Enhanced T cell apoptosis in common variable immunodeficiency: negative role of the fas/fasligand system and of the Bcl-2 family proteins and possible role of TNF-RS.
CVI is a primary immunodeficiency characterized by a failure of B cell differentiation associated with an array of T cell defects, such as enhanced T cell apoptosis. In this study we investigated the mechanisms underlying CVI enhanced T cell death. We analysed both the expression of Fas using flow cytometry techniques and the expression of FasL mRNA using RT-PCR in CVI T cells. We could not find any significant differences between CVI and normal subjects with regard to Fas expression, although there was a subgroup of CVI patients with very high Fas expression which was accompanied by an up-regulation of FasL mRNA. However, attempts to induce Fas-mediated apoptosis in these high Fas expressing cells, as evaluated by propidium iodide staining and APO2.7 staining, were unsuccessful. We also investigated intracellular levels of Bcl-2, bcl-xl and bax in CD4(+) and CD8(+) CVI T cells, as well as the bax/Bcl-2 ratio, using flow cytometry techniques but could not detect any differences between CVI and normal subjects. Finally we analysed TNF-RI and TNF-RII mRNA expression in CD4(+) and CD8(+) CVI T cells using semiquantitative RT-PCR and found a significant increase in expression of both TNF-Rs in CD4(+) T cells from CVI patients. Our data suggest that the increased expression of both TNF-Rs on T cells may be one of the mechanisms responsible for the accelerated T cell apoptosis in CVI.
Di Renzo
M
M
Division of Clinical Immunology, The Mount Sinai Medical Center, 1425 Madison Avenue, New York City, New York, USA. cd28apo@hotmail.com
Serrano
D
D
Zhou
Z
Z
George
I
I
Becker
K
K
Cunningham-Rundles
C
C
D000293:Adolescent; D000328:Adult; D000368:Aged; D015703:Antigens, CD / Q000235:genetics / Q000276:immunology*; D017209:Apoptosis; D002648:Child; D017074:Common Variable Immunodeficiency / Q000276:immunology*; D053222:Fas Ligand Protein; D015870:Gene Expression; D006801:Humans; D008562:Membrane Glycoproteins / Q000235:genetics / Q000276:immunology*; D008875:Middle Aged; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis / Q000276:immunology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis / Q000276:immunology*; D012333:RNA, Messenger; D018124:Receptors, Tumor Necrosis Factor / Q000235:genetics / Q000276:immunology*; D047888:Receptors, Tumor Necrosis Factor, Type I; D047889:Receptors, Tumor Necrosis Factor, Type II; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology*; D051028:bcl-2-Associated X Protein; D051020:bcl-X Protein; D019014:fas Receptor / Q000235:genetics / Q000276:immunology*
D015703:Antigens, CD; C494826:BAX protein, human; C494811:BCL2L1 protein, human; C505661:FASLG protein, human; D053222:Fas Ligand Protein; D008562:Membrane Glycoproteins; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D012333:RNA, Messenger; D018124:Receptors, Tumor Necrosis Factor; D047888:Receptors, Tumor Necrosis Factor, Type I; D047889:Receptors, Tumor Necrosis Factor, Type II; D051028:bcl-2-Associated X Protein; D051020:bcl-X Protein; D019014:fas Receptor