Isolement et caracterisation des lymphocytes T ayant une affinite pour la prostaglandine E2

SIGLET 55552 / INIST-CNRS - Institut de l'Information Scientifique et TechniqueFRFranc

Mycophenolate mofetil as an alternate immunosuppressor for autoimmune lymphoproliferative syndrome

Autoimmune lymphoproliferative syndrome (ALPS) is a disorder due to a genetic defect concerning programmed cell death (apoptosis). Most patients are carriers of a heterozygous mutation affecting the TNFRSF6 (Fas). Treatment of autoimmune complications of ALPS includes corticosteroids, gamma-globulin infusions, and in refractory cases, splenectomy, cytostatic agents, and bone marrow transplantation. A 10-year-old boy with ALPS manifested by recurrent febrile episodes, lymphadenopathy, splenomegaly, and cytopenias refractory to corticosteroid therapy is presented. Treatment with mycophenolate mofetil, an immunosuppressive agent typically used in organ transplantation was initiated. This treatment was successful with resolution of thrombocytopenia, decrease in lymphadenopathy, and improvement of his general clinical condition for over 2 years of duration

Combined immunodeficiency associated with increased apoptosis of lymphocytes and radiosensitivity of fibroblasts

Severe immunodeficiency characterized by lymphopenia was found in two siblings, one of whom was examined in detail. The calcium flux, pattern of tyrosine phosphorylation of proteins, and interleukin 2 (IL-2) production and proliferation in response to mitogens suggested that the peripheral blood T cells activated normally. The peripheral blood T cells were shown to have an activated phenotype with increased expression of CD45RO+ and CD95/Fas, Increased spontaneous apoptosis occurred in unstimulated lymphocyte cultures. The elevated apoptosis was not due to alterations in expression or to mutations in Bcl-2, Bd-X-L, or Flip, nor could the spontaneous apoptosis be prevented by blocking Fas, suggesting that it was independent of Fas signaling. This is the first inherited combined immunodeficiency associated with impaired Lymphocyte survival. Fibroblasts derived from the patient showed appreciable radiosensitivity in clonal assays, but apoptosis was not elevated. Our results show that the fibroblasts represent a new radiosensitive phenotype not associated with cell cycle checkpoint defects, V(D)J recombination defects, or elevated chromosome breakage. We suggest that the affected gene plays a role in an undetermined damage response mechanism that results in elevated spontaneous apoptosis in lymphoid cells and radiosensitivity in fibroblasts

FAS-L, IL-10, and double-negative CD4- CD8- TCR alpha/beta+ T cells are reliable markers of autoimmune lymphoproliferative syndrome (ALPS) associated with FAS loss of function.

Autoimmune lymphoproliferative syndrome (ALPS) is characterized by splenomegaly, lymphadenopathy, hypergammaglobulinemia, accumulation of double-negative TCRalphabeta(+) CD4(-)CD8(-) T cells (DNT cells), and autoimmunity. Previously, DNT cell detection and a functional defect of T cells in a FAS-induced apoptosis test in vitro had been used for ALPS diagnosis. However, a functional defect can also be detected in mutation-positive relatives (MPRs) who remain free of any ALPS-related disease. In contrast, lymphocytes from patients carrying a somatic mutation of FAS exhibit normal sensitivity to FAS-induced apoptosis in vitro. We assessed the soluble FAS-L concentration in the plasma of ALPS patients carrying FAS mutations. Overall, we showed that determination of the FAS-L represents, together with the IL-10 concentration and the DNT cell percentage, a reliable tool for the diagnosis of ALPS.Evaluation StudiesJournal ArticleResearch Support, Non-U.S. Gov'tSCOPUS: ar.jinfo:eu-repo/semantics/publishe

Long-term outcome following hematopoietic stem-cell transplantation in Wiskott-Aldrich syndrome: collaborative study of the European Society for Immunodeficiencies and European Group for Blood and Marrow Transplantation

Wiskott-Aldrich syndrome (WAS) is a rare X-linked immunodeficiency with microthrombocytopenia, eczema, recurrent infections, autoimmune disorders, and malignancies that are life-threatening in the majority of patients. In this long-term, retrospective, multicenter study, we analyzed events that occurred in 96 WAS patients who received transplants between 1979 and 2001 who survived at least 2 years following hematopoietic stem-cell transplantation (HSCT). Events included chronic graft-versus-host disease (cGVHD), autoimmunity, infections, and sequelae of before or after HSCT complications. Three patients (3%) died 2.1 to 21 years following HSCT. Overall 7-year event-free survival rate was 75%. It was lower in recipients of mismatched related donors, also in relation with an older age at HSCT and disease severity. The most striking finding was the observation of cGVHD-independent autoimmunity in 20% of patients strongly associated with a mixed/split chimerism status (P < .001), suggesting that residual-host lymphocytes can mediate autoimmune disease despite the coexistence of donor lymphocytes. Infectious complications (6%) related to splenectomy were also significant and may warrant a more restrictive approach to performing splenectomy in WAS patients. Overall, this study provides the basis for a prospective, standardized, and more in-depth detailed analysis of chimerism and events in long-term follow-up of WAS patients who receive transplants to design better-adapted therapeutic strategies

Variants in TRIM22 that affect NOD2 signaling are associated with very early onset inflammatory bowel disease

Severe forms of inflammatory bowel disease (IBD) that develop in very young children can be caused by variants in a single gene. We performed whole-exome sequence (WES) analysis to identify genetic factors that might cause granulomatous colitis and severe perianal disease, with recurrent bacterial and viral infections, in an infant of consanguineous parents.We performed targeted WES analysis of DNA collected from the patient and her parents. We validated our findings by a similar analysis of DNA from 150 patients with very early onset IBD not associated with known genetic factors analyzed in Toronto, Oxford, and Munich. We compared gene expression signatures in inflamed vs. non-inflamed intestinal and rectal tissues collected from patients with treatment-resistant Crohn's disease who participated in a trial of ustekinumab. We performed functional studies of identified variants in primary cells from patients and cell culture.We identified a homozygous variant in the tripartite motif containing 22 gene (TRIM22) of the patient, as well as in 2 patients with a disease similar phenotype. Functional studies showed that the variant disrupted the ability of TRIM22 to regulate nucleotide binding oligomerization domain containing 2 (NOD2)-dependent activation of interferon-beta signaling and NF-κB. Computational studies demonstrated a correlation between the TRIM22-NOD2 network and signaling pathways and genetic factors associated very early onset and adult-onset IBD. The network also associated with antiviral and mycobacterial effectors and markers of inflammation such as fecal calprotectin, c-reactive protein, and Crohn's disease activity index scores.In WES and targeted exome sequence analyses of an infant with severe IBD, characterized by granulomatous colitis and severe perianal disease, we identified a homozygous variant of TRIM22 that affect the ability of its product to regulate NOD2. Combined computational and functional studies showed that the TRIM22-NOD2 network regulates antiviral and anti-bacterial signaling pathways that contribute to inflammation. Further study of this network could lead to new disease markers and therapeutic targets for patients with very early and adult-onset IBD