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X-Linked Lymphoproliferative Disease Type 1: A Clinical and Molecular Perspective.

ABSTRACT: X-linked lymphoproliferative disease (XLP) was first described in the 1970s as a fatal lymphoproliferative syndrome associated with infection with Epstein-Barr virus (EBV). Features include hemophagocytic lymphohistiocytosis (HLH), lymphomas, and dysgammaglobulinemias. Molecular cloning of the causative gene, SH2D1A, has provided insight into the nature of disease, as well as helped characterize multiple features of normal immune cell function. Although XLP type 1 (XLP1) provides an example of a primary immunodeficiency in which patients have problems clearing primarily one infectious agent, it is clear that XLP1 is also a disease of severe immune dysregulation, even independent of EBV infection. Here, we describe clinical features of XLP1, how molecular and biological studies of the gene product, SAP, and the associated signaling lymphocyte activation molecule family receptors have provided insight into disease pathogenesis including specific immune cell defects, and current therapeutic approaches including the potential use of gene therapy. Together, these studies have helped change the outcome of this once almost uniformly fatal disease.

SUBMITTER: Panchal N

PROVIDER: S-EPMC5893764 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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X-Linked Lymphoproliferative Disease Type 1: A Clinical and Molecular Perspective.

Panchal Neelam N Booth Claire C Cannons Jennifer L JL Schwartzberg Pamela L PL

Frontiers in immunology 20180404

X-linked lymphoproliferative disease (XLP) was first described in the 1970s as a fatal lymphoproliferative syndrome associated with infection with Epstein-Barr virus (EBV). Features include hemophagocytic lymphohistiocytosis (HLH), lymphomas, and dysgammaglobulinemias. Molecular cloning of the causative gene, <i>SH2D1A</i>, has provided insight into the nature of disease, as well as helped characterize multiple features of normal immune cell function. Although XLP type 1 (XLP1) provides an examp ...[more]

PMID: 29670631

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Project description:BackgroundX-linked lymphoproliferative disease (XLP) is a primary immunodeficiency presenting with a variety of clinical manifestations, the most common being dysgammaglobulinemia and B-cell lymphoma. The first gene causing XLP, when defective, was termed SH2D1A or SAP for signaling lymphocyte activation molecule (SLAM)-associated protein. The absence of SH2D1A leads to an overwhelming and uncontrolled TH1- shifted cytotoxic immune response, which might, at least in part, explain the severe clinical picture. A second gene, XIAP (X-linked inhibitor of apoptosis), was later identified.MethodsAn 8 year old Mexican boy was admitted in June 2008 for bronchopneumonia, with no previous history of recurrent or severe infections. He had a family history of a brother deceased at 7 years from fulminate hepatitis, who was diagnosed with agammaglobulinemia. A laboratory evaluation for primary immunodeficiency was made, including serum immunoglobulins: IgG 30 mg/dL, IgA <5 mg/dL IgM 8.6 mg/dL; and flow citometry for lymphocyte subpopulations: CD3+ 2590 mm3 (56%) CD4+ 1004 mm3 (42%), CD8+ 1267 mm3(53%) CD16/56 171mm3 (41%) CD19+ 1493 mm3 (35%). The patient was started on monthly intravenous gammaglobulin (IVIG) therapy. He was admitted in December 2008 with fever and severe abdominal pain; an exploratory laparotomy revealed a rectal-sigmoid tumor. The biopsy reported an atypical Burkitt lymphoma (Immunophenotype “B”: Bcl 2+, CD10+) with surgical margins negative for malignancy. Bone marrow aspirate and biopsy were negative for malignancy. In February 2009, management with chemotherapy was started with the diagnosis of Burkitt's lymphoma stage III. Patient received 6 courses of chemotherapy with complete response to induction; for consolidation, 4 doses of rituximab were given. PCR amplification and direct automated sequencing by the Sanger method was performed in both genes known to be responsible for XLP in chromosome X.ResultsA hemizygous splice-site deletion in SAP was found, in intron 2: c.187_201+10del25, which deletes exon 2 splice donor site, and is predicted to result in the skipping of exon 2, and thus in a truncated, nonfunctional protein. XIAP was also sequenced and no mutation was found.ConclusionsFinal diagnosis: XLP.The patient is currently in the program for hematopoietic stem-cell transplantation.

Project description:X-linked lymphoproliferative syndrome (XLP) is a rare primary immunodeficiency disease that can be divided into two types: SAP deficiency (XLP1) and XIAP deficiency (XLP2), caused by mutations in the SH2D1A and XIAP genes, respectively. Few cases of XLP (particularly XIAP deficiency) have been reported in mainland China; hence, little is known about the characteristics of Chinese patients with XLP. We identified 13 and 7 patients with SAP and XIAP deficiency, respectively, in our center. Of our 20 patients, 19/20 (95%) presented with disease symptoms at a very early age: six in infancy and 13 in childhood. One XIAP- and three SAP-deficient patients died, while 3/7(42.9%) and 4/13(30.8%), respectively, developed hemophagocytic lymphohistiocytosis (HLH). Epstein-Barr virus (EBV) infection was significantly more common in SAP-deficient 10/13 (76.9%) than XIAP-deficient 2/7 (28.6%) patients, as was hypogammaglobulinemia (10/13 (76.9%) vs. 1/7 (14.3%)). None of the seven XIAP-deficient patients had colitis or lymphoma. Nine SAP-deficient patients and five XIAP-deficient patients showed markedly deficient SAP and XIAP expression, respectively, in lymphocytes. Significantly reduced levels of switched memory B cells were observed in six SAP-deficient patients with persistent hypogammaglobulinemia. One of 13 (7.7%) SAP-deficient patients and 1 of 7 (12.3%) XIAP-deficient patients have received HSCT treatment and are now alive and well; the other alive patients were waiting for HSCT. We also summarized clinical, genetic, and immunological characteristics of all 55 patients (including our 20 patients) reported in the literature in mainland China today.Conclusion: The overall characteristics of SAP deficiency in mainland China were consistent with those in previous reports, whereas manifestations of XIAP deficiency varied significantly. None of inflammatory bowel disease (IBD) has been reported among XIAP-deficient patients in our center; however, whether Chinese XIAP-deficient patients will develop colitis in the future warrants further investigation. HSCT is the only curative therapy for XLP and this therapy should be urgently considered.What is Known:• SAP and XIAP deficiencies share common clinical feature, HLH, whereas they also have their own specific manifestations.• IBD affects 25-30% of XIAP-deficient patients, which has been reported in other countries especially in European country and Japan.What is New:• This is the largest patient cohort study of XLP in China.• We firstly summarized the clinical features and outcomes of Chinese XIAP-deficient patients and found only 1 in 22 patients developed IBD and diet background may contribute to it; Asian SAP-deficient patients carrying SH2D1A R55X mutation were more prone to HLH.

Dataset Information

X-Linked Lymphoproliferative Disease Type 1: A Clinical and Molecular Perspective.

Publications

X-Linked Lymphoproliferative Disease Type 1: A Clinical and Molecular Perspective.

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