Expression and function of the small immune adaptor protein SAP

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Nagy, Noemi (author)

Expression and function of the small immune adaptor protein SAP

BookEnglish2006

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Stockholm :Karolinska Institutet, Department of Microbiology, Tumor and Cell Biology,2006
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LIBRIS-ID:oai:openarchive.ki.se:10616/39111
ISBN:917357029X
10616/39111hdl
http://hdl.handle.net/10616/39111URI

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Language:English
Summary in:English

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SwePubSwePub

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Subject category:vet swepub-contenttype
Subject category:dok swepub-publicationtype

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The Epstein-Barr virus (EBV) carrier state is widespread in humans. Primary infection can cause infectious mononucleosis (IM) that presents with variable clinical severity, but almost always subsides. For 50% of boys with a rare hereditary immunodeficiency, X-linked lymphoproliferative disease (XLP), primary infection with E13V has a fatal course. In addition, XLP patients have elevated (200 times) risk for development of lymphomas. The underlying cause of the syndrome is lack of the function of a protein SAP, due to mutations of the encoding gene named also DSHP or SH2DIA. SAP binds to a group of cell surface proteins belonging to the SLAM-family. We found an increase of SAP in T and NK cells after their activation. This correlated well with the inadequacy of cell mediated immune functions in the affected individuals, indicating the importance of SAP. SAP was absent in B cells infected with EBV and in the established lymphoblastoid cell lines (LCL), in SAC+IL-2 or CD40L+IL-4 activated B cells. EBV carrying - but not EBV negative - Burkitt lymphoma (BL) lines with the Type I EBV expression pattern were SAP positive. The type III lines had no SAP. The difference between the EBV negative BLs and the group I EBV positive lines is the first marker that distinguishes these 2 groups. Our results suggest that CD40 ligation can be the physiological signal for SAP down-regulation in B cells. We have also detected SAP in 5 EBV negative cell lines derived from Hodgkin's disease. In the continuation of our studies we focused our attention on the high incidence of lymphoma development in the XLP patients. Since lymphomas appear with high frequency even in EBV negative XLP patients, we considered that in addition to the immunological defect, the absence of SAP may lead to an intrinsic B cell dysfunction. This could possibly affect apoptosis/cell cycle control/DNA repair. We identified SAP as one of the targets of p53. We used a temperature sensitive p53 system and a panel of cell lines with endogenous wt p53. With the help of chromatin immunoprecipitation assay (ChIP) we have proven the functionality of one of the 2 possible p53 binding sites. DNA damage induced by ã-irradiation, induced SAP expression in primary T cells. Induction of SAP by p53 was tissue specific. Our results suggest that SAP contributes to the execution of some p53 functions. We have introduced SAP by retroviral transduction to various cell lines and found that SAP elevated the sensitivity of cells to DNA damage. This was established by cell survival and colony formation assays. We also showed that the proportion of apoptotic cells was higher in the SAP positive populations. Thus SAP has a pro-apoptotic role. We found that in activated T cells the SAP level is increased in the late phase of activation. The high levels of SAP showed a negative correlation with cell proliferation. Furthermore, clones of the T-ALL cell line with low and high SAP expression showed that the latter are more prone to activation induced cell death. Altogether, we have shown that absence of SAP function modifies cell proliferation / cell survival and by this we have introduced a new dimension to SAP and to XLP. Loss of this function can contribute to the maintenance of over-activated, proliferating T cells in the fatal IM and also to the development of lymphomas.

Subject headings and genre

XLP, SAP, EBV, BL, lymphocytes, lymphoma, p53, apoptosis, AICD

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