Journal
JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY
Volume 138, Issue 1, Pages 210-+Publisher
MOSBY-ELSEVIER
DOI: 10.1016/j.jaci.2016.03.022
Keywords
Primary immunodeficiency; phosphoinositide 3-kinase; p85 alpha; p110 delta; activated phosphoinositide 3-kinase delta syndrome; p110 delta-activating mutations causing senescent T cells; lymphadenopathy; and immunodeficiency; hyper-IgM; adenopathy; immunodeficiency; antibody deficiency
Categories
Funding
- European Union's 7th RTD Framework Programme (ERC advanced grant PID-IMMUNE) [249816]
- French Agence Nationale de la Recherche, Investments for the Future'' program [ANR-10-IAHU-01]
- Institut National de la Sante et de la Recherche Medicale
- Fondation pour la Recherche Medicale [ING20130526624]
- la Ligue Contre le Cancer (Comite de Paris)
- Centre de Reference Deficits Immunitaires Hereditaires (CEREDIH)
- Agence Nationale de la Recherche [ANR-15-CE15-0020]
- Gebert Ruf Stiftung program Rare Diseases-New Approaches'' [GRS-046/10]
- EU-FP7 [CELL-PID HEALTH-261387]
- Zurich Centre for Integrative Human Physiology (ZIHP)
- Gottfried und Julia Bangerter-Rhyner-Stiftung
- Rossi Stiftung
- European Research Council [260477]
- EU FP7 [261441]
- National Institute for Health Research (NIHR) Cambridge Biomedical Research Centre
- MEXT/JSPS
- Ministry of Health Labor and Welfare
- Ministry of Defense
- Japan Agency for Medical Research and Development, AMED
- National Institute for Health Research-Leeds Musculoskeletal Biomedical Research Unit (and Leeds Teaching Hospitals Charitable Foundation)
- National Children's Research Centre, Our Lady's Children's Hospital Crumlin, Dublin, Ireland
- Intramural Research Program of the National Institutes of Health/National Institute of Allergy and Infectious Diseases
- Postdoctoral Research Associate (PRAT) Fellowship, National Institute of General Medical Sciences(NIGMS)/NIH
- EU-FP7 NET4CGD
- European Research Council (ERC) [260477] Funding Source: European Research Council (ERC)
- Agence Nationale de la Recherche (ANR) [ANR-15-CE15-0020] Funding Source: Agence Nationale de la Recherche (ANR)
- Medical Research Council [MR/M012328/2, MR/M012328/1] Funding Source: researchfish
- MRC [MR/M012328/1, MR/M012328/2] Funding Source: UKRI
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Background: Activated phosphoinositide 3-kinase delta syndrome (APDS) 2 (p110 delta-activating mutations causing senescent T cells, lymphadenopathy, and immunodeficiency [PASLI]-R1), a recently described primary immunodeficiency, results from autosomal dominant mutations in PIK3R1, the gene encoding the regulatory subunit (p85 alpha, p55 alpha, and p50 alpha) of class IA phosphoinositide 3-kinases. Objectives: We sought to review the clinical, immunologic, and histopathologic phenotypes of APDS2 in a genetically defined international patient cohort. Methods: The medical and biological records of 36 patients with genetically diagnosed APDS2 were collected and reviewed. Results: Mutations within splice acceptor and donor sites of exon 11 of the PIK3R1 gene lead to APDS2. Recurrent upper respiratory tract infections (100%), pneumonitis (71%), and chronic lymphoproliferation (89%, including adenopathy [75%], splenomegaly [43%], and upper respiratory tract lymphoid hyperplasia [48%]) were the most common features. Growth retardation was frequently noticed (45%). Other complications were mild neurodevelopmental delay (31%); malignant diseases (28%), most of them being B-cell lymphomas; autoimmunity (17%); bronchiectasis (18%); and chronic diarrhea (24%). Decreased serum IgA and IgG levels (87%), increased IgM levels (58%), B-cell lymphopenia (88%) associated with an increased frequency of transitional B cells (93%), and decreased numbers of naive CD4 and naive CD8 cells but increased numbers of CD8 effector/memory T cells were predominant immunologic features. The majority of patients (89%) received immunoglobulin replacement; 3 patients were treated with rituximab, and 6 were treated with rapamycin initiated after diagnosis of APDS2. Five patients died from APDS2-related complications. Conclusion: APDS2 is a combined immunodeficiency with a variable clinical phenotype. Complications are frequent, such as severe bacterial and viral infections, lymphoproliferation, and lymphoma similar to APDS1/PASLI-CD. Immunoglobulin replacement therapy, rapamycin, and, likely in the near future, selective phosphoinositide 3-kinase delta inhibitors are possible treatment options.
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