Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: UMLS:C0021051 (immunodeficiency)
71,517 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Human natural killer (NK) T cells are unique T lymphocytes that express an invariant T cell receptor (TCR) Valpha24-Vbeta11 and have been implicated to play a role in various diseases. A subset of NKT cells express CD4 and hence are potential targets for human immunodeficiency virus (HIV)-1 infection. We demonstrate that both resting and activated human Valpha24(+) T cells express high levels of the HIV-1 coreceptors CCR5 and Bonzo (CXCR6), but low levels of CCR7, as compared with conventional T cells. Remarkably NKT cells activated with alpha-galactosylceramide (alpha-GalCer)-pulsed dendritic cells were profoundly more susceptible to infection with R5-tropic, but not X4-tropic, strains of HIV-1, compared with conventional CD4(+) T cells. Furthermore, resting CD4(+) NKT cells were also more susceptible to infection. After initial infection, HIV-1 rapidly replicated and depleted the CD4(+) subset of NKT cells. In addition, peripheral blood NKT cells were markedly and selectively depleted in HIV-1 infected individuals. Although the mechanisms of this decline are not clear, low numbers or absence of NKT cells may affect the course of HIV-1 infection. Taken together, our findings indicate that CD4(+) NKT cells are directly targeted by HIV-1 and may have a potential role during viral transmission and spread in vivo.
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PMID:CD1d-restricted human natural killer T cells are highly susceptible to human immunodeficiency virus 1 infection. 1192 31

Dendritic cells (DCs) play a pivotal role in T cell-mediated immunity and have been shown to induce strong antitumor immune responses in vitro and in vivo. Various approaches utilizing different vaccine cell formats, cell numbers, vaccination schedule, site of vaccination and maturation stages of DCs were investigated worldwide. While clinical trials have demonstrated the safety of such strategies, the clinical outcome was less than expected in most cases. This is due to in part host immunodeficiency imposed by tumors and immunoediting of tumor cells. To overcome these obstacles, new approaches to improve DC-mediated immunotherapeutic strategies are under investigation. First, functional enhancement of monocyte-derived DCs can be generated with using flt3-ligand (FL). Second, diverse antigenic determinants from heat shock-treated tumor cells may improve the immunogenicity of DC-based vaccines. Third, inclusion of ex vivo expanded NK/NKT cells in DC-based vaccines could be beneficial since the bidirectional interaction of these two cell types are known to enhance NK cell effector function and to induce DC maturation. Application of these approaches may induce a broadened antitumor immune response and thereby promote the elimination of tumor antigen-negative variant clones that had escaped immunosurveillance or undergone immunoediting. We are currently examining the feasibility of these immunotherapeutic approaches using a murine pancreatic cancer model system.
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PMID:Strategies to improve dendritic cell-based immunotherapy against cancer. 1525 50

SAP is an adaptor protein expressed in T cells and natural killer cells. It plays a critical role in immunity, as it is mutated in humans with X-linked lymphoproliferative syndrome (XLP), a fatal immunodeficiency characterized by an abnormal response to Epstein-Barr virus (EBV) infection. SAP interacts with the SLAM family receptors and promotes transduction signal events by these receptors through its capacity to recruit and activate the Src kinase FynT. Because it has been previously established that FynT is selectively required for the development of NKT cells, we examined NKT cells in SAP-deficient mice and in humans with XLP. In the absence of SAP, the development of NKT cells is severely impaired both in mice and in humans. These results imply that SAP is a potent regulator of NKT cell development. They also identify for the first time a defect in NKT cells associated with a human primary immunodeficiency, revealing a potential role of NKT cells in the immune response to EBV.
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PMID:Defective NKT cell development in mice and humans lacking the adapter SAP, the X-linked lymphoproliferative syndrome gene product. 1573 56

Signaling lymphocyte activation molecule (SLAM) family receptors are critically involved in modulating innate and adaptive immune responses. Several SLAM family receptors have been shown to interact with the adaptor molecule SAP; however, subsequent intracellular signaling is poorly defined. Notably, mutations in SLAM-associated protein (SAP) lead to X-linked lymphoproliferative disease, a rare but fatal immunodeficiency. Although the SLAM family member Ly9 (CD229) is known to interact with SAP, the functions of this receptor have remained elusive. Therefore, we have generated Ly9-/- mice and compared their phenotype with that of SLAM-/- and SAP-/- mice. We report that Ly9-/- T cells exhibit a mild Th2 defect associated with reduced IL-4 production after stimulation with anti-TCR and anti-CD28 in vitro. This defect is similar in magnitude to the previously reported Th2 defect in SLAM-/- mice but is more subtle than that observed in SAP-/- mice. In contrast to SLAM-/- and SAP-/- mice, T cells from Ly9-/- mice proliferate poorly and produce little IL-2 after suboptimal stimulation with anti-CD3 in vitro. We have also found that Ly9-/- macrophages exhibit no defects in cytokine production or bacterial killing as was observed in SLAM-/- macrophages. Additionally, Ly9-/- mice differ from SAP-/- mice in that they foster normal development of NKT cells and mount appropriate T and B cell responses to lymphocytic choriomeningitis virus. We have identified significant phenotypic differences between Ly-9-/- mice as compared with both SLAM-/- and SAP-/- mice. Although Ly9, SLAM, and SAP play a common role in promoting Th2 polarization, Ly-9 is uniquely involved in enhancing T cell activation.
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PMID:Ly9 (CD229)-deficient mice exhibit T cell defects yet do not share several phenotypic characteristics associated with SLAM- and SAP-deficient mice. 1636 21

The homeostasis of the immune response requires tight regulation of the proliferation and apoptosis of activated lymphocytes. In humans, defects in immune homeostasis result in lymphoproliferation disorders including autoimmunity, haemophagocytic lymphohystiocytosis and lymphomas. The X-linked lymphoproliferative syndrome (XLP) is a rare, inherited immunodeficiency that is characterized by lymphohystiocytosis, hypogammaglobulinaemia and lymphomas, and that usually develops in response to infection with Epstein-Barr virus (EBV). Mutations in the signalling lymphocyte activation molecule (SLAM)-associated protein SAP, a signalling adaptor molecule, underlie 60% of cases of familial XLP. Here, we identify mutations in the gene that encodes the X-linked inhibitor-of-apoptosis XIAP (also termed BIRC4) in patients with XLP from three families without mutations in SAP. These mutations lead to defective expression of XIAP. We show that apoptosis of lymphocytes from XIAP-deficient patients is enhanced in response to various stimuli including the T-cell antigen receptor (TCR)-CD3 complex, the death receptor CD95 (also termed Fas or Apo-1) and the TNF-associated apoptosis-inducing ligand receptor (TRAIL-R). We also found that XIAP-deficient patients, like SAP-deficient patients, have low numbers of natural killer T-lymphocytes (NKT cells), indicating that XIAP is required for the survival and/or differentiation of NKT cells. The observation that XIAP-deficiency and SAP-deficiency are both associated with a defect in NKT cells strengthens the hypothesis that NKT cells have a key role in the immune response to EBV. Furthermore, by identifying an XLP immunodeficiency that is caused by mutations in XIAP, we show that XIAP is a potent regulator of lymphocyte homeostasis in vivo.
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PMID:XIAP deficiency in humans causes an X-linked lymphoproliferative syndrome. 1708 92

SAP (SLAM-associated protein) was identified in 1998 as an adaptor molecule involved in the intracellular signaling pathways elicited through the cell surface receptor SLAM and as the protein defective in the human immunodeficiency X-linked lymphoproliferative disease (XLP). During the past eight years, it has been established that the SLAM family of cell surface receptors (SLAM, 2B4, NTB-A, Ly9, CD84) and the SAP family of adaptors (SAP, EAT-2, ERT) play critical roles in lymphocyte development, differentiation, and acquisition of effector functions. Studies of these proteins have shown unexpected roles in cytokine production by T cells and myeloid cells, T cell-dependent humoral immune responses, NK cell-mediated cytotoxicity, and NKT cell development. This review highlights recent findings that have improved our understanding of the roles of the SLAM and SAP families of molecules in immune regulation and discusses how perturbations in the signaling pathways involving these proteins can result in different disease states.
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PMID:Regulation of cellular and humoral immune responses by the SLAM and SAP families of molecules. 1720 83

Signaling lymphocytic activation molecule (SLAM) family receptors mediate important regulatory signals in immune cells, as a result of their exquisite ability to associate with members of the SLAM-associated protein (SAP) family of adaptors. As discussed herein, recent findings show that the SLAM and SAP families carry out pivotal functions in innate-like and conventional lymphocytes. They are critically needed for the development of innate-like lymphocytes such as NKT cells. In addition, they influence several of the functions of conventional lymphocytes, including the ability of CD4(+) T cells to secrete certain cytokines and mediate B cell help; CD8(+) T cell proliferation and cytokine production; NK cell-mediated cytotoxicity; and B cell antibody production. These unique functional properties appear to be facilitated by the ability of SLAM-related receptors to serve as self-ligands during homotypic interactions between immune cells. The importance of the SLAM-SAP pathway in normal immunity is highlighted by the finding that SAP is mutated in humans suffering from the immunodeficiency X-linked lymphoproliferative disease.
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PMID:Consequence of the SLAM-SAP signaling pathway in innate-like and conventional lymphocytes. 1803 94

X-linked lympho-proliferative (XLP) is an immunodeficiency condition caused by mutation or deletion of the gene encoding the adaptor protein SAP/SH2D1A. Besides defects in T cell and NK cell function and an absence of NKT cells, XLP can also manifest as lymphomas resulting primarily from uncontrolled B cell proliferation upon acute infection by Epstein-Barr virus. While it has been demonstrated that SAP regulates the functions of T cells and NK cells through the SLAM family of immunoreceptors, its role in B cells has not been defined. Here we show that SAP forms a ternary complex with the kinase Lyn and the inhibitory IgG Fc receptor FcgammaRIIB to regulate B cell proliferation and survival. SAP binds directly and simultaneously to the Lyn SH3 domain and an Immuno-receptor Tyrosine-based Inhibitory Motif (ITIM) in FcgammaRIIB, resulting in the activation of the latter. Moreover, SAP associates with FcgammaRIIB in mouse splenic B cells and promotes its tyrosine phosphorylation. Expression of SAP in the A20 B cell line led to a marked reduction in Blnk phosphorylation, a decrease in Akt activation, and a near-complete ablation of phosphorylation of the MAP kinases Erk1/2, p38 and JNK upon colligation of FcgammaRIIB with the B cell receptor (BCR). In contrast, an XLP-causing SAP mutant was much less efficient in eliciting these effects in B cells. Furthermore, compared to A20 cells, SAP transfectants displayed a significantly reduced rate of proliferation and an increased sensitivity to activation-induced cell death. Collectively these data identify an intrinsic function for SAP in inhibitory signaling in B cells and suggests that SAP may play an important role in balancing positive versus negative immune responses.
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PMID:The X-linked lymphoproliferative syndrome gene product SAP regulates B cell function through the FcgammaRIIB receptor. 1866 72

NKT cells are a specialized population of T lymphocytes that have an increasingly recognized role in immunoregulation, including controlling the response to viral infections. The characteristics of NKT cells in the peripheral blood of macaques during simian immunodeficiency virus (SIV) or chimeric simian/human immunodeficiency virus (HIV) (SHIV) infection were assessed. NKT cells comprised a mean of 0.19% of peripheral blood lymphocytes across the 64 uninfected macaques studied. Although the range in the percentages of NKT cells was large (0 to 2.2%), levels were stable over time within individual macaques without SIV/SHIV infection. The majority of NKT cells in macaques were CD4(+) (on average 67%) with smaller populations being CD8(+) (21%) and CD4/CD8 double positive (13%). A precipitous decline in CD4(+) NKT cells occurred in all six macaques infected with CXCR4-tropic SHIV(mn229) early after infection, with a concomitant rise in CD8(+) NKT cells in some animals. The depletion of CD4(+) NKT cells was tightly correlated with the depletion of total CD4(+) T cells. R5-tropic SIV(mac251) infection of macaques resulted in a slower and more variable decline in CD4(+) NKT cells, with animals that were able to control SIV virus levels maintaining higher levels of CD4(+) NKT cells. An inverse correlation between the depletion of total and CD4(+) NKT cells and SIV viral load during chronic infection was observed. Our results demonstrate the infection-driven depletion of peripheral CD4(+) NKT cells during both SHIV and SIV infection of macaques. Further studies of the implications of the loss of NKT cell subsets in the pathogenesis of HIV disease are needed.
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PMID:Peripheral NKT cells in simian immunodeficiency virus-infected macaques. 1905 81

The fatal immune dysregulation that sometimes follows EBV infection in boys has been linked to mutations in two X chromosome-encoded genes, SLAM-associated protein (SAP) and X-linked inhibitor of apoptosis (XIAP). In this study we describe 2 girls from a consanguineous Turkish family who died after developing severe immune dysregulation and therapy-resistant EBV-positive B cell proliferation following EBV infection. SNP array-based genome-wide linkage analysis revealed IL-2-inducible T cell kinase (ITK) as a candidate gene for this immunodeficiency syndrome. Both girls harbored a homozygous missense mutation that led to substitution of a highly conserved residue (R335W) in the SH2 domain of ITK. Characteristics of ITK deficiency in mouse models, such as absence of NKT cells and high levels of eomesodermin in CD8+ cells, were seen in either one or both of the girls. Two lines of evidence suggested that R335W caused instability of the ITK protein. First, in silico modeling of the mutant protein predicted destabilization of the SH2 domain. Additionally, Western blot analysis revealed that, unlike wild-type ITK, the R335W mutant was nearly undetectable when expressed in 293 T cells. Our results suggest that ITK deficiency causes what we believe to be a novel immunodeficiency syndrome that leads to a fatal inadequate immune response to EBV. Because ITK deficiency resembles EBV-associated lymphoproliferative disorders in boys, we suggest that this molecular cause should be considered during diagnosis and treatment.
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PMID:Girls homozygous for an IL-2-inducible T cell kinase mutation that leads to protein deficiency develop fatal EBV-associated lymphoproliferation. 1942 69


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