Mice deficient in the X‐linked lymphoproliferative disease gene <i>sap</i> exhibit increased susceptibility to murine gammaherpesvirus‐68 and hypo‐gammaglobulinemia

Yin, Ling; Al-Alem, Umaima; Liang, Jun; Tong, Wei; Li, Cuiling; Badiali, Manuela; Médard, Jean Jacques; Sümegi, János; Wang, Zhao Qi; Romeo, Giovanni

doi:10.1002/jmv.10504

Cited by 70 publications

(81 citation statements)

References 35 publications

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“…However, viral infection failed to bypass the well-characterized defect in the ability of SAP-deficient mice to develop germinal center cells. In addition, we confirmed the previous observation of others (22,28) that Ig class switching fails to occur following ␥HV68 infection (data not shown).…”

Section: ␥Hv68-induced Polyclonal Activation Fails To Bypass Sap-assosupporting

confidence: 93%

Perturbation of B Cell Activation in SLAM-Associated Protein-Deficient Mice Is Associated with Changes in Gammaherpesvirus Latency Reservoirs

Kim

Burkum

Cookenham

et al. 2007

The Journal of Immunology

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Signaling lymphocyte activation molecule (SLAM)-associated protein (SAP)) interactions with SLAM family proteins play important roles in immune function. SAP-deficient mice have defective B cell function, including impairment of germinal center formation, production of class-switched Ig, and development of memory B cells. B cells are the major reservoir of latency for both EBV and the homologous murine gammaherpesvirus, gammaherpesvirus 68. There is a strong association between the B cell life cycle and viral latency in that the virus preferentially establishes latency in activated germinal center B cells, which provides access to memory B cells, a major reservoir of long-term latency. In the current studies, we have analyzed the establishment and maintenance of γHV68 latency in wild-type and SAP-deficient mice. The results show that, despite SAP-associated defects in germinal center and memory B cell formation, latency was established and maintained in memory B cells at comparable frequencies to wild-type mice, although the paucity of memory B cells translated into a 10-fold reduction in latent load. Furthermore, there were defects in normal latency reservoirs within the germinal center cells and IgD+“naive” B cells in SAP-deficient mice, showing a profound effect of the SAP mutation on latency reservoirs.

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Section: ␥Hv68-induced Polyclonal Activation Fails To Bypass Sap-assosupporting

confidence: 93%

Perturbation of B Cell Activation in SLAM-Associated Protein-Deficient Mice Is Associated with Changes in Gammaherpesvirus Latency Reservoirs

Kim

Burkum

Cookenham

et al. 2007

The Journal of Immunology

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“…This is in line with the uncontrolled T-cell proliferation occurring in fatal infectious mononucleosis of XLP patients. Involvement of SAP in the termination/control of T-cell responses is suggested by the elevated numbers of T cells in SAP-deficient mice infected with LCMV or with murine gammaherpesvirus-68 (Czar et al, 2001;Wu et al, 2001;Yin et al, 2003). The upregulated SAP expression in the late phases of T-cell activation (Nagy et al, 2000) also suggest a role of SAP in T-cell homeostasis.…”

Section: Discussionmentioning

confidence: 99%

Wild-type p53 activates SAP expression in lymphoid cells

et al. 2004

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SAP is an adaptor molecule with one SH2 domain and it is expressed in activated T and NK cells, where it is required for the appropriate signaling from the SLAM family of surface receptors. Deleted or mutated SAP genes that encode functionally defective protein are associated with the X-linked lymphoproliferative disease (XLP). This primary immunodeficiency is characterized by extreme sensitivity to Epstein-Barr virus (EBV) infection, dysgammaglobulinemia and a high rate of lymphoma development. The vigorous T-and B-cell proliferation that follows EBV infection and the high incidence of lymphomas (30%) in XLP patients might reflect functional defects in cell cycle and/ or apoptosis control. Our experiments show that SAP is a target of p53. In Burkitt lymphoma (BL) lines transfected with a temperatur-sensitive (ts) p53, SAP mRNA and protein expression was dependent on wild-type (wt) p53. Activation of endogenous wt p53 in BLs and lymphoblastoid cell lines led to the induction of SAP and this was inhibited by the specific p53 inhibitor pifithrin-a. Cell lines that carried mutant p53 did not express SAP under similar conditions. Moreover, we have shown binding of wt p53 to the promoter region of SAP by ChIP assay. Our results suggest that SAP contributes to the execution of some p53 functions.

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“…Mice-SAP-deficient (sap Ϫ/Ϫ ) mice, Fyn-deficient (fyn Ϫ/Ϫ ) mice, and mice expressing the SAP arginine 78-to-alanine 78 mutant (sap R78A ) were reported previously (8,20,21). cDNAs, Mutagenesis, and Constructs-A cDNA encoding Ly108 (clone number 8397616) was obtained from American Type Culture Collection.…”

Section: Methodsmentioning

confidence: 99%

Control of T Lymphocyte Signaling by Ly108, a Signaling Lymphocytic Activation Molecule Family Receptor Implicated in Autoimmunity

Zhong

Veillette

2008

Journal of Biological Chemistry

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The signaling lymphocytic activation molecule family of receptors has been implicated in the pathophysiology of autoimmunity in humans and mice. One member of the family, Ly108, was strongly linked to lupus susceptibility in mice. High expression of a Ly108 isoform, Ly108-1, was observed in lymphocytes of lupus-prone mice. Herein, we examined the molecular basis for the influence of Ly108 on lupus susceptibility by studying Ly108 signal transduction in T cells. We observed that Ly108 was able to mediate a tyrosine phosphorylation signal implicating Ly108, Vav-1, and c-Cbl in a manner strictly dependent on engagement of the extracellular domain of Ly108 and co-expression of the Src homology 2 (SH2) domain-containing adaptor signaling lymphocytic activation molecule (SLAM)-associated protein (SAP). Evaluation of T cells from mice carrying mutations in the SAP-FynT pathway indicated that Ly108-triggered protein tyrosine phosphorylation was due to the capacity of SAP to recruit FynT. Importantly, Ly108-1 was more apt at triggering tyrosine phosphorylation signals in T cells when compared with the predominant Ly108 isoform found in non-lupus-prone mice, Ly108-2. This difference was due in part to the presence in Ly108-1 of a unique intra-cytoplasmic tyrosine-based motif that promoted Ly108 signal transduction. Together these data provided a molecular explanation for the involvement of Ly108 in lupus susceptibility in mice.

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Mice deficient in the X‐linked lymphoproliferative disease gene sap exhibit increased susceptibility to murine gammaherpesvirus‐68 and hypo‐gammaglobulinemia

Cited by 70 publications

References 35 publications

Perturbation of B Cell Activation in SLAM-Associated Protein-Deficient Mice Is Associated with Changes in Gammaherpesvirus Latency Reservoirs

Perturbation of B Cell Activation in SLAM-Associated Protein-Deficient Mice Is Associated with Changes in Gammaherpesvirus Latency Reservoirs

Wild-type p53 activates SAP expression in lymphoid cells

Control of T Lymphocyte Signaling by Ly108, a Signaling Lymphocytic Activation Molecule Family Receptor Implicated in Autoimmunity

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