Defective B cell responses in the absence of SH2D1A

Abstract

More than half of patients with X-linked lympho-proliferative disease, which is caused by a defect in the intracellular adapter protein SH2D1A, suffer from an extreme susceptibility to EpsteinBarr virus. One-third of these patients, however, develop dysgammaglobulenemia without an episode of severe mononucleosis. Here we show that in SH2D1A ؊/؊ mice, both primary and secondary responses of all Ig subclasses are severely impaired in response to specific antigens. Because germinal centers were absent in SH2D1A ؊/؊ mice upon primary immunization, and because SH2D1A was detectable in wt germinal center B cells, we examined whether SH2D1A ؊/؊ B cell functions were impaired. Using the adoptive cotransfer of B lymphocytes from hapten-primed SH2D1A ؊/؊ mice with CD4 ؉ T cells from primed wt mice into irradiated wt mice provided evidence that signal transduction events controlled by SH2D1A are essential for B cell activities resulting in antigen specific IgG production. Defects in naïve SH2D1A ؊/؊ B cells became evident upon cotransfer with nonprimed wt CD4 ؉ cells into Rag2 ؊/؊ recipients. Thus, both defective T and B cells exist in the absence of SH2D1A, which may explain the progressive dysgammaglobulinemia in a subset of X-linked lympho-proliferative disease patients without involvement of Epstein-Barr virus.Epstein-Barr virus ͉ germinal center ͉ immunoglobulin ͉ SLAM͞CD150

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

“…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).…”

“…SAP-deficient mice have defective Th2 cell development and abnormal Ig classswitching (20, 21, 24 -27). In addition, they generate reduced numbers of germinal centers and memory B cells (20,21,(27)(28)(29), which may be due both to impaired CD4 T cell function as well as intrinsic B cell defects (27)(28)(29)(30). SAP-deficient mice have also been reported to develop enhanced Th1 responses characterized by excessive IFN-␥ production, and exaggerated CTL activity (20,21,29,31,32).…”

“…B cell activation and function have been shown to be impaired in SAP-deficient mice, manifest by reduced numbers of germinal centers and failure to generate class-switched Abs and memory B cells following infection with a variety of pathogens (20 -22, 28, 29, 33). There is evidence to suggest that both inherent B cell defects and defects in CD4 T cells contribute to the impaired B cell function (27)(28)(29)(30). Infection with ␥HV68 induces a striking splenomegaly, due to concordant increases in splenic B and T cells (44), and a strong CD4-dependent polyclonal B cell response (45).…”

Increased proliferation of CD8+ T cells in SAP‐deficient mice is associated with impaired activation‐induced cell death

“…This is likely due to the impaired FynT activation in SAP -/-CD8 + T cells, since FynT -/-T lymphocytes are known to be relatively resistant to AICD [43]. Although DC have been implicated in the control of CD8 + T cell responses through regulated FasL expression, we can rule out the possibility that a defect in SAP -/-APC is responsible for the reduced AICD, since SAP is not expressed in DC and macrophages [2,12,44]. In addition, the induction of apoptosis by known apoptotic stimuli in mutant cells is very similar to that of WT cells, suggesting that the apoptotic machinery is likely to be intact in these cells.…”

“…It has been well established that SAP is an essential adaptor due to its capacity to recruit FynT to SLAM and p85 of PI3 K to 2B4, respectively [9,10]. SAP is expressed in activated T, NK and NKT cells, as well as in germinal center B cells [11,12], and is indispensable for normal NKT cell development, generation of a proper Th2 response and Ig class switching in humans and mice [13][14][15][16][17][18]. In XLP patients, both EBV-infected B cells and EBVspecific CTL hyper-proliferate, although the underlying mechanism is still controversial.…”