Disseminated BCG infection mimicking metastatic nasopharyngeal carcinoma in an immunodeficient child with a novel hypomorphic NEMO mutation.

Background: Nuclear factor-κB essential modulator (NEMO) deficiency is a developmental and immunological disorder. The genetic and phenotypic correlation has been described.

Methods: We report a unique clinical presentation and the identification of a novel missense mutation in the NEMO gene in a 3-year-old boy with bacillus Calmette-Guerin (BCG) infection.

Inflammatory polyps following successful HLA-matched cord blood transplantation in a patient with X-linked lymphoproliferative syndrome.

Gastrointestinal complications following HSCT are numerous and include a variety of issues resulting in hepatic, biliary, pancreatic, and intestinal compromise. In the context of an underlying state of immune dysregulation, novel complications may arise including autoimmunity. To our knowledge, this is the first report of a patient with XLP who was successfully treated with HSCT using an HLA-matched unrelated cord blood unit that was complicated by the development of inflammatory polyps of the colon.

Human X-linked variable immunodeficiency caused by a hypomorphic mutation in XIAP in association with a rare polymorphism in CD40LG.

The present study focuses on a large family with an X-linked immunodeficiency in which there are variable clinical and laboratory phenotypes, including recurrent viral and bacterial infections, hypogammaglobulinemia, Epstein-Barr virus-driven lymphoproliferation, splenomegaly, colitis, and liver disease. Molecular and genetic analyses revealed that affected males were carriers of a hypomorphic hemizygous mutation in XIAP (XIAP(G466X)) that cosegregated with a rare polymorphism in CD40LG (CD40 ligand(G219R)). These genes are involved in the X-linked lymphoproliferative syndrome 2 and the X-linked hyper-IgM syndrome, respectively.

X-Linked Lymphoproliferative Syndrome and Common Variable Immunodeficiency May Not Be Differentiated by SH2D1A and XIAP/BIRC4 Genes Sequence Analysis.

The X-linked lymphoproliferative syndrome (XLP) is a rare, inherited immunodeficiency characterized by recurrent episodes of hemophagocytic lymphohistiocytosis, hypogammaglobulinemia, and/or lymphomas. Recently, X-linked inhibitor of apoptosis (XIAP/BIRC4) gene defects, in families with XLP but without SH2D1A gene defects, has been defined. The distinction from primary immunodeficiencies with a defined genetic cause is mandatory.

Primary immunodeficiency diseases associated with increased susceptibility to viral infections and malignancies.

Primary immunodeficiencies (PIDs) are commonly characterized by an increased susceptibility to specific infections and, in certain instances, a higher than usual incidence of malignancies. Although improved diagnosis and early treatment of PIDs have reduced early morbidity and mortality from infection, the development of cancer remains a significant cause of premature death. The emergence of cancer in patients with PIDs often results from impairments in the immune response that lead to weakened surveillance against oncogenic viruses, premalignant or malignant cells, or both.

SLAM family receptors and SAP adaptors in immunity.

The signaling lymphocyte activation molecule (SLAM)-associated protein, SAP, was first identified as the protein affected in most cases of X-linked lymphoproliferative (XLP) syndrome, a rare genetic disorder characterized by abnormal responses to Epstein-Barr virus infection, lymphoproliferative syndromes, and dysgammaglobulinemia. SAP consists almost entirely of a single SH2 protein domain that interacts with the cytoplasmic tail of SLAM and related receptors, including 2B4, Ly108, CD84, Ly9, and potentially CRACC. SLAM family members are now recognized as important immunomodulatory receptors with roles in cytotoxicity, humoral immunity, autoimmunity, cell survival, lymphocyte development, and cell adhesion.

[Spectrum of primary immunodeficiencies in a tertiary hospital over a period of 10 years].

Introduction: More than 200 primary immunodeficiencies (PID) have been described and about 60% present during childhood. Early diagnosis and treatment have been shown to improve patient outcome.

Aim: Analysis of patients with a PID diagnosed in a paediatric tertiary care hospital-referral centre over a period of 10 years.

Clinical similarities and differences of patients with X-linked lymphoproliferative syndrome type 1 (XLP-1/SAP deficiency) versus type 2 (XLP-2/XIAP deficiency).

X-linked lymphoproliferative syndromes (XLP) are primary immunodeficiencies characterized by a particular vulnerability toward Epstein-Barr virus infection, frequently resulting in hemophagocytic lymphohistiocytosis (HLH). XLP type 1 (XLP-1) is caused by mutations in the gene SH2D1A (also named SAP), whereas mutations in the gene XIAP underlie XLP type 2 (XLP-2). Here, a comparison of the clinical phenotypes associated with XLP-1 and XLP-2 was performed in cohorts of 33 and 30 patients, respectively.

A tissue-specific, activation-inducible, lentiviral vector regulated by human CD40L proximal promoter sequences.

The application of new protocols for gene therapy against monogenic diseases requires the development of safer therapeutic vectors, particularly in the case of diseases in which expression of the mutated gene is subject to fine regulation, as it is with CD40L (CD154). CD40L, the gene mutated in the X-linked hyper-immunoglobulin M syndrome (HIGM1), is tightly regulated to allow surface expression of its product only on T cells stimulated by antigen encounter. Previous studies in an HIGM1 animal model showed that transduction of progenitor cells corrected the syndrome but caused a thymic lymphoproliferative disease because of the unregulated expression of the transgene by constitutive vectors.

X-linked lymphoproliferative syndrome: a genetic condition typified by the triad of infection, immunodeficiency and lymphoma.

X-linked lymphoproliferative disease (XLP) is an inherited immunodeficiency characterized by the clinical triad of increased susceptibility to primary Epstein-Barr virus (EBV) infection, dysgammaglobulinaemia and lymphoma. Most cases are caused by germline mutations in the SH2D1A gene, which encodes the adaptor molecule Signalling Lymphocytic Activation Molecule (SLAM)-associated protein (SAP). Recently, a subset of patients with an XLP-like phenotype was found to carry mutations in XIAP, the gene encoding the X-linked inhibitor of apoptosis protein (XIAP).

A unique clinical presentation of X-linked lymphoproliferative syndrome with a novel mutation in SH2D1A and review of the literature.

X-linked lymphoproliferative syndrome is a well-described syndrome often characterized by progression to fatal infectious mononucleosis. Many mutations of the SH2D1A gene have been identified in patients with X-linked lymphoproliferative syndrome. These mutations are often associated with either decreased or impaired function of the protein product, signaling lymphocytic activation molecule-associated protein.

Clues to immune tolerance: the monogenic autoimmune syndromes.

Autoimmune disease affects a significant proportion of the population. The etiology of most autoimmune diseases is largely unknown, but it is thought to be multifactorial with both environmental and genetic influences. Rare monogenic autoimmune diseases, however, offer an invaluable window into potential disease mechanisms.

Atypical familial hemophagocytic lymphohistiocytosis due to mutations in UNC13D and STXBP2 overlaps with primary immunodeficiency diseases.

Background: Familial hemophagocytic lymphohistiocytosis is a genetic disorder of lymphocyte cytotoxicity that usually presents in the first two years of life and has a poor prognosis unless treated by hematopoietic stem cell transplantation. Atypical courses with later onset and prolonged survival have been described, but no detailed analysis of immunological parameters associated with typical versus atypical forms of familial hemophagocytic lymphohistiocytosis has been performed.

Design And Methods: We analyzed disease manifestations, NK-cell and T-cell cytotoxicity and degranulation, markers of T-cell activation and B-cell differentiation as well as Natural Killer T cells in 8 patients with atypical familial hemophagocytic lymphohistiocytosis due to mutations in UNC13D and STXBP2.

X-linked lymphoproliferative syndromes: brothers or distant cousins?

X-linked lymphoproliferative disease (XLP1), described in the mid-1970s and molecularly defined in 1998, and XLP2, reported in 2006, are prematurely lethal genetic immunodeficiencies that share susceptibility to overwhelming inflammatory responses to certain infectious triggers. Signaling lymphocytic activation molecule-associated protein (SAP; encoded by SH2D1A) is mutated in XLP1, and X-linked inhibitor of apoptosis (XIAP; encoded by BIRC4) is mutated in XLP2. XLP1 is a disease with multiple and variable clinical consequences, including fatal hemophagocytic lymphohistiocytosis (HLH) triggered predominantly by Epstein-Barr virus, lymphomas, antibody deficiency, and rarer consequences of immune dysregulation.

Early and rapid detection of X-linked lymphoproliferative syndrome with SH2D1A mutations by flow cytometry.

Background: X-linked lymphoproliferative syndrome (XLP) is a rare immunodeficiency with extreme vulnerability to Epstein-Barr virus (EBV) infection. It presents with fatal infectious mononucleosis, lymphoproliferative disorder, or dysgammaglobulinemia. The majority of affected males have mutations in the SH2D1A/SLAM-associated protein (SAP) gene.

X-linked lymphoproliferative disease presenting as pancytopenia in a 10-month-old boy.

X-linked lymphoproliferative disease, also known as Duncan's syndrome, is a rare genetic disorder that causes exaggerated immune responses to Epstein-Barr virus (EBV) infection and often leads to death. Patient presentation varies but can include signs and symptoms typical of EBV, pancytopenia, and fulminant hepatitis.

Adult-onset presentations of genetic immunodeficiencies: genes can throw slow curves.

Purpose Of Review: The molecular and genetic mechanisms behind adult presentations of primary immunodeficiency diseases are examined, with particular emphasis on cases where this was heralded by severe, recurrent, or opportunistic infection.

Recent Findings: A detailed analysis over the last two decades of the relationship between genotype and clinical phenotype for a number of genetic immunodeficiencies has revealed multiple mechanisms that can account for the delayed presentation of genetic disorders that typically present in childhood, including hypomorphic gene mutations and X-linked gene mutations with age-related skewing in random X-chromosome inactivation. Adult-onset presentations of chronic granulomatous disease, X-linked agammaglobulinemia, IL-12/Th1/IFN-gamma and IL-23/Th17/IL-17 pathway defects, and X-linked lymphoproliferative disorder are used to illustrate these mechanisms.

Clinical aspects and genetic analysis of taiwanese patients with wiskott-Aldrich syndrome protein mutation: the first identification of x-linked thrombocytopenia in the chinese with novel mutations.

Background: Wiskott-Aldrich syndrome (WAS) is an X-linked immunodeficiency characterized by microthrombocytopenia, eczema, and recurrent infections. However, the more than 500 patient mutations described are mainly based on Caucasian and Japanese populations. This study investigated Taiwanese patients with WASP mutations since 1985 as part of a long-term comprehensive study in primary immunodeficiency diseases (PIDs) covering 23 million inhabitants.

The apoptosis modulating role of SAP (SLAM associated protein) contributes to the symptomatology of the X linked lymphoproliferative disease.

Deletion or mutation of the SH2D1A gene located at Xq25 is responsible for the development of the X-linked lymphoproliferative disease, XLP. Primary infection of the affected individuals with EBV leads to fulminant and often fatal infectious mononucleosis, FIM. Moreover, they run a 200 fold elevated risk for lymphoma development.

Phenotypic differences between mice deficient in XIAP and SAP, two factors targeted in X-linked lymphoproliferative syndrome (XLP).

Mutations in the X-linked inhibitor of apoptosis (XIAP) have recently been identified in patients with the rare genetic disease, X-linked lymphoproliferative syndrome (XLP), which was previously thought to be solely attributable to mutations in a distinct gene, SAP. To further understand the roles of these two factors in the pathogenesis of XLP, we have compared mice deficient in Xiap with known phenotypes of Sap-null mice. We show here that in contrast to Sap-deficient mice, animals lacking Xiap have apparently normal NKT cell development and no apparent defect in humoral responses to T cell-dependent antigens.

Girls homozygous for an IL-2-inducible T cell kinase mutation that leads to protein deficiency develop fatal EBV-associated lymphoproliferation.

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.

Monogenic autoimmune diseases: insights into self-tolerance.

Autoimmune diseases affect a significant segment of the population and are typically thought to be multifactorial in etiology. Autoimmune diseases due to single gene defects are rare, but offer an invaluable window into understanding how defects in the immune system can lead to autoimmunity. In this review, we will focus on autoimmune polyendocrinopathy syndrome type 1 and recent advances in our understanding of this disease.

SAP binds to CD22 and regulates B cell inhibitory signaling and calcium flux.

The signaling lymphocyte activation molecule (SLAM)-associated protein (SAP or SH2D1A) is an important regulator of immune function which, when mutated or deleted, causes the X-linked lymphoproliferative syndrome (XLP). Because B cell lymphoma is a major phenotype of XLP, it is important to understand the function of SAP in B cells. Here we report that SAP is expressed endogenously in mouse splenic B cells, is inducibly expressed in the human BJAB cells, and co-localizes and interacts with CD22.

The importance of epigenetic alterations in the development of epstein-barr virus-related lymphomas.

Epstein-Barr virus (EBV), a human gammaherpesvirus, is associated with a series of malignant tumors. These include lymphomas (Burkitt's lymphoma, Hodgkin's disease, T/NK-cell lymphoma, post-transplant lymphoproliferative disease, AIDS-associated lymphoma, X-linked lymphoproliferative syndrome), carcinomas (nasopharyngeal carcinoma, gastric carcinoma, carcinomas of major salivary glands, thymic carcinoma, mammary carcinoma) and a sarcoma (leiomyosarcoma). The latent EBV genomes persist in the tumor cells as circular episomes, co-replicating with the cellular DNA once per cell cycle.

SLAM receptors and SAP influence lymphocyte interactions, development and function.

Mutations that affect the adaptor molecule SLAM-associated protein (SAP) underlie the primary immunodeficiency disease X-linked lymphoproliferative syndrome. SAP is required for mediating signals from members of the signalling lymphocytic activation molecule (SLAM) family of immunomodulatory receptors. Recent data have highlighted a role for SAP in the development of innate-like T-cell lineages, including natural killer T cells, and in the regulation of the interactions between B cells and T cells that are required for germinal-centre formation and long-term humoral immunity.