The Experts below are selected from a list of 1695 Experts worldwide ranked by ideXlab platform
Cox Terhorst - One of the best experts on this subject based on the ideXlab platform.
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CLINICAL OBSERVATIONS, INTERVENTIONS, AND THERAPEUTIC TRIALS Alterations of the X-Linked Lymphoproliferative Disease gene SH2D1A in common variable immunodeficiency syndrome
2016Co-Authors: Olin Sil, Silvia Calpe, Michelle Choi, Hans Oettgen, Laurie Myers, Amos Etzioni, Rebecca Buckley, Cox TerhorstAbstract:X-Linked Lymphoproliferative (XLP) dis-ease is a primary immunodeficiency caused by a defect in the SH2D1A gene. At least 3 major manifestations character-ize its clinical presentation: fatal infec-tious mononucleosis (FIM), lymphomas, and immunoglobulin deficiencies. Com-mon variable immunodeficiency (CVID) is a syndrome characterized by immuno-globulin deficiency leading to susceptibil-ity to infection. In some patients with CVID, a defective btk or CD40-L gene has been found, but most often there is no clearly identified etiology. Here, 2 unre-lated families in whom male members were affected by CVID were examined for a defect in the XLP gene. In one family previously reported in the literature as having progressive immunoglobulin defi-ciencies, 3 brothers were examined for recurrent respiratory infections, whereas female family members showed only el-evated serum immunoglobulin A levels. A grandson of one of the brothers died of a severe Aspergillus infection secondary to progressive immunoglobulin defi-ciency, FIM, aplastic anemia, and B-cell lymphoma. In the second family, 2 broth-ers had B lymphocytopenia and immuno-globulin deficiencies. X-Linked agamma-globulinemia syndrome was excluded genetically, and they were classified as having CVID. The occurrence of FIM in a male cousin of the brothers led to the XLP diagnosis. Because the SH2D1A gene was found altered in both families, these find-ings indicate that XLP must be consid-ered when more than one male patient with CVID is encountered in the same family, and SH2D1A must be analyzed in all male patients with CVID. Moreover, these data link defects in the SH2D1A gene to abnormal B-lymphocyte develop-ment and to dysgammaglobulinemia in female members of families with XLP Disease. (Blood. 2001;98:1321-1325) © 2001 by The American Society of Hematolog
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slam family receptors and the slam associated protein sap modulate t cell functions
Seminars in Immunopathology, 2010Co-Authors: Cynthia Detre, Xavier Romero, Marton Keszei, George C Tsokos, Cox TerhorstAbstract:One or more of the signaling lymphocytic activation molecule (SLAM) family (SLAMF) of cell surface receptors, which consists of nine transmembrane proteins, i.e., SLAMF1-9, are expressed on most hematopoietic cells. While most SLAMF receptors serve as self-ligands, SLAMF2 and SLAMF4 use each other as counter structures. Six of the receptors carry one or more copies of a unique intracellular tyrosine-based switch motif, which has high affinity for the single SH2-domain signaling molecules SLAM-associated protein and EAT-2. Whereas SLAMF receptors are costimulatory molecules on the surface of CD4+, CD8+, and natural killer (NK) T cells, they also involved in early phases of lineage commitment during hematopoiesis. SLAMF receptors regulate T lymphocyte development and function and modulate lytic activity, cytokine production, and major histocompatibility complex-independent cell inhibition of NK cells. Furthermore, they modulate B cell activation and memory generation, neutrophil, dendritic cell, macrophage and eosinophil function, and platelet aggregation. In this review, we will discuss the role of SLAM receptors and their adapters in T cell function, and we will examine the role of these receptors and their adapters in X-Linked Lymphoproliferative Disease and their contribution to Disease susceptibility in systemic lupus erythematosus.
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cutting edge signaling lymphocytic activation molecule associated protein controls nkt cell functions
Journal of Immunology, 2005Co-Authors: Brian K Chung, Ala Aoukaty, Jan P Dutz, Cox TerhorstAbstract:X-Linked Lymphoproliferative Disease (XLP) is a fatal immunological disorder that typically manifests following EBV infection. XLP patients exhibit a number of immune defects including abnormal T, B, and NK lymphocyte function. These defects have been attributed to mutations of Src homology 2 domain-containing gene 1A ( SH2D1A ), the gene encoding signaling lymphocytic activation molecule-associated protein (SAP), an intracellular adaptor molecule expressed in lymphocytes. We have observed that SAP knockout (SAPKO) mice and humans with XLP have a complete lack of CD1d-restricted NKT cells. As expected, SAPKO mice injected with the NKT cell agonist, α-galactosylceramide failed to generate NKT cell IFN-γ or IL-4. Furthermore, in contrast to wild-type littermates, SAPKO mice coinjected with OVA and α-galactosylceramide failed to mount OVA-specific CTL responses. These data suggest that an absence of NKT cells may underlie part of the immune dysregulation seen in SAPKO mice and in XLP patients.
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the sap and slam families in immune responses and x linked Lymphoproliferative Disease
Nature Reviews Immunology, 2003Co-Authors: Pablo Engel, Michael J Eck, Cox TerhorstAbstract:SAP (signalling lymphocytic activation molecule (SLAM)-associated protein) is a T- and natural killer (NK)-cell-specific protein containing a single SH2 domain encoded by a gene that is defective or absent in patients with X-Linked Lymphoproliferative syndrome (XLP). The SH2 domain of SAP binds with high affinity to the cytoplasmic tail of the haematopoietic cell-surface glycoprotein SLAM and five related receptors. SAP regulates signal transduction of the SLAM-family receptors by recruiting SRC kinases. Similarly, the SAP-related proteins EAT2A and EAT2B are thought to control signal transduction that is initiated by SLAM-related receptors in professional antigen-presenting cells. In this review, we discuss recent findings on the structure and function of proteins of the SAP and SLAM families.
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x linked Lymphoproliferative Disease a progressive immunodeficiency
Annual Review of Immunology, 2001Co-Authors: Duncan Howie, Ninghai Wang, Pablo Engel, Maria Simarro Grande, Cox TerhorstAbstract:Our understanding of the X-Linked Lymphoproliferative syndrome (XLP) has advanced significantly in the last two years. The gene that is altered in the condition (SAP/SH2D1A) has been cloned and its protein crystal structure solved. At least two sets of target molecules for this small SH2 domain-containing protein have been identified: A family of hematopoietic cell surface receptors, i.e. the SLAM family, and a second molecule, which is a phosphorylated adapter. A SAP-like protein, EAT-2, has also been found to interact with this family of surface receptors. Several lines of evidence, including structural studies and analyses of missense mutations in XLP patients, support the notion that SAP/SH2D1A is a natural inhibitor of SH2-domain-dependent interactions with members of the SLAM family. However, details of its role in signaling mechanisms are yet to be unravelled. Further analyses of the SAP/SH2D1A gene in XLP patients have made it clear that the development of dys-gammaglobulinemia and B cell lymphoma can occur without evidence of prior EBV infection. Moreover, preliminary results of virus infections of a mouse in which the SAP/SH2D1A gene has been disrupted suggest that EBV infection is not per se critical for the development of XLP phenotypes. It appears therefore that the SAP/SH2D1A gene controls signaling via the SLAM family of surface receptors and thus may play a fundamental role in T cell and APC interactions during viral infections.
Umaimainthan Palendira - One of the best experts on this subject based on the ideXlab platform.
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Cerebral Vasculitis in X-Linked Lymphoproliferative Disease Cured by Matched Unrelated Cord Blood Transplant
Journal of clinical immunology, 2015Co-Authors: Paul A. Gray, Umaimainthan Palendira, Tracey A. O'brien, Mayura Wagle, Stuart G. Tangye, Tony Roscioli, Sharon Choo, Rosemary Sutton, John B. Ziegler, Katie FrithAbstract:ᅟ Vasculitis occurs rarely in association with X-Linked Lymphoproliferative Disease (XLP). There are four published cases of non-EBV XLP-associated cerebral vasculitis reported, none of whom have survived without major cognitive impairment.
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cellular immune controls over epstein barr virus infection new lessons from the clinic and the laboratory
Trends in Immunology, 2014Co-Authors: Alan B Rickinson, Umaimainthan Palendira, Heather M Long, Christian Munz, Andrew D HislopAbstract:Epstein–Barr virus (EBV), a human herpesvirus with potent B cell growth transforming ability, induces multiple cellular immune responses in the infected host. How these host responses work together to prevent virus pathogenicity, and how immune imbalance predisposes to Disease, remain poorly understood. Here, we describe three ongoing lines of enquiry that are shedding new light on these issues. These focus on: (i) patients with infectious mononucleosis or its fatal equivalent, X-Linked Lymphoproliferative Disease; (ii) EBV infection in a range of new, genetically defined, primary immune deficiency states; and (iii) experimental infection in two complementary animal models, the rhesus macaque and the human haemopoietic stem cell reconstituted mouse.
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expansion of somatically reverted memory cd8 t cells in patients with x linked Lymphoproliferative Disease caused by selective pressure from epstein barr virus
Journal of Experimental Medicine, 2012Co-Authors: Umaimainthan Palendira, Carol Low, Andrew I Bell, Cindy S, Rachel Abbott, Tri Giang Phan, Sean D RimintonAbstract:Patients with the primary immunodeficiency X-Linked Lymphoproliferative Disease (XLP), which is caused by mutations in SH2D1A, are highly susceptible to Epstein-Barr virus (EBV) infection. Nonetheless, some XLP patients demonstrate less severe clinical manifestations after primary infection. SH2D1A encodes the adaptor molecule SLAM-associated protein (SAP), which is expressed in T and natural killer cells and is required for cytotoxicity against B cells, the reservoir for EBV. It is not known why the clinical presentation of XLP is so variable. In this study, we report for the first time the occurrence of somatic reversion in XLP. Reverted SAP-expressing cells resided exclusively within the CD8(+) T cell subset, displayed a CD45RA(-)CCR7(-) effector memory phenotype, and were maintained at a stable level over time. Importantly, revertant CD8(+) SAP(+) T cells, but not SAP(-) cells, proliferated in response to EBV and killed EBV-infected B cells. As somatic reversion correlated with EBV infection, we propose that the virus exerts a selective pressure on the reverted cells, resulting in their expansion in vivo and host protection against ongoing infection.
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molecular pathogenesis of ebv susceptibility in xlp as revealed by analysis of female carriers with heterozygous expression of sap
PLOS Biology, 2011Co-Authors: Umaimainthan Palendira, Carol Low, Tri Giang Phan, Anna Chan, Andrew D Hislop, Edwin Ho, Elissa K DeenickAbstract:X-Linked Lymphoproliferative Disease (XLP) is a primary immunodeficiency caused by mutations in SH2D1A which encodes SAP. SAP functions in signalling pathways elicited by the SLAM family of leukocyte receptors. A defining feature of XLP is exquisite sensitivity to infection with EBV, a B-lymphotropic virus, but not other viruses. Although previous studies have identified defects in lymphocytes from XLP patients, the unique role of SAP in controlling EBV infection remains unresolved. We describe a novel approach to this question using female XLP carriers who, due to random X-inactivation, contain both SAP+ and SAP− cells. This represents the human equivalent of a mixed bone marrow chimera in mice. While memory CD8+ T cells specific for CMV and influenza were distributed across SAP+ and SAP− populations, EBV-specific cells were exclusively SAP+. The preferential recruitment of SAP+ cells by EBV reflected the tropism of EBV for B cells, and the requirement for SAP expression in CD8+ T cells for them to respond to Ag-presentation by B cells, but not other cell types. The inability of SAP− clones to respond to Ag-presenting B cells was overcome by blocking the SLAM receptors NTB-A and 2B4, while ectopic expression of NTB-A on fibroblasts inhibited cytotoxicity of SAP− CD8+ T cells, thereby demonstrating that SLAM receptors acquire inhibitory function in the absence of SAP. The innovative XLP carrier model allowed us to unravel the mechanisms underlying the unique susceptibility of XLP patients to EBV infection in the absence of a relevant animal model. We found that this reflected the nature of the Ag-presenting cell, rather than EBV itself. Our data also identified a pathological signalling pathway that could be targeted to treat patients with severe EBV infection. This system may allow the study of other human Diseases where heterozygous gene expression from random X-chromosome inactivation can be exploited.
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molecular pathogenesis of ebv susceptibility in xlp as revealed by analysis of female carriers with heterozygous expression of sap
PLOS Biology, 2011Co-Authors: Umaimainthan Palendira, Carol Low, Tri Giang Phan, Anna Chan, Andrew D Hislop, Elissa K Deenick, Matthew C CookAbstract:X-Linked Lymphoproliferative Disease (XLP) is a primary immunodeficiency caused by mutations in SH2D1A which encodes SAP. SAP functions in signalling pathways elicited by the SLAM family of leukocyte receptors. A defining feature of XLP is exquisite sensitivity to infection with EBV, a B-lymphotropic virus, but not other viruses. Although previous studies have identified defects in lymphocytes from XLP patients, the unique role of SAP in controlling EBV infection remains unresolved. We describe a novel approach to this question using female XLP carriers who, due to random X-inactivation, contain both SAP+ and SAP− cells. This represents the human equivalent of a mixed bone marrow chimera in mice. While memory CD8+ T cells specific for CMV and influenza were distributed across SAP+ and SAP− populations, EBV-specific cells were exclusively SAP+. The preferential recruitment of SAP+ cells by EBV reflected the tropism of EBV for B cells, and the requirement for SAP expression in CD8+ T cells for them to respond to Ag-presentation by B cells, but not other cell types. The inability of SAP− clones to respond to Ag-presenting B cells was overcome by blocking the SLAM receptors NTB-A and 2B4, while ectopic expression of NTB-A on fibroblasts inhibited cytotoxicity of SAP− CD8+ T cells, thereby demonstrating that SLAM receptors acquire inhibitory function in the absence of SAP. The innovative XLP carrier model allowed us to unravel the mechanisms underlying the unique susceptibility of XLP patients to EBV infection in the absence of a relevant animal model. We found that this reflected the nature of the Ag-presenting cell, rather than EBV itself. Our data also identified a pathological signalling pathway that could be targeted to treat patients with severe EBV infection. This system may allow the study of other human Diseases where heterozygous gene expression from random X-chromosome inactivation can be exploited.
Kim E. Nichols - One of the best experts on this subject based on the ideXlab platform.
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affinity purification mass spectrometry analysis of pd 1 uncovers sap as a new checkpoint inhibitor
Proceedings of the National Academy of Sciences of the United States of America, 2018Co-Authors: Michael Peled, Kim E. Nichols, Anna S Tocheva, Sabina Sandigursky, Shruti Nayak, Elliot A Philips, Marianne Strazza, Inbar Azoulayalfaguter, Manor Askenazi, Benjamin G NeelAbstract:Programmed cell death-1 (PD-1) is an essential inhibitory receptor in T cells. Antibodies targeting PD-1 elicit durable clinical responses in patients with multiple tumor indications. Nevertheless, a significant proportion of patients do not respond to anti–PD-1 treatment, and a better understanding of the signaling pathways downstream of PD-1 could provide biomarkers for those whose tumors respond and new therapeutic approaches for those whose tumors do not. We used affinity purification mass spectrometry to uncover multiple proteins associated with PD-1. Among these proteins, signaling lymphocytic activation molecule-associated protein (SAP) was functionally and mechanistically analyzed for its contribution to PD-1 inhibitory responses. Silencing of SAP augmented and overexpression blocked PD-1 function. T cells from patients with X-Linked Lymphoproliferative Disease (XLP), who lack functional SAP, were hyperresponsive to PD-1 signaling, confirming its inhibitory role downstream of PD-1. Strikingly, signaling downstream of PD-1 in purified T cell subsets did not correlate with PD-1 surface expression but was inversely correlated with intracellular SAP levels. Mechanistically, SAP opposed PD-1 function by acting as a molecular shield of key tyrosine residues that are targets for the tyrosine phosphatase SHP2, which mediates PD-1 inhibitory properties. Our results identify SAP as an inhibitor of PD-1 function and SHP2 as a potential therapeutic target in patients with XLP.
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affect the expression and function of
2016Co-Authors: Nathan J Hare, Kim E. Nichols, Cindy S, Frank Alvaro, Stuart G. TangyeAbstract:Missense mutations in SH2D1A identified in patients with X-Linked Lymphoproliferative Disease differentiall
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restimulation induced apoptosis of t cells is impaired in patients with x linked Lymphoproliferative Disease caused by sap deficiency
Journal of Clinical Investigation, 2009Co-Authors: Andrew L. Snow, Philip Roehrs, Lisa R Young, Jack Van Hoff, Deepali Dhar, Kim E. Nichols, Scott M Krummey, Kejian Zhang, Rebecca A Marsh, Alexandra H FilipovichAbstract:X-Linked Lymphoproliferative Disease (XLP) is a rare congenital immunodeficiency that leads to an extreme, usually fatal increase in the number of lymphocytes upon infection with EBV. It is most commonly defined molecularly by loss of expression of SLAM-associated protein (SAP). Despite this, there is little understanding of how SAP deficiency causes lymphocytosis following EBV infection. Here we show that T cells from individuals with XLP are specifically resistant to apoptosis mediated by TCR restimulation, a process that normally constrains T cell expansion during immune responses. Expression of SAP and the SLAM family receptor NK, T, and B cell antigen (NTB-A) were required for TCR-induced upregulation of key pro-apoptotic molecules and subsequent apoptosis. Further, SAP/NTB-A signaling augmented the strength of the proximal TCR signal to achieve the threshold required for restimulation-induced cell death (RICD). Strikingly, TCR ligation in activated T cells triggered increased recruitment of SAP to NTB-A, dissociation of the phosphatase SHP-1, and colocalization of NTB-A with CD3 aggregates. In contrast, NTB-A and SHP-1 contributed to RICD resistance in XLP T cells. Our results reveal what we believe to be novel roles for NTB-A and SAP in regulating T cell homeostasis through apoptosis and provide mechanistic insight into the pathogenesis of Lymphoproliferative Disease in XLP.
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regulation of cellular and humoral immune responses by the slam and sap families of molecules
Annual Review of Immunology, 2007Co-Authors: Kim E. Nichols, Stuart G. TangyeAbstract: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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expansion of functionally immature transitional b cells is associated with human immunodeficient states characterized by impaired humoral immunity
Journal of Immunology, 2006Co-Authors: Kim E. Nichols, Jennifer L Cannons, Stuart G. Tangye, Amanda K Cuss, Danielle T Avery, Li Jun Yu, Peter J ShawAbstract: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 + CD24 high CD38 high 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 CD24 high CD38 high B cells to proliferate, secrete Ig, and migrate in vitro was greatly reduced compared with mature B cell populations. Moreover, CD24 high CD38 high 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.
Pablo Engel - One of the best experts on this subject based on the ideXlab platform.
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the adaptor protein 3bp2 binds human cd244 and links this receptor to vav signaling erk activation and nk cell killing
Journal of Immunology, 2005Co-Authors: Ifigenia Saboritvillarroya, Juana M Del Valle, Pilar Lauzurica, Xavier Romero, Enric Esplugues, Pablo Engel, Margarita MartinAbstract:Adaptor proteins, molecules that mediate intermolecular interactions, are crucial for cellular activation. The adaptor 3BP2 has been shown to positively regulate NK cell-mediated cytotoxicity. In this study we present evidence for a physical interaction between 3BP2 and the CD244 receptor. CD244, a member of the CD150 family, is a cell surface protein expressed on NK, CD8+ T, and myeloid cells. CD244 interacts via its Src homology 2 domain with the X-Linked Lymphoproliferative Disease gene product signaling lymphocytic activation molecule-associated protein (SAP)/SH2 domain protein 1A. 3BP2 interacts with human but not murine CD244. CD244-3BP2 interaction was direct and regulated by phosphorylation, as shown by a three-hybrid analysis in yeast and NK cells. Tyr337 on CD244, part of a consensus motif for SAP/SH2 domain protein 1A binding, was critical for the 3BP2 interaction. Although mutation of Tyr337 to phenylalanine abrogated human 3BP2 binding, we still observed SAP association, indicating that this motif is not essential for SAP recruitment. CD244 ligation induced 3BP2 phosphorylation and Vav-1 recruitment. Overexpression of 3BP2 led to an increase in the magnitude and duration of ERK activation, after CD244 triggering. This enhancement was concomitant with an increase in cytotoxicity due to CD244 ligation. However, no differences in IFN-γ secretion were found when normal and 3BP2-transfected cells were compared. These results indicate that CD244-3BP2 association regulates cytolytic function but not IFN-γ release, reinforcing the hypothesis that, in humans, CD244-mediated cytotoxicity and IFN-γ release involve distinct NK pathways.
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differential expression of sap and eat 2 binding leukocyte cell surface molecules cd84 cd150 slam cd229 ly9 and cd244 2b4
Tissue Antigens, 2004Co-Authors: Xavier Romero, Sandra March, Montserrat Miralpeix, Ramon Vilella, D. Benitez, Pablo EngelAbstract:The CD150 (SLAM) family consists of nine leukocyte cell-surface proteins involved in lymphocyte activation that belong to the immunoglobulin (Ig) superfamily. Six members of this family - CD84, CD150 (SLAM), CD229 (Ly9), CD244 (2B4), NTB-A, and CS1 - associate with adapter proteins - SLAM-associated protein (SAP) and EAT-2. SAP is a short intracellular molecule that is mutated in humans with X-Linked Lymphoproliferative Disease. Flow cytometric analysis of the expression of CD84, CD150, CD229, and CD244 cell-surface receptors on several leukocyte and lymphocyte subsets was performed. CD84 and CD150 were present on thymocytes, mature T cells and antigen-presenting cells. The expression of CD84 and CD150 was high on memory T cells. CD150 expression was strongly up-regulated after cell activation. In contrast to CD84, CD150 was absent on resting monocytes and immature dendritic cells (DCs). CD229 presented a pattern of expression restricted to lymphocytes. CD244 was preferentially expressed on natural killer cells, CD8 + effector cells, resting monocytes, basophils, and eosinophils. We describe a broader distribution of CD84, CD150, CD229, and CD244 than previously reported and show that they are differentially expressed on hematopoietic cells. The heterogeneous expression of these receptors indicates that these molecules may play non-redundant functions in the regulation of both innate and adaptive immune responses.
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the sap and slam families in immune responses and x linked Lymphoproliferative Disease
Nature Reviews Immunology, 2003Co-Authors: Pablo Engel, Michael J Eck, Cox TerhorstAbstract:SAP (signalling lymphocytic activation molecule (SLAM)-associated protein) is a T- and natural killer (NK)-cell-specific protein containing a single SH2 domain encoded by a gene that is defective or absent in patients with X-Linked Lymphoproliferative syndrome (XLP). The SH2 domain of SAP binds with high affinity to the cytoplasmic tail of the haematopoietic cell-surface glycoprotein SLAM and five related receptors. SAP regulates signal transduction of the SLAM-family receptors by recruiting SRC kinases. Similarly, the SAP-related proteins EAT2A and EAT2B are thought to control signal transduction that is initiated by SLAM-related receptors in professional antigen-presenting cells. In this review, we discuss recent findings on the structure and function of proteins of the SAP and SLAM families.
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cd84 functions as a homophilic adhesion molecule and enhances ifn gamma secretion adhesion is mediated by ig like domain 1
Journal of Immunology, 2001Co-Authors: Margarita Martin, Xavier Romero, Enric Esplugues, De La Fuente, Nuria Zapater, Pilar Pizcueta, Jaime Bosch, Pablo EngelAbstract:CD84 is a member of the CD2 subset of the Ig superfamily of cell surface molecules. Its cytoplasmic tail binds to Src homology 2 domain-containing protein 1A (signaling lymphocytic activation molecule-associated protein), a protein encoded by the X-Linked Lymphoproliferative Disease gene. It is preferentially expressed on B lymphocytes, monocytes, and platelets. We show that it is also expressed on thymocytes and T cells. CD84 was positive on CD4−CD8− thymocytes, and its expression decreased with cell maturation. It is expressed on mature T cells preferentially on CD45RO+. To identify the CD84 ligand, we generated a soluble Ig fusion protein containing the human CD84 extracellular domains (CD84-Ig). Because receptor-ligand interactions occur between several members of this subfamily, we assayed CD84-Ig binding with all members of the CD2 family. CD84-Ig bound to CD84-transfected cells, whereas no binding was detected with cells expressing other CD2 subfamily receptors, showing that CD84 binds to itself. Anti-CD84 mAbs recognizing epitopes wholly within domain 1 of CD84 blocked the binding of the CD84-Ig fusion protein to CD84-transfected cells and platelets. Data from CD84 domain human/mouse chimeras further revealed that only the first extracellular domain of the molecule is involved in the ligand receptor recognition. The CD84-CD84 interaction was independent of its cytoplasmic tail. Finally, concurrent ligation of human CD84 with mAbs or CD84-Ig and CD3 enhanced IFN-γ secretion in human lymphocytes. Thus, CD84 is its own ligand and acts as a costimulatory molecule.
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x linked Lymphoproliferative Disease a progressive immunodeficiency
Annual Review of Immunology, 2001Co-Authors: Duncan Howie, Ninghai Wang, Pablo Engel, Maria Simarro Grande, Cox TerhorstAbstract:Our understanding of the X-Linked Lymphoproliferative syndrome (XLP) has advanced significantly in the last two years. The gene that is altered in the condition (SAP/SH2D1A) has been cloned and its protein crystal structure solved. At least two sets of target molecules for this small SH2 domain-containing protein have been identified: A family of hematopoietic cell surface receptors, i.e. the SLAM family, and a second molecule, which is a phosphorylated adapter. A SAP-like protein, EAT-2, has also been found to interact with this family of surface receptors. Several lines of evidence, including structural studies and analyses of missense mutations in XLP patients, support the notion that SAP/SH2D1A is a natural inhibitor of SH2-domain-dependent interactions with members of the SLAM family. However, details of its role in signaling mechanisms are yet to be unravelled. Further analyses of the SAP/SH2D1A gene in XLP patients have made it clear that the development of dys-gammaglobulinemia and B cell lymphoma can occur without evidence of prior EBV infection. Moreover, preliminary results of virus infections of a mouse in which the SAP/SH2D1A gene has been disrupted suggest that EBV infection is not per se critical for the development of XLP phenotypes. It appears therefore that the SAP/SH2D1A gene controls signaling via the SLAM family of surface receptors and thus may play a fundamental role in T cell and APC interactions during viral infections.
Lorenzo Moretta - One of the best experts on this subject based on the ideXlab platform.
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haemophagocytic lymphohistiocytosis proposal of a diagnostic algorithm based on perforin expression
British Journal of Haematology, 2002Co-Authors: Maurizio Arico, Rita Clementi, Lorenzo Moretta, Michaela R Allen, Simona Brusa, Daniela Pende, Rita Maccario, Cesare DanesinoAbstract:Haemophagocytic lymphohistiocytosis (HLH) is a rare, fatal disorder of early infancy. Mutations of the PRF1 gene have been identified in a subset of patients. However, the distinction between the different genetically determined and environmental subtypes of the Disease remains a major issue to be solved. This may result in delayed or inappropriate application of bone marrow transplantation (BMT). We propose an algorithm that uses a combination of three rapid laboratory tests, i.e. perforin expression by peripheral lymphocytes, assessment of the behaviour of the 2B4 lymphocyte receptor and natural killer (NK) cell activity, to identify the different subgroups of HLH. In 19 patients diagnosed according to current criteria, we tested perforin expression, 2B4 receptor function and NK cell activity. PRF1 mutations were found in all seven patients showing absent perforin expression. In one male with abnormal behaviour of the 2B4 receptor, SH2D1A mutation confirmed the diagnosis of X-Linked Lymphoproliferative Disease. Four patients with normal NK cell activity had evidence of associated infections. Of the seven with impaired NK cell activity, two had a probable genetically determined subtype of HLH and five appeared as sporadic, infection-associated cases. Improving the diagnostic approach may restrict the use of BMT, the only recognized curative treatment, to HLH patients with a documented poor prognosis while patients with milder disorders may be treated less intensively. Our flow chart could also lead to better selection of patients for specific gene analysis.
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gntb a a novel sh2d1a associated surface molecule contributing to the inability of natural killer cells to kill epstein barr virus infected b cells in x linked Lymphoproliferative Disease
Journal of Experimental Medicine, 2001Co-Authors: Cristina Bottino, Silvia Parolini, Michela Falco, Raffaella Augugliaro, Roberto Biassoni, Emanuela Marcenaro, Simona Sivori, Elena Landi, Luigi D Notarangelo, Lorenzo MorettaAbstract:In humans, natural killer (NK) cell function is regulated by a series of receptors and coreceptors with either triggering or inhibitory activity. Here we describe a novel 60-kD glycoprotein, termed NTB-A, that is expressed by all human NK, T, and B lymphocytes. Monoclonal antibody (mAb)-mediated cross-linking of NTB-A results in the induction of NK-mediated cytotoxicity. Similar to 2B4 (CD244) functioning as a coreceptor in the NK cell activation, NTB-A also triggers cytolytic activity only in NK cells expressing high surface densities of natural cytotoxicity receptors. This suggests that also NTB-A may function as a coreceptor in the process of NK cell activation. Molecular cloning of the cDNA coding for NTB-A molecule revealed a novel member of the immunoglobulin superfamily belonging to the CD2 subfamily. NTB-A is characterized, in its extracellular portion, by a distal V-type and a proximal C2-type domain and by a cytoplasmic portion containing three tyrosine-based motifs. NTB-A undergoes tyrosine phosphorylation and associates with the Src homology 2 domain–containing protein (SH2D1A) as well as with SH2 domain–containing phosphatases (SHPs). Importantly, analysis of NK cells derived from patients with X-Linked Lymphoproliferative Disease (XLP) showed that the lack of SH2D1A protein profoundly affects the function not only of 2B4 but also of NTB-A. Thus, in XLP-NK cells, NTB-A mediates inhibitory rather than activating signals. These inhibitory signals are induced by the interaction of NTB-A with still undefined ligands expressed on Epstein-Barr virus (EBV)-infected target cells. Moreover, mAb-mediated masking of NTB-A can partially revert this inhibitory effect while a maximal recovery of target cell lysis can be obtained when both 2B4 and NTB-A are simultaneously masked. Thus, the altered function of NTB-A appears to play an important role in the inability of XLP-NK cells to kill EBV-infected target cells.
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activating receptors and coreceptors involved in human natural killer cell mediated cytolysis
Annual Review of Immunology, 2001Co-Authors: Alessandro Moretta, Cristina Bottino, Roberto Biassoni, Daniela Pende, Massimo Vitale, Claudia Cantoni, Maria Cristina Mingari, Lorenzo MorettaAbstract:Natural killer cells can discriminate between normal cells and cells that do not express adequate amounts of major histocompatibility complex (MHC) class I molecules. The discovery, both in mouse and in human, of MHC-specific inhibitory receptors clarified the molecular basis of this important NK cell function. However, the triggering receptors responsible for positive NK cell stimulation remained elusive until recently. Some of these receptors have now been identified in humans, thus shedding some light on the molecular mechanisms involved in NK cell activation during the process of natural cytotoxicity. Three novel, NK-specific, triggering surface molecules (NKp46, NKp30, and NKp44) have been identified. They represent the first members of a novel emerging group of receptors collectively termed natural cytotoxicity receptors (NCR). Monoclonal antibodies (mAbs) to NCR block to differing extents the NK-mediated lysis of various tumors. Moreover, lysis of certain tumors can be virtually abrogated by the simultaneous masking of the three NCRs. There is a coordinated surface expression of the three NCRs, their surface density varying in different individuals and also in the NK cells isolated from a given individual. A direct correlation exists between the surface density of NCR and the ability of NK cells to kill various tumors. NKp46 is the only NCR involved in human NK-mediated killing of murine target cells. Accordingly, a homologue of NKp46 has been detected in mouse. Molecular cloning of NCR revealed novel members of the Ig superfamily displaying a low degree of similarity to each other and to known human molecules. NCRs are coupled to different signal transducing adaptor proteins, including CD3 zeta, Fc epsilon RI gamma, and KARAP/DAP12. Another triggering NK receptor is NKG2D. It appears to play either a complementary or a synergistic role with NCRs. Thus, the triggering of NK cells in the process of tumor cell lysis may often depend on the concerted action of NCR and NKG2D. In some instances, however, it may uniquely depend upon the activity of NCR or NKG2D only. Strict NKG2D-dependency can be appreciated using clones that, in spite of their NCR(dull) phenotype, efficiently lyse certain epithelial tumors or leukemic cell lines. Other triggering surface molecules including 2B4 and the novel NKp80 appear to function as coreceptors rather than as true receptors. Indeed, they can induce natural cytotoxicity only when co-engaged with a triggering receptor. While an altered expression or function of NCR or NKG2D is being explored as a possible cause of immunological disorders, 2B4 dysfunction has already been associated with a severe form of immunodeficiency. Indeed, in patients with the X-Linked Lymphoproliferative Disease, the inability to control Epstein-Barr virus infections may be consequent to a major dysfunction of 2B4 that exerts inhibitory instead of activating functions.
