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Premature terminal differentiation protects from deregulated lymphocyte activation by ITK-Syk.

The development of hematopoietic neoplasms is often associated with mutations, altered gene expression or chromosomal translocations. Recently, the t(5, 9)(q33;q22) translocation was found in a subset of peripheral T cell lymphomas and was shown to result in an IL-2-inducible kinase-spleen tyrosine kinase (ITK-Syk) fusion transcript. In this study, we show that T cell-specific expression of the ITK-Syk oncogene in mice leads to an early onset and aggressive polyclonal T cell lymphoproliferation with concomitant B cell expansion and systemic inflammation by 7-9 wk of age. Because this phenotype

Terminal deoxynucleotidyl transferase deficiency decreases autoimmune disease in MRL-Fas(lpr) mice.

The neonatal Ab and TCR repertoires are much less diverse, and also very different from, the adult repertoires due to the delayed onset of terminal deoxynucleotidyl transferase (TdT) expression in ontogeny. TdT adds nontemplated N nucleotides to the junctions of Igs and TCRs, and thus its absence removes one of the major components of junctional diversity in complementarity-determining region 3 (CDR3). We have generated TdT-deficient MRL/lpr, Fas-deficient (MRL-Fas(lpr)) mice, and show that they have an increased lifespan, decreased incidence of skin lesions, and much lower serum levels of ant

Novel mode of ligand binding by the SH2 domain of the human XLP disease gene product SAP/SH2D1A.

BACKGROUND: The Src homology 2 (SH2) domains of cytoplasmic signaling proteins generally bind phosphotyrosine (pTyr) sites in the context of carboxy-terminal residues. SAP (also known as SH2D1A or DSHP), the product of the gene that is mutated in human X-linked lymphoproliferative (XLP) disease, comprises almost exclusively a single SH2 domain, which may modulate T-cell signaling by engaging T-cell co-activators such as SLAM, thereby blocking binding of other signaling proteins that contain SH2 domains. The SAP-SLAM interaction can occur in a phosphorylation-independent manner. RESULTS: To ch

The human T-cell leukemias: clinical, cytomorphologic, immunophenotypic, and genotypic characteristics.

The distribution of the conventional lymphoid cell markers on T lymphocytes and the principal panels of monoclonal antibodies used to recognize distinctive T-lymphocyte-associated differentiation antigens are discussed. These reagents have been used to probe the early and late stages of T-cell differentiation, and a hypothetical schema of T-cell differentiation has been constructed. Application of these reagents to the investigation of neoplastic T cells has resulted in the determination of the subset of origin and the stage of differentiation of the neoplastic cells in T-cell-derived lymphopr

A case of hepatosplenic gamma-delta T-cell lymphoma with a transient response to fludarabine and alemtuzumab.

Hepatosplenic gamma-delta T-cell lymphoma is a rare, usually fatal lymphoma and available literature on management is sparse. Allografting is probably the only curative option. We describe a further case with a dramatic, though transient response to Fludarabine and Alemtuzumab combination, following a failure of conventional chemotherapy. Given the dreadful prognosis with conventional chemotherapy, it is a regimen worth pursuing as a disease reduction strategy prior to allograft where appropriate.

Genetic and epigenetic silencing of microRNA-203 enhances ABL1 and BCR-ABL1 oncogene expression.

The mammalian genome contains several hundred microRNAs that regulate gene expression through modulation of target mRNAs. Here, we report a fragile chromosomal region lost in specific hematopoietic malignancies. This 7 Mb region encodes about 12% of all genomic microRNAs, including miR-203. This microRNA is additionally hypermethylated in several hematopoietic tumors, including chronic myelogenous leukemias and some acute lymphoblastic leukemias. A putative miR-203 target, ABL1, is specifically activated in these hematopoietic malignancies in some cases as a BCR-ABL1 fusion protein (Philadelph

CD19 signaling pathways play a major role for murine AIDS induction and progression.

Infection of genetically susceptible mice with the LP-BM5 mixture of murine leukemia viruses including an etiologic defective virus (BM5def) causes an immunodeficiency syndrome called murine AIDS (MAIDS). The disease is characterized by interactions between B cells and CD4(+) T cells resulting in polyclonal activation of both cell types. It is known that BM5def is expressed at highest levels in B cells and that B cells serve as viral APC. The CD19-CD21 complex and CD22 on the surface of B cells play critical roles as regulators of B cell responses to a variety of stimuli, influencing cell acti

Gender and androgen treatment influence the expression of proto-oncogenes and apoptotic factors in lacrimal and salivary tissues of MRL/lpr mice.

The objectives of this study were to (1) determine whether Fas antigen, Fas ligand, p53, and proto-oncogene mRNAs may be detected in lacrimal and submandibular glands of the MRL/lpr mouse model of Sjögren's syndrome, and (2) examine whether gender and androgen or cyclophosphamide therapy influence the mRNA expression of these apoptotic factors. Tissues were obtained from treated or untreated MRL/lpr mice after the onset of disease and processed for the analysis of mRNAs by RT-PCR and Southern blot hybridization. Our results demonstrated that (1) Fas antigen (exons 1-->2 or 3-->7+), Fas ligand,

Cbl-b is a negative regulator of receptor clustering and raft aggregation in T cells.

Stimulation of T cells via the antigen and costimulatory receptors leads to the organization of a supramolecular activation cluster called the immune synapse. We report that loss of the molecular adaptor Cbl-b in T cells frees antigen receptor-triggered receptor clustering, lipid raft aggregation, and sustained tyrosine phosphorylation from the requirement for CD28 costimulation. Introduction of the cbl-b mutation into a vav1-/- background relieved the functional defects of vav1-/- T cells and caused spontaneous autoimmunity. Wiscott Aldrich Syndrome protein (WASP) was found to be essential fo

Interferon alfa-2b in patients with low-grade lymphomatoid granulomatosis and chemotherapy with DA-EPOCH-R in patients with high-grade lymphomatoid granulomatosis: an open-label, single-centre, phase 2 trial.

BACKGROUND: Lymphomatoid granulomatosis is a rare Epstein-Barr virus-associated B-cell lymphoproliferative disorder with a median overall survival of less than 2 years. In this study, we hypothesised that low-grade lymphomatoid granulomatosis is immune-dependent and high-grade lymphomatoid granulomatosis is immune-independent. On the basis of this hypothesis, we investigated the activity and safety of new treatment with immunotherapy in patients with low-grade disease and standard chemotherapy in patients with high-grade disease. METHODS: In this open-label, single-centre, phase 2 trial, we e

Preimplantation maternal stress impairs embryo development by inducing oviductal apoptosis with activation of the Fas system.

STUDY QUESTION: What are the mechanisms by which the preimplantation restraint stress (PIRS) impairs embryo development and pregnancy outcome? SUMMARY ANSWER: PIRS impairs embryo development by triggering apoptosis in mouse oviducts and embryos,and this involves activation of the Fas system. WHAT IS KNOWN ALREADY: Although it is known that the early stages of pregnancy are more vulnerable than later stages to prenatalstress, studies on the effect of preimplantation stress on embryo developmentare limited. Furthermore, the mechanisms by which psychological stress impairs embryo development ar

Inborn Errors of Immunity and Cancer.

Inborn Errors of Immunity (IEI) are a heterogeneous group of disorders characterized by a defect in the function of at least one, and often more, components of the immune system. The aim of this narrative review is to discuss the epidemiology, the pathogenesis and the correct management of tumours in patients with IEI. PubMed was used to search for all of the studies published over the last 20 years using the keywords: "inborn errors of immunity" or "primary immunodeficiency" and "cancer" or "tumour" or "malignancy". Literature analysis showed that the overall risk for cancer in children with

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… According to the ICR data, EBV is found in 30–60% of patients with lymphoproliferative disorders and IEI [ 29 ]. … The role of EBV has been hypothesized for many different B cell lymphoproliferative disorders (BLPDs) in patients with IEI, including virus-associated haemophagocytic syndrome, Burkitt’s lymphoma, classic Hodgkin’s lymphoma, posttransplant lymphoproliferative disorders (PTLDs) and HIV-associated lymphoproliferative …

Clinical Presentation, Renal Histopathological Findings, and Outcome in Patients with Monoclonal Gammopathy and Kidney Disease.

Monoclonal gammopathies are associated with acute and chronic kidney injury. Nephrotoxicity of the secreted monoclonal (M)-protein is related to its biological properties and blood concentration. Little is known about epidemiology, clinical manifestations, and outcome of monoclonal gammopathies in patients with kidney disease. We retrospectively collected data about demographics, clinical manifestations, and renal histological lesions of all patients (n = 1334) who underwent kidney biopsy between January 2000 and March 2017. Monoclonal gammopathy was detected in 174 (13%) patients with a mean

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… Logistic regression analysis was done to compute odds ratios (OR), 95% confidence intervals (95% CI), and P values of lymphoproliferative disorders in predicting direct kidney injury. … Non-Hodgkin's Lymphoma Twelve patients (6.8%) with monoclonal gammopathy had a diagnosis of NHL, whose term includes several heterogeneous lymphoproliferative disorders. …

Tabelecleucel in Post-transplant Epstein-Barr Virus-Associated Lymphoproliferative Disease: Patient and Oncologist Perspectives.

This article is coauthored by the parents of a young patient and the medical team who cared for her.Together, they recount their shared experience with tabelecleucel, a novel therapy for Epstein-Barr virus-associated post-transplant lymphoproliferative disease (EBV + PTLD). The patient's parents offer a deeply personal perspective, reflecting on several years of struggle marked by unwavering hope and trust in the medical professionals who have supported their daughter throughout her journey. The pediatric hemato-oncologist who advocated for the use of tabelecleucel described the case as unique

Intestinal/Multivisceral Transplantation

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… Epstein-Barr Virus and Posttransplant Lymphoproliferative Disorders Epstein-Barr virus (EBV) is a herpes virus that can infect several cell lines including lymphocytes and has been associated with different malignancies, including posttransplant lymphoproliferative disorders (PTLD), a group of heterogeneous … Frey NV The management of posttransplant lymphoproliferative disorder Med Oncol 2007 24 2 125 36 17848735 10.1007/BF02698031 134. …

Ureteral Involvement in Non-Hodgkin Lymphoma: A Rare Case Report With Diagnostic Challenges.

Ureteral involvement by diffuse large B-cell lymphoma (DLBCL) is an extremely rare clinical entity that can mimic primary urothelial carcinoma and pose a significant diagnostic challenge. A 70-year-old female patient initially presented to a urologist with renal colic. The patient denied fever, night sweats, unintentional weight loss, or prior hematologic disorders, and no peripheral lymphadenopathy was detected on physical examination. Multislice computed tomography (MSCT) revealed a ureteral mass, followed by cystoscopy with ureteral stent placement. Due to the strong clinical and radiologic

Diagnosis and management of monoclonal gammopathy of clinical significance.

The term "monoclonal gammopathy of clinical significance" (MGCS) refers to any plasma cell or B-cell clonal disorder that does not meet the current criteria for malignant disorders but produces a monoclonal protein that directly or indirectly results in organ damage. The most commonly affected organs are the kidneys, nerves, and skin. This review summarizes the current classification of MGCS and its diagnostic and treatment approaches.

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… Paraproteinemia, most often IgGl, plasma cell dyscrasia, and/or other associated lymphoproliferative disorder | Minor criteria 5. Intrapulmonary shunting 6. … Type I cryoglobulinemia is characterized by a single monoclonal immunoglobulin from plasma cells or lymphoproliferative disorders. …

Sequential Development of Waldenström's Macroglobulinemia After High-Grade Lymphomatoid Granulomatosis.

Lymphomatoid granulomatosis (LYG) is a rare Epstein-Barr virus-driven B-cell lymphoproliferative disease that often progresses to high-grade lymphoma. We describe a case of high-grade LYG causing Pancoast syndrome, diagnosed via transbronchial biopsy after a failed incisional biopsy. Complete remission was achieved with R-CHOP (rituximab, doxorubicin, cyclophosphamide, vincristine, and prednisolone), but 2.5 years later, the patient developed lymphoplasmacytic lymphoma/Waldenström's macroglobulinemia (LPL/WM). Despite bendamustine-rituximab improving LPL/WM, LYG recurred, underscoring its trea

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… Even more rarely, LYG is an EBV-associated B-cell lymphoproliferative disorder for which precise epidemiological data are lacking due to its extreme rarity. … The coexistence or sequential development of LPL/WM following other EBV-related lymphoproliferative disorders is extremely rare and, to our knowledge, has not been reported before. …

Innovative therapeutic concepts of progressive multifocal leukoencephalopathy.

Progressive multifocal leukoencephalopathy (PML) is an opportunistic viral disease of the brain-caused by human polyomavirus 2. It affects patients whose immune system is compromised by a corresponding underlying disease or by drugs. Patients with an underlying lymphoproliferative disease have the worst prognosis with a mortality rate of up to 90%. Several therapeutic strategies have been proposed but failed to show any benefit so far. Therefore, the primary therapeutic strategy aims to reconstitute the impaired immune system to generate an effective endogenous antiviral response. Recently, an

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… Functional B cells are necessary for adequate viral defense and the risk for PML is quite high, especially in chronic lymphocytic leukemia (CLL) and other B-cell-associated lymphoproliferative disorders. … Holmes A Wellings T Walsh O Rowlings P Progressive multifocal leukoencephalopathy associated with a lymphoproliferative disorder treated with pembrolizumab J Neurovirol 2020 26 961 963 32910430 10.1007/s13365-020-00899-0 65. …

Validation of the EBMT Risk Score for South Brazilian Patients Submitted to Allogeneic Hematopoietic Stem Cell Transplantation.

Background. Allogeneic hematopoietic stem cell transplantation (HSCT) is still associated with a high transplant-related mortality rate. In 2009, the EBMT risk score was validated as a simple tool to predict the outcome after allogeneic HSCT for acquired hematological disorders. Objectives. The aim of this study was to validate the applicability of the EBMT risk score for allogeneic HSCT on South Brazilian patients. Methods. A retrospective observational study was performed based on patients' records and data base at Hospital de Clínicas de Porto Alegre, including all allogeneic transplants fo

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… Late stage disease (2 points) includes acute leukemia in all other disease stages, CML in blast crisis, MDS, lymphoproliferative disorders, and MM in all other stages than those previously defined. … Lymphoproliferative disorders, MDS, and MM had no sufficient number of patients to allow a reliable analysis. …