Primary Immunodeficiencies Inducing EBV-Associated Severe Illnesses.

Epstein-Barr virus (EBV) is a ubiquitous human gamma-herpesvirus that infects about 95% of the adult population. The majority of primary infections occurs in early childhood and is generally subclinical; it can cause infectious mononucleosis (IM), which is usually a self-limiting lymphoproliferative disorder. However, infection of EBV occasionally results in severe, often lethal diseases, which include fatal IM, hemophagocytic syndrome, polyclonal lymphoproliferative disorders, and malignant lymphoma.

Comparative study of specific ebv antibodies between children manifest classic triad of mononucleosis with unaffected children in hazrat rasool akram hospital (1998-2000).

Epstein barr virus (EBV) is one of seven known herpes virus pathogenic for humans.Since it is ubiquitous, it infects nearly 95% of individuals worldwide by adulthood .EBV is the etiologic agent of infectious mononucleosis(TM)and is implicated in burkitt lymphoma,nasopharyngeal carcinoma and x-linked lymphoproliferative syndrome.

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

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.

The role of SLAM family receptors in immune cell signaling.

The signaling lymphocyte-activating molecule (SLAM) family immunoreceptors are expressed in a wide array of immune cells, including both T and B lymphocytes. By virtue of their ability to transduce tyrosine phosphorylation signals through the so-called ITSM (immunoreceptor tyrosine-based switch motif) sequences, they play an important part in regulating both innate and adaptive immune responses. The critical role of the SLAM immunoreceptors in mediating normal immune reactions was highlighted in recent findings that SAP, a SLAM-associated protein, modulates the activities of various immune cells through interactions with different members of the SLAM family expressed in these cells.

Familial and acquired hemophagocytic lymphohistiocytosis.

Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening condition of severe hyperinflammation caused by the uncontrolled proliferation of activated lymphocytes and histiocytes secreting high amounts of inflammatory cytokines. Cardinal signs and symptoms are prolonged fever, hepatosplenomegaly and pancytopenia. Characteristic biochemical markers include elevated triglycerides, ferritin and low fibrinogen.

Cytotoxic drug sensitivity of Epstein-Barr virus transformed lymphoblastoid B-cells.

Background: Epstein-Barr virus (EBV) is the causative agent of immunosuppression associated lymphoproliferations such as post-transplant lymphoproliferative disorder (PTLD), AIDS related immunoblastic lymphomas (ARL) and immunoblastic lymphomas in X-linked lymphoproliferative syndrome (XLP). The reported overall mortality for PTLD often exceeds 50%. Reducing the immunosuppression in recipients of solid organ transplants (SOT) or using highly active antiretroviral therapy in AIDS patients leads to complete remission in 23-50% of the PTLD/ARL cases but will not suffice for recipients of bone marrow grafts.

Hemophagocytic lymphohistiocytosis and related disorders.

Purpose Of Review: The rate of diagnosis of hemophagocytic lymphohistiocytosis, a genetically heterogeneous and, frequently, rapidly fatal autosomal recessive disorder of immune regulation, is increasing worldwide. Awareness has grown through the Histiocyte Society and the publication of newly-recognized genetic causes. I summarize current knowledge regarding the pathophysiology, diagnosis and treatment of hemophagocytic lymphohistiocytosis.

XIAP deficiency in humans causes an X-linked lymphoproliferative syndrome.

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).

Simultaneous manifestation of fulminant infectious mononucleosis with haemophagocytic syndrome and B-cell lymphoma in X-linked lymphoproliferative disease.

X-linked lymphoproliferative disease is a rare T and NK cell immune deficiency which most frequently presents as fulminant infectious mononucleosis following infection with the Epstein-Barr virus (EBV). We report the case of a 4-year-old boy from a Spanish family presenting with severe infectious mononucleosis. In the course of the disease he developed hepatic failure, pancytopenia and neurologic impairment, leading to death after less than 2 months.

Immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome (IPEX) associated with pemphigoid nodularis: a case report and review of the literature.

The immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome (IPEX) is a rare disorder caused by mutations of the FOXP3 gene. The FOXP3 gene encodes a DNA-binding protein of the forkhead/winged-helix family and is the central controller of the development of CD4+CD25+ regulatory T cells. CD4+CD25+ regulatory T cells help prevent autoimmune disease; a deficiency of these cells causes increased immunologic reactivity and autoimmunity.

[Case of X-linked lymphoproliferative syndrome (XLP) with multiple nodular lesions in the brain].

We reported a case of X-linked lymphoproliferative syndrome (XLP) with multiple nodular lesions in the brain and lungs. A 21-year-old man was admitted because of one month history of low grade fever, headache, nausea, and amnesia. He developed agammaglobulinemia following Epstein-Barr virus infection at 3-year-old, and thereafter was administered 7.

Rituximab for lymphoproliferative disease prior to haematopoietic stem cell transplantation for X-linked severe combined immunodeficiency.

Lymphoproliferative disease (LPD) is a complication of congenital and acquired immunodeficiency states. There are a number of treatment options for LPD arising after haematopoietic stem cell or solid organ transplantation including reduction of immunosuppression, targeted therapies, such as the anti-CD20 monoclonal antibody, rituximab, and EBV specific cytotoxic lymphocytes. Treatment of LPD in children with congenital immunodeficiency syndromes remains unsatisfactory and is associated with a high mortality rate.

Diffuse CNS vasculopathy with chronic Epstein-Barr virus infection in X-linked lymphoproliferative disease.

We report a patient with X-linked lymphoproliferative disease (XLP) who developed multiple central nervous system (CNS) manifestations of Epstein-Barr virus infection. XLP, or Duncan syndrome, is a rare inherited disorder characterized by the inability to clear Epstein-Barr virus infection. In addition to Epstein-Barr virus encephalitis, CNS lymphoproliferative disease, and lymphoma, this patient also developed MR angiographic evidence of diffuse fusiform aneurysmal dilation of intracranial vessels.

Treatment of HCV infection with interferon alpha-2b and ribavirin in a patient with X-linked lymphoproliferative syndrome.

Chronic hepatitis C (HCV) infection in patients with primary immunodeficiency increases the risk of an accelerated progression of HCV-related liver disease. Here, we report a patient with X-linked lymphoproliferative syndrome infected with HCV and Epstein-Barr virus (EBV). After combination treatment with interferon alpha-2b and ribavirin, clearance of HCV-RNA was achieved, and noteworthily, EBV DNA also became undetectable.

Fine-tuning of immune responses by SLAM-related receptors.

The modulation of antigen receptor signals is important for a productive immune response. The main function of the recently identified members of the signaling lymphocyte activating molecule (SLAM)-related receptors (SRR) is the fine-tuning of immune cell activation. Disruption of SRR function is the cause for severe immune disorders such as X-linked lymphoproliferative syndrome (XLP), where XLP patients carry a mutation in SLAM-associated protein (SAP) (SH2D1A), an important adaptor molecule for the signal transduction of SRR.

Familial and acquired hemophagocytic lymphohistiocytosis.

Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening condition characterized by uncontrolled hyperinflammation on the basis of various inherited or acquired immune deficiencies. Cardinal symptoms are prolonged fever, hepatosplenomegaly and cytopenias. Central nervous system (CNS) symptoms are common.

Monogenic autoimmune diseases - lessons of self-tolerance.

The molecular defects recently identified in the rare monogenic autoimmune diseases (AIDs) have pinpointed critical steps in the pathways that contribute to the development of normal immune responses and self-tolerance. Recent studies of autoimmune polyendocrinopathy syndrome type 1, autoimmune lymphoproliferative syndrome, immunodysregulation, polyendocrinopathy and enteropathy, X-linked, IL-2 receptor alpha-chain deficiency, and, in particular, their corresponding mouse models, have revealed the details of the molecular mechanisms of normal immune tolerance, and exposed how defects in these mechanisms result in human autoimmunity. In addition to a deeper understanding of the immune system, detailed molecular characterization of monogenic AIDs will help us to understand the mechanisms behind common polygenic AIDs and, furthermore, to develop novel therapies and intervention strategies to treat them.

Wiskott-Aldrich syndrome complicated by an atypical lymphoproliferative disorder: a case report.

Wiskott-Aldrich syndrome (WAS) is an X-linked syndrome consisting of eczema, recurrent pyogenic infection, and thrombocytopenia with decreased platelet volume. Immunologic studies reveal normal immunoglobulin G (IgG), decreased IgM, elevated IgA and IgE levels, and decreased T-cell function. Patients with WAS often have increased susceptibility to lymphoproliferative disorders (LPDs).

Signaling lymphocyte activation molecule-associated protein is a negative regulator of the CD8 T cell response in mice.

The primary manifestation of X-linked lymphoproliferative syndrome, caused by a dysfunctional adapter protein, signaling lymphocyte activation molecule-associated protein (SAP), is an excessive T cell response upon EBV infection. Using the SAP-/- mouse as a model system for the human disease, we compared the response of CD8+ T cells from wild-type (wt) and mutant mice to various stimuli. First, we observed that CD8+ T cells from SAP-/- mice proliferate more vigorously than those from wt mice upon CD3/CD28 cross-linking in vitro.

Epstein-Barr virus LMP1 inhibits the expression of SAP gene and upregulates Th1 cytokines in the pathogenesis of hemophagocytic syndrome.

The primary infection of Epstein-Barr virus (EBV) may result in fatal infectious mononucleosis or hemophagocytic syndrome (HPS) in 2 diseases; that is, X-linked lymphoproliferative disorder (XLP) and hemophagocytic lymphohistiocytosis (HLH). XLP is linked to mutations of the SAP/SH2D1A gene with dysregulated T-cell activation in response to EBV infection. Patients with sporadic HLH, however, usually have no mutation of the SAP/SH2D1A gene, and EBV latent membrane protein-1 (LMP1) can up-regulate Th1 cytokines in EBV-infected T cells.

The impact of telomere erosion on memory CD8+ T cells in patients with X-linked lymphoproliferative syndrome.

Patients with X-linked lymphoproliferative syndrome (XLP) experience excessive T cell proliferation after primary Epstein-Barr virus (EBV) infection, due to mutations in the signalling lymphocyte activation molecule (SLAM) associated protein (SAP) molecule. We examined the impact of dysfunctional proliferative control on the extent of CD8+ T cell differentiation in XLP patients who recovered from primary EBV infection. Although these young patients have normal numbers of lytic and latent EBV-epitope-specific CD8+ T cells, they were extremely differentiated as defined by loss of CCR7 and CD27, low telomerase activity and very short telomeres.

CD229 (Ly9) lymphocyte cell surface receptor interacts homophilically through its N-terminal domain and relocalizes to the immunological synapse.

CD229 is a member of the CD150 family of the Ig superfamily expressed on T and B cells. Receptors of this family regulate cytokine production and cytotoxicity of lymphocytes and NK cells. The cytoplasmic tail of CD229 binds to SAP, a protein that is defective in X-linked lymphoproliferative syndrome.

Identification of Grb2 as a novel binding partner of the signaling lymphocytic activation molecule-associated protein binding receptor CD229.

Ag recognition by the TCR determines the subsequent fate of the T cell and is regulated by the involvement of other cell surface molecules, termed coreceptors. CD229 is a lymphocyte cell surface molecule that belongs to the CD150 family of receptors. Upon tyrosine phosphorylation, CD229 recruits various signaling molecules to the membrane.