhibition of T-cell antigen receptor signaling by a complex between a kinase and a phosphatase [J].
Cloutier, JF ;
Veillette, A .
JOURNAL OF EXPERIMENTAL MEDICINE, 1999, 189 (01) :111-121