Impaired humoral immunity in X-linked lymphoproliferative disease is associated with defective IL-10 production by CD4+ T cells

Cindy, S.; Hare, Nathan J.; Nichols, Kim E.; Dupré, Loı̈c; Andolfi, Grazia; Roncarolo, Maria Grazia; Adelstein, Stephen; Hodgkin, Philip D.; Tangye, Stuart G.

doi:10.1172/jci23139

Cited by 104 publications

(179 citation statements)

References 63 publications

(103 reference statements)

Supporting

Mentioning

164

Contrasting

Order By: Relevance

“…However, XLP patients have a marked reduction in memory (CD27 ϩ ) B cells (Fig. 1a) (21,26). It was recently reported that some patients with CVID not only lacked memory B cells, but also B cells with an immature phenotype were occasionally detected (20).…”

Section: Cd24 High Cd38 High B Cells Are Expanded In Xlpmentioning

confidence: 93%

“…The frequency and absolute number of total PB B cells in XLP patients is normal (21,26). However, XLP patients have a marked reduction in memory (CD27 ϩ ) B cells (Fig.…”

Section: Cd24 High Cd38 High B Cells Are Expanded In Xlpmentioning

confidence: 95%

“…Recently, we demonstrated a deficiency in the number of memory B cells in patients with X-linked lymphoproliferative disease (XLP; Refs. 21,26), an immunodeficiency caused by mutations in SH2D1A (27)(28)(29) and characterized by fulminant infectious mononucleosis, hypogammaglobulinemia, and malignant lymphoma (26).…”

mentioning

confidence: 99%

See 2 more Smart Citations

Expansion of Functionally Immature Transitional B Cells Is Associated with Human-Immunodeficient States Characterized by Impaired Humoral Immunity

Cuss

Avery

Cannons

et al. 2006

The Journal of Immunology

Self Cite

176

188

View full text Add to dashboard Cite

X-linked lymphoproliferative disease (XLP) is a severe immunodeficiency associated with a marked reduction in circulating memory B cells. Our investigation of the B cell compartment of XLP patients revealed an increase in the frequency of a population of B cells distinct from those previously defined. This population displayed increased expression of CD10, CD24, and CD38, indicating that it could consist of circulating immature/transitional B cells. Supporting this possibility, CD10+CD24highCD38high B cells displayed other immature characteristics, including unmutated Ig V genes and elevated levels of surface IgM; they also lacked expression of Bcl-2 and a panel of activation molecules. The capacity of CD24highCD38high B cells to proliferate, secrete Ig, and migrate in vitro was greatly reduced compared with mature B cell populations. Moreover, CD24highCD38high B cells were increased in the peripheral blood of neonates, patients with common variable immunodeficiency, and patients recovering from hemopoietic stem cell transplant. Thus, an expansion of functionally immature B cells may contribute to the humoral immunodeficient state that is characteristic of neonates, as well as patients with XLP or common variable immunodeficiency, and those recovering from a stem cell transplant. Further investigation of transitional B cells will improve our understanding of human B cell development and how alterations to this process may precipitate immunodeficiency or autoimmunity.

show abstract

Section: Cd24 High Cd38 High B Cells Are Expanded In Xlpmentioning

confidence: 93%

“…The frequency and absolute number of total PB B cells in XLP patients is normal (21,26). However, XLP patients have a marked reduction in memory (CD27 ϩ ) B cells (Fig.…”

Section: Cd24 High Cd38 High B Cells Are Expanded In Xlpmentioning

confidence: 95%

See 1 more Smart Citation

Expansion of Functionally Immature Transitional B Cells Is Associated with Human-Immunodeficient States Characterized by Impaired Humoral Immunity

Cuss

Avery

Cannons

et al. 2006

The Journal of Immunology

Self Cite

176

188

View full text Add to dashboard Cite

show abstract

“…The CD4 1 T cells produced lower quantities of IL-10 and failed to provide help for B-cell responses. 61 Similarly, mice deficient in SAP show severe functional defects in CD4 1 T cells as evidenced by their inability to confer long-lived humoral responses. 62 Studies further demonstrate that CD4 1 T-cell function in HIGM patients, which lack CD40L, is strictly compromised.…”

Section: The Darker Side Of Follicular Helper T Cells S Shekhar and Xmentioning

confidence: 99%

The darker side of follicular helper T cells: from autoimmunity to immunodeficiency

Shekhar

Yang

2012

Cell Mol Immunol

View full text Add to dashboard Cite

Follicular helper T (T FH ) cells represent a distinct subset of CD4 1 helper T (T H ) cells specialized in providing help to B cells. They are characterized by their unique transcriptional profile (Bcl6), surface marker expression (CXCR5, PD-1, ICOS and CD40L) and cytokine production pattern (IL-21 and IL-6). T FH cells provide help to B cells both to form germinal centers (GCs) and to differentiate into memory B cells and plasma cells for generation of humoral responses. However, there is emerging evidence that implicates T FH cells in the development of various human pathologies, such as autoimmune diseases, immunodeficiency and lymphoma. This review focuses on the current progress in this area including mouse and human studies. A clearer understanding of the mechanisms of T FH cell-mediated immunity and pathology may be exploited for rational development of therapeutic strategies.

show abstract

“…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.…”

mentioning

confidence: 99%

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

et al. 2007

View full text Add to dashboard Cite

Defective signaling lymphocyte activation molecule (SLAM)-associated protein (SAP) is responsible for the human X-linked lymphoproliferative syndrome. Defects in T helper 2, natural killer, natural killer T and B cells have been demonstrated in SAP-deficient humans and mice, and increased proliferation of CD8 + T cells has been observed. In the current study, we investigated the properties of CD8 + T cell proliferation and activation-induced cell death (AICD), using OT-I T cell receptor (TCR)-transgenic mice on either wild-type (WT) or SAP -/-background. Interestingly, we found that ovalbumin peptide-activated SAP -/-CD8 + T cells have lower AICD compared to their WT counterparts. Furthermore, the induction of p73, a key mediator of TCRinduced apoptosis through the mitochondrial apoptotic pathway, was significantly reduced at both the mRNA and protein levels in the activated mutant cells. Meanwhile, a reduced level of activated caspase 9 was observed in the mutant cells. We conclude that reduced AICD in activated SAP -/-CD8 + T cells is associated with impaired p73 induction, indicating that the initiation of the mitochondrial apoptotic pathway might be impaired. Our data demonstrate an intrinsic defect in SAP -/-CD8 + T cells and shed light on the increased responsiveness of CD8 + T cells in SAP -/-mice. IntroductionX-linked lymphoproliferative syndrome (XLP), an abnormal immune response to EBV infection characterized by fatal infectious mononucleosis, dys-gammaglobulinemia and B cell lymphoma, is caused by mutations in the SH2D1A gene, which encodes signaling lymphocyte activation molecule (SLAM)-associated protein (SAP) [1][2][3][4]. The adaptor SAP binds with high affinity to tyrosine motifs in the cytoplasmic domain of SLAM family immune receptors, including SLAM (CD150), CD244, CD229, SLAMF6, SLAMF7 and CD84, suggesting that SAP functions are important in modulating signals initiated by the SLAM family receptors [5][6][7][8]. 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. Previous studies with SAP -/-mice, performed by several laboratories including ours, showed an increased antigen-specific CD8 + T cell population and IFN-c production after infection with lymphocytic choriomeningitis virus (LCMV), murine c-herpesvirus 68 (MHV-68) and Toxoplasma gondii, but impaired Th2 cell differentiation and decreased IgG production [15,19,20]. In addition, we demonstrate that SAP -/-mice confer greater cytotoxic activity and increased proliferation of CD8 + T cells compared to WT mice, strongly suggesting that SAP fine-tunes th...

show abstract

Impaired humoral immunity in X-linked lymphoproliferative disease is associated with defective IL-10 production by CD4+ T cells

Cited by 104 publications

References 63 publications

Expansion of Functionally Immature Transitional B Cells Is Associated with Human-Immunodeficient States Characterized by Impaired Humoral Immunity

Expansion of Functionally Immature Transitional B Cells Is Associated with Human-Immunodeficient States Characterized by Impaired Humoral Immunity

The darker side of follicular helper T cells: from autoimmunity to immunodeficiency

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

Contact Info

Product

Resources

About

Impaired humoral immunity in X-linked lymphoproliferative disease is associated with defective IL-10 production by CD4+ T cells

Cited by 104 publications

References 63 publications

Expansion of Functionally Immature Transitional B Cells Is Associated with Human-Immunodeficient States Characterized by Impaired Humoral Immunity

Expansion of Functionally Immature Transitional B Cells Is Associated with Human-Immunodeficient States Characterized by Impaired Humoral Immunity

The darker side of follicular helper T cells: from autoimmunity to immunodeficiency

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

Contact Info

Product

Resources

About

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