Le syndrome lymphoprolifératif avec auto-immunité : Un défaut hérité ou acquis d’apoptose lymphocytaire

Le syndrome lymphoprolifératif avec auto-immunité (ALPS, auto-immune lymphoproliferative syndrome) a été décrit il y a plus de 30 ans. Ce syndrome tumoral bénin, d’apparition précoce (en moyenne avant cinq ans), associe des adénopathies multifocales, une splénomégalie et, éventuellement, une hépatomégalie. Cette lymphoprolifération chronique s’accompagne d’une hypergammaglobulinémie, essentiellement G et A, et se caractérise par l’accumulation dans le sang et les organes lymphoïdes secondaires d’une population polyclonale de lymphocytes Tαβ matures n’exprimant ni CD4 ni CD8, appelés lymphocytes T « doubles négatifs » (LTαβ DN). Des manifestations auto-immunes sont retrouvées chez plus de deux tiers des patients ALPS, le plus souvent sous la forme de cytopénies auto-immunes (anémie hémolytique, thrombopénie et neutropénie). Des atteintes d’organes ou de systèmes (glomérulonéphrites, hépatites, uvéites, syndrome de Guillain-Barré) sont plus rarement observées. Cet article fait le point sur les défauts de la voie de signalisation Fas mis en évidence dans la genèse de l’ALPS.Control of lymphocyte homeostasis is essential to ensure efficient immune responses and to prevent autoimmunity. Expansion followed by contraction of the lymphocyte pool are the basis of adaptive immune responses, and apoptosis is a crucial cellular modus operandi of the contraction phase. The death receptor Fas is a key player in lymphocyte apoptosis induction and patients lacking a functional Fas receptor develop a chronic lymphoproliferation termed autoimmune lymphoproliferative syndrome (ALPS). In rare instances, defects of the Fas signaling pathway have been associated with the ALPS condition. Although these defects with familial history are usually caused by inherited mutations of the corresponding genes, somatic mosaicism of these Fas mutations were also found in sporadic cases of ALPS. These findings might have important implications in deciphering the pathophysiological bases of other autoimmune diseases

Clinical spectrum and features of activated phosphoinositide 3-kinase δ syndrome: A large patient cohort study.

BACKGROUND: Activated phosphoinositide 3-kinase δ syndrome (APDS) is a recently described combined immunodeficiency resulting from gain-of-function mutations in PIK3CD, the gene encoding the catalytic subunit of phosphoinositide 3-kinase δ (PI3Kδ). OBJECTIVE: We sought to review the clinical, immunologic, histopathologic, and radiologic features of APDS in a large genetically defined international cohort. METHODS: We applied a clinical questionnaire and performed review of medical notes, radiology, histopathology, and laboratory investigations of 53 patients with APDS. RESULTS: Recurrent sinopulmonary infections (98%) and nonneoplastic lymphoproliferation (75%) were common, often from childhood. Other significant complications included herpesvirus infections (49%), autoinflammatory disease (34%), and lymphoma (13%). Unexpectedly, neurodevelopmental delay occurred in 19% of the cohort, suggesting a role for PI3Kδ in the central nervous system; consistent with this, PI3Kδ is broadly expressed in the developing murine central nervous system. Thoracic imaging revealed high rates of mosaic attenuation (90%) and bronchiectasis (60%). Increased IgM levels (78%), IgG deficiency (43%), and CD4 lymphopenia (84%) were significant immunologic features. No immunologic marker reliably predicted clinical severity, which ranged from asymptomatic to death in early childhood. The majority of patients received immunoglobulin replacement and antibiotic prophylaxis, and 5 patients underwent hematopoietic stem cell transplantation. Five patients died from complications of APDS. CONCLUSION: APDS is a combined immunodeficiency with multiple clinical manifestations, many with incomplete penetrance and others with variable expressivity. The severity of complications in some patients supports consideration of hematopoietic stem cell transplantation for severe childhood disease. Clinical trials of selective PI3Kδ inhibitors offer new prospects for APDS treatment.T.C. is supported by National Children’s Research Centre, Our Lady’s Children’s Hospital Crumlin, Dublin, Ireland. A.C. has a Wellcome Trust Postdoctoral Training Fellowship for Clinicians (103413/Z/13/Z). K.O. is supported by funding from BBSRC, MRC, Wellcome Trust and GSK. R.D. and D.S.K are funded by National Institute for Health Research (NIHR) Cambridge Biomedical Research Centre, Cambridge, UK. C.S. and S.E. are supported by the German Federal Ministry of Education and Research (BMBF 01 EO 0803 grant to the Center of Chronic immunodeficiency and BMBF 01GM1111B grant to the PID-NET initiative). S.N.F is supported in part by the Southampton UK National Institute for Health Research (NIHR) Wellcome Trust Clinical Research Facility and NIHR Respiratory Biomedical Research Unit. M.A.A.I. is funded by NHS Innovation London and King’s College Hospital Charitable Trust. A.F., S.L., A.D., F.R-L and S.K. are supported by the European Union’s 7th RTD Framework Programme (ERC advanced grant PID-IMMUNE contract 249816) and a government grant managed by the French Agence Nationale de la Recherche as part of the "Investments for the Future" program (ANR-10-IAHU-01). S.L. is supported by the Agence Nationale de la Recherche (ANR) (ANR-14-CE14-0028-01), the Foundation ARC pour la Recherche sur le Cancer (France), the Rare Diseases Foundation (France) and François Aupetit Association (France). S.L. is a senior scientist and S.K is a researcher at the Centre National de la Recherche Scientifique-CNRS (France). A.D. and S.K. are supported by the “Institut National de la Santé et de la Recherche Médicale". S.K. also supported by the Fondation pour la Recherche Médicale (grant number: ING20130526624), la Ligue Contre le Cancer (Comité de Paris) and the Centre de Référence Déficits Immunitaires Héréditaires (CEREDIH). S.O.B is supported by the Higher Education Funding Council for England. B.V. is supported by the UK Biotechnology and Biological Sciences Research Council [BB/I007806/1], Cancer Research UK [C23338/A15965) and the National Institute for Health Research (NIHR) University College London Hospitals Biomedical Research Centre. B.V. is consultant to Karus Therapeutics (Oxford, UK). S.N. is a Wellcome Trust Senior Research Fellow in Basic Biomedical Science (095198/Z/10/Z). S.N. is also supported by the European Research Council Starting grant 260477, the EU FP7 collaborative grant 261441 (PEVNET project) and the National Institute for Health Research (NIHR) Cambridge Biomedical Research Centre, UK. A.M.C. is funded by the Medical Research Council, British Lung Foundation, University of Sheffield and Cambridge NIHR-BRC. Research in A.M.C. laboratory has received non-commercial grant support from GSK, Novartis, and MedImmune.This is the author accepted manuscript. The final version is available from Elsevier via http://dx.doi.org/10.1016/j.jaci.2016.06.02

Long-term follow-up of IPEX syndrome patients after different therapeutic strategies : an international multicenter retrospective study

Background: Immunodysregulation polyendocrinopathy enteropathy x-linked(IPEX) syndrome is a monogenic autoimmune disease caused by FOXP3 mutations. Because it is a rare disease, the natural history and response to treatments, including allogeneic hematopoietic stem cell transplantation (HSCT) and immunosuppression (IS), have not been thoroughly examined. Objective: This analysis sought to evaluate disease onset, progression, and long-term outcome of the 2 main treatments in long-term IPEX survivors. Methods: Clinical histories of 96 patients with a genetically proven IPEX syndrome were collected from 38 institutions worldwide and retrospectively analyzed. To investigate possible factors suitable to predict the outcome, an organ involvement (OI) scoring system was developed. Results: We confirm neonatal onset with enteropathy, type 1 diabetes, and eczema. In addition, we found less common manifestations in delayed onset patients or during disease evolution. There is no correlation between the site of mutation and the disease course or outcome, and the same genotype can present with variable phenotypes. HSCT patients (n = 58) had a median follow-up of 2.7 years (range, 1 week-15 years). Patients receiving chronic IS (n 5 34) had a median follow-up of 4 years (range, 2 months-25 years). The overall survival after HSCT was 73.2% (95% CI, 59.4-83.0) and after IS was 65.1% (95% CI, 62.8-95.8). The pretreatment OI score was the only significant predictor of overall survival after transplant (P = .035) but not under IS. Conclusions: Patients receiving chronic IS were hampered by disease recurrence or complications, impacting long-term.disease-free survival. When performed in patients with a low OI score, HSCT resulted in disease resolution with better quality of life, independent of age, donor source, or conditioning regimen

Syndromes lymphoprolifératifs avec auto-immunité (ALPS) (modèles pathologiques d'études des voies d'apoptose lymphocytaire chez l'homme)

L'apoptose lymphocytaire est un processus physiologique qui permet de contrôler la prolifération des lymphocytes périphériques. Elle est déclenchée par l'intermédiaire de récepteurs membranaires spécifiques tels que la molécule Fas. Chez l'homme, un syndrome lymphoprolifératif, associé de façon variable à des manifestations auto-immunes, (ALP5) a été initialement associé à des mutations germinales du gène Fas dans un 1er groupe de patients. Au cours de ce travail de thèse, nous avons mis en évidence que des mutations somatiques de Fas pouvaient être également associéesà l'ALPS. De plus, chez un un patient porteur d'une mutation de Fas, nous avons mis en évidence un défaut d'un autre récepteur de la même famille que Fas, TRAIL-R2. La combinaison de ces deux défauts pourrait participer au déclenchement de l'ALPS.PARIS5-BU-Necker : Fermée (751152101) / SudocPARIS-BIUP (751062107) / SudocSudocFranceF

Scaling the tips of the ALPS.

This special issue contains four review articles that describe advances in analysis of mutations responsible for the autoimmune lymphoproliferative syndrome (ALPS). This disease is triggered by a family of mutations in genes involved in the extrinsic apoptotic pathway such as FAS, FASL and CASP10. Advances in sequencing technology have enabled extended genetic testing of patients with various defects in alternative biological have pathways that can cause ALPS-like syndromes. Various gene mutations were identified which affect the CTLA-4 immune checkpoint, the STAT3 pathway and the RAS/MAPK pathway. Tips gleaned from analyses of the different gene mutations involved in ALPS and ALPS-like syndromes are contributing to a better understanding of their functional consequences. Genetic diagnoses of the disease should help us to identify specific therapeutic targets and design personalized treatment for each patient