Cellular and molecular pathogenesis of X-linked lymphoproliferative disease

In the past few years important advances have been made in the understanding of the molecular mechanisms leading to X-linked lymphoproliferative disease (XLP). It has been possible to identify the gene defective in XLP and to demonstrate that, in normal individuals, it encodes the Src homology 2 domain-containing protein 1 A (SH2D1A) that plays a crucial role in signaling via a number of surface molecules expressed by cells of the immune system. At present a variety of mutations have been identified that result in lack of defective SH2D1A molecules. Importantly, it has recently been demonstrated that lack of SH2D1A affects the function of surface molecules that are involved in the mechanism of natural killer-mediated recognition and killing of Epstein-Barr virus-infected B cells.     

Molecular and immunological basis of X-linked lymphoproliferative disease

Summary: X‐linked lymphoproliferative (XLP) disease is a human immune dysfunction characterized primarily by an inappropriate response to Epstein–Barr virus infection. In 1998, it was discovered that XLP is caused by inactivating mutations in the SAP/SH2D1A/DSHP gene. This gene codes for an immune cell‐specific polypeptide termed SAP (SLAM‐associated protein) that is composed almost exclusively of an Src homology 2 (SH2) domain. By way of its SH2 domain, SAP interacts with tyrosine‐based motifs located in the cytoplasmic region of members of the SLAM (signaling lymphocyte activation molecule) family of receptors. Recent findings indicate that SAP is required for the function of SLAM‐related receptors, as a consequence of its capacity to promote the recruitment and activation of the Src‐related protein tyrosine kinase FynT, thereby allowing SLAM receptor‐mediated protein tyrosine phosphorylation signals in immune cells. Functional and genetic analyses suggest that the phenotype associated with XLP is caused in large part by defects in the functions of SLAM‐related receptors due to SAP deficiency.     

X-linked lymphoproliferative disease: genetics and biochemistry

Primary immunodeficiencies comprise a broad group of disorders due to germline mutations in genes regulating lymphocyte development and function. One of these genes, DSHP (also known as SH2D1A, SAP), is mutated in X-linked lymphoproliferative syndrome (XLP), an inherited immunodeficiency characterized by increased susceptibility to primary Epstein-Barr virus (EBV) infection, hypogammaglobulinenia, and lymphoma. Expressed primarily in T and NK cells, DSHP consists of a single SH2 domain and short carboxyl-terminal tail. The presence of a single SH2 domain, without other functional motifs, suggests that DSHP may be a physiologic competitor of other SH2 domain-containing proteins whose binding to phosphotyrosine controls lymphocyte activation and/or function. DSHP binds to the cytoplasmic domains of CDw150 (Signaling Lymphocyte Activation Molecule, SLAM) and 2B4, and may regulate signals transmitted by these receptors in T and NK cells, respectively. Unlike other SH2 domain-containing proteins, DSHP associates with both phosphorylated and non-phosphorylated tyrosine residues, and crystallography studies have revealed novel properties of the DSHP SH2 domain. Future studies exploring the function of DSHP during lymphocyte proliferation and activation should improve our ability to diagnose and treat XLP and possibly other human diseases associated with EBV.     

First prenatal diagnosis of X-linked lymphoproliferative disease

A family study was performed in order to diagnose X-linked lymphoproliferative (XLP) disease in a fetus. The molecular genetic analysis indicated that the fetus, as well as its healthy 7-year-old brother, inherited XLP. Analysis of immunoglobulin subclasses from the 7-year-old brother supported the DNA-based diagnosis. This is the first XLP family of African descent. © 1992 Wiley-Liss, Inc.     

Differential cellular susceptibility to Epstein-Barr virus infection in a patient with X-linked lymphoproliferative disease

Epstein-Barr virus (EBV) is often associated with lethal lymphoproliferative diseases in immunologically compromised individuals. Recently, we have studied a 20-month-old boy with X-linked lymphoproliferative disease (XLP) who had succumbed to infectious mononucleosis (IM) complicated by fulminant hepatitis and virus-associated hemophagocytic syndrome following EBV infection. EBV genomes were detected in peripheral blood lymphocytes (PBL), cervical and mesenteric lymph nodes, liver, spleen, thymus, and bone marrow. According to restriction endonuclease analyses, the EBV-DNA pattern was similar in all samples except for the EBV-DNA from the bone marrow. Additionally, circular EBV-DNA (suggesting a latent infection) predominated in spontaneously established lymphoblastoid cell lines (LCLs) derived from both the lymph node and cord lymphocytes co-cultured with PBL. In contrast, both circular and linear EBV-DNA (suggesting a lytic infection) were noted in spontaneously established LCLs derived from his PBL. Furthermore, LCLs derived from both the lymph node and cord lymphocytes co-cultured with PBL expressed fewer reactive cells for early antigen (EA) and viral capsid antigen (VCA) than spontaneous LCLs from his PBL, thus providing evidence for different B cellular susceptibility to EBV infection in this patient with XLP. Finally, defective EBV-specific cytotoxic T cell activity was observed in this patient. Latent EBV infected cells may easily escape immunosurveillance by the host. These findings may explain the fatal course of EBV infection in this patient.     

First prenatal diagnosis of X-linked lymphoproliferative disease.

A family study was performed in order to diagnose X-linked lymphoproliferative (XLP) disease in a fetus. The molecular genetic analysis indicated that the fetus, as well as its healthy 7-year-old brother, inherited XLP. Analysis of immunoglobulin subclasses from the 7-year-old brother supported the DNA-based diagnosis. This is the first XLP family of African descent.     

X-linked lymphoproliferative disease: three atypical cases.

Common variable immunodeficiency (CVID) is the most frequently occurring primary immunodeficiency in both children and adults. The molecular basis of CVID has not been defined, and diagnosis involves exclusion of other molecularly defined disorders. X-linked lymphoproliferative disease (XLP) is a rare disorder in which severe immunodysregulatory phenomena typically follow Epstein-Barr virus (EBV) infection. Boys who survive initial EBV infection have a high incidence of severe complications, including progressive immunodeficiency, aplastic anaemia, lymphoproliferative disease and lymphoma. Survival beyond the second decade is unusual, although bone marrow transplantation can be curative. Until recently reliable diagnostic testing for XLP has not been available, but the identification of the XLP gene, known as SH2D1A, and coding for a protein known as SAP, means that molecular diagnosis is now possible, both by protein expression assays, and mutation detection, although the mutation detection rate in several series is only 55-60%. We describe three male patients initially diagnosed as affected by CVID, one of whom developed fatal complications suggestive of XLP, and all of whom lack expression of SAP. Two out of three have disease-causing mutations in the SAP gene, consistent with published data for XLP. These findings raise the possibility that a subgroup of patients with CVID may be phenotypic variants of XLP. Further studies are necessary to investigate this possibility, and also to clarify the prognostic significance of SAP abnormalities in such patients in the absence of typical features of XLP.     

X-linked lymphoproliferative disease: linkage studies using DNA probes

Linkage studies have been carried out with 28 X-linked polymorphic probes to try to locate the gene for X-linked lymphoproliferative disease (XLP). DNA from three families has been analysed, including three affected boys among 21 family members. None of the probes tested has been found to be linked to XLP. However, the data are recorded for the use of other workers on this rare disease.     

X-linked lymphoproliferative disease: prenatal detection of an unaffected histocompatible male

Chorionic Villous Biopsy (CVS) for diagnosis of XLP was undertaken at 10 weeks gestation in an obligate carrier. The fetus was found to be male by cytogenetic analysis. XLP (Xq25-q26) is closely linked to the RFLP markers DXS10, DXS37 and DXS42, but only DXS10 (distal to XLP) was informative for prenatal diagnosis in this family. RFLP analysis using this marker gave a 7% risk that the fetus was affected, based on the known recombination frequency between DXS10 and XLP. Further investigation was then undertaken to obtain a rapid and more accurate diagnosis using the three highly polymorphic PCR based markers. These were the AC repeat markers DXS424 (XL5A) and DXS425 (XL90A3) and the tetramer repeat marker within HPRT. DX425 is approximately 10 cM proximal to DXS10 and HPRT but is not known with certainty to map proximal or distal to XLP. DXS424 is proximal to DXS10 and HPRT and was inferred to be proximal to XLP on the basis of map distance from HPRT estimated by linkage analysis of data from CEPH pedigrees. This was confirmed by a recombinant in the XLP family between DXS424 and DXS425, placing DXS424 proximal to XLP. Diagnosis by linkage using DXS424 and DXS425, at least one of which is proximal to XLP, and distal markers DXS10 and HPRT, increased the accuracy of diagnosis using flanking marker analysis to greater than 99% that the fetus was unaffected. HLA DR typing of the CVS showed that the fetus was DR identical to a male sibling with XLP. HLA compatibility was confirmed at delivery by full HLA typing and MLC.(ABSTRACT TRUNCATED AT 250 WORDS)     

Methods of detection of new families with X-linked lymphoproliferative disease.

During the past decade, 240 males with X-linked lymphoproliferative disease (XLP) within 59 unrelated kindreds have been identified worldwide. One half of the patients have developed fatal infections mononucleosis, about one third have acquired hypogammaglobulinemia, and another one fourth have developed malignant lymphoma. Less commonly occurring phenotypes include hyperimmunoglobulinemia M, bone marrow hypoplasia, and necrotizing lymphoid vasculitis. The fatal infectious mononucleosis phenotype occurs at about 2.5 years of age, and median survival is only 33 days following onset of illness. The acquired hypogammaglobulinemia and malignant lymphoma phenotypes are associated with longer survivals, but to date no patient has been documented as living into the fifth decade of life. We summarized recent research findings and technological advances that permit accurate diagnosis of carrier females and detection of males with the XLP gene before Epstein-Barr virus infection.     

Diagnosis of X-linked lymphoproliferative disease by analysis of SLAM-associated protein expression

X-linked lymphoproliferative disease (XLP) is an inherited immunodeficiency in which affected boys show abnormal responses to Epstein-Barr virus infection. The gene defective in XLP has been identified and designated SH2D1A and encodes a protein termed SLAM-associated protein (SAP). Mutation analysis in individuals with typical XLP presentations and family histories has only detected abnormalities in approximately 60% of patients. Thus, genetic analysis alone cannot confirm a diagnosis of XLP We have developed a SAP expression assay that can be used as a diagnostic indicator of XLP We show that SAP is constitutively expressed in normal individuals, in patients with severe sepsis and in patients with other primary immunodeficiencies. In six XLP patients, four with classical and two with atypical presentations, SAP expression was absent. In the latter two, who were previously assigned as having common variable immunodeficiency (CVID), the diagnosis of XLP was initially made using the protein expression assay. In two further patients in whom no mutation could be detected by genetic analysis, lack of SAP expression strongly suggests that these individuals have XLP. We therefore suggest that XLP should be suspected in certain boys previously diagnosed as having CVID and recommend that patients are investigated both by genetic analysis of SH2D1A and by expression of SAP protein.     

Molecular pathogenesis of Parkinson's disease

Parkinson's disease (PD) is a common and incurable neurodegenerative disease, affecting 1% of the population over the age of 65. Despite a well-described clinical and pathological phenotype, the molecular mechanisms which lead to neurodegeneration remain elusive. However, there is a wealth of evidence from both toxin based models and genetic based models, which suggest a major etiologic role for mitochondrial dysfunction, protein aggregation, the ubiquitin-proteasome system and kinase signalling pathways in the pathogenesis of PD. Ultimately, an understanding of the molecular events which precipitate neurodegeneration in idiopathic PD will enable the development of targeted and effective therapeutic strategies. We review the latest evidence for the proposed molecular processes and discuss their relevance to the pathogenesis of sporadic PD.     

Chromosome deletion of Xq25 in an individual with X-linked lymphoproliferative disease

High resolution chromosome analysis was done on lymphoblastoid cell lines, established during the past decade from affected males with X-linked lymphoproliferative disease (XLP) or from obligate female carriers, from 14 families. One cell line, from a male with XLP, has a partial deletion of band Xq25. The constitutional nature of the deletion is confirmed in chromosome studies of peripheral blood from the affected individual and represents the first such structural defect to be described in this disorder. Cell lines from the remaining 13 families do not have cytogenetically detectable deletions. This observation will facilitate precise localization, cloning and sequencing of the gene causing XLP.     

Natural killer T cells and X-linked lymphoproliferative syndrome

PURPOSE OF REVIEW: Recent progress in elucidating the physiopathology of X-linked lymphoproliferative syndrome (XLP) has raised novel and important issues regarding the biology of natural killer T cells. Here I will review this information and discuss the issues involved. RECENT FINDINGS: XLP is a rare inherited immunodeficiency characterized by a high susceptibility to severe infection by the Epstein-Barr virus. Mutations in the gene SH2D1A (or alternatively SAP) underlie 80% of familial XLP (XLP-1) cases. Recently the remaining 20% of familial XLP (XLP-2) cases were shown to harbor mutations in the gene XIAP (X-linked inhibitor of apoptosis protein). Both SAP and XIAP deficiencies are associated with a defect in the development and/or homeostasis of natural killer T cells. SUMMARY: It can be hypothesized that the susceptibility to Epstein-Barr virus in XLP might result from the defect of natural killer T cells. The role of these cells in viral infection is unclear, but several herpes viruses have developed strategies to escape natural killer T cells. The discovery that SAP and XIAP deficiency leads to a defect in natural killer T cells has also shed light on novel signaling pathways required for natural killer T cell development and/or homeostasis.