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Immunodeficiència primària; Limfoproliferació; Inhibidor de mTOR Inmunodeficiencia primaria; Linfoproliferación; Inhibidor de mTOR Primary immunodeficiency; Lymphoproliferation; MTOR inhibitor Background Activated phosphoinositide 3-kinase delta syndrome (APDS) is a combined immunodeficiency with a heterogeneous phenotype considered reversible by allogeneic hematopoietic cell transplantation (HCT). Objectives This study sought to characterize HCT outcomes in APDS. Methods Retrospective data were collected on 57 patients with APDS1/2 (median age, 13 years; range, 2-66 years) who underwent HCT. Results Pre-HCT comorbidities such as lung, gastrointestinal, and liver pathology were common, with hematologic malignancy in 26%. With median follow-up of 2.3 years, 2-year overall and graft failure–free survival probabilities were 86% and 68%, respectively, and did not differ significantly by APDS1 versus APDS2, donor type, or conditioning intensity. The 2-year cumulative incidence of graft failure following first HCT was 17% overall but 42% if mammalian target of rapamycin inhibitor(s) (mTORi) were used in the first year post-HCT, compared with 9% without mTORi. Similarly, 2-year cumulative incidence of unplanned donor cell infusion was overall 28%, but 65% in the context of mTORi receipt and 23% without. Phenotype reversal occurred in 96% of evaluable patients, of whom 17% had mixed chimerism. Vulnerability to renal complications continued post-HCT, adding new insights into potential nonimmunologic roles of phosphoinositide 3-kinase not correctable through HCT. Conclusions Graft failure, graft instability, and poor graft function requiring unplanned donor cell infusion were major barriers to successful HCT. Post-HCT mTORi use may confer an advantage to residual host cells, promoting graft instability. Longer-term post-HCT follow-up of more patients is needed to elucidate the kinetics of immune reconstitution and donor chimerism, establish approaches that reduce graft instability, and assess the completeness of phenotype reversal over time. This research was funded in part from the Intramural Program of the National Cancer Institute, National Institutes of Health. The funding source had no involvement in study design; collection, analysis, and interpretation of data; writing of the report; or in the decision to submit the article for publication.

Predominantly antibody deficiencies (PADs) are the most frequent forms of primary immunodeficiency diseases (PIDs). Commonly accompanied with complications involving several body systems, immunoglobulin substitution therapy along with prophylactic antibiotics remained the cornerstone of treatment for PADs and related complications. Patients with respiratory complications should be prescribed an appropriate therapy as soon as possible and have to be adhering to more and longer medical therapies. Recent studies identified a gap for screening protocols to monitor respiratory manifestations in patients with PADs. In the present chapter, the pulmonary manifestations of different PADs for each have been discussed. The chapter is mainly focused on X-linked agammaglobulinemia, common variable immunodeficiency, activated PI3K-δ syndrome, LRBA deficiency, CD19 complex deficiencies, CD20 deficiency, other monogenic defects associated with hypogammaglobulinemia, immunoglobulin class switch recombination deficiencies affecting B-cells, transient hypogammaglobulinemia of infancy, and selective IgA deficiency.

Gain-of-function variants in p110δ, the catalytic subunit of phosphatidylinositol 3-kinase (PI3K) expressed in lymphocytes, cause activated PI3-kinase δ syndrome (APDS), a primary immunodeficiency that is characterized by recurrent infections, viremia, lymphadenopathy, and autoimmunity. The mechanism of autoimmunity in APDS has not been well-understood. Here, we show the profound skewing of peripheral CD4+ T cells to a T follicular helper (TFH) phenotype in a patient with APDS bearing a novel p110δ variant, Y524S. We also saw a diminishment of transient Foxp3 expression in activated T cells. Mechanistic studies revealed that both the new variant and a previously described, pathogenic variant (E81K) enhanced an interaction between intracellular Osteopontin and p85α. This interaction had been shown in mice to promote TFH differentiation. Our results demonstrate a new influence of PI3K on human T cell differentiation that is unrelated to its lipid-kinase activity and suggest that TFH should be monitored in APDS patients.

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. European Union's 7th RTD Framework Programme (ERC advanced grant PID-IMMUNE) - 249816 French National Research Agency (ANR) - ANR-10-IAHU-01 Centre de Reference Deficits Immunitaires Hereditaires (CEREDIH) French National Research Agency (ANR)-European Commission - ANR-15-CE15-0020 Gebert Ruf Stiftung program "Rare Diseases-New Approaches'' - GRS-046/10 European Commission - CELL-PID HEALTH-261387 Zurich Centre for Integrative Human Physiology (ZIHP) Gottfried und Julia Bangerter-Rhyner-Stiftung Rossi Stiftung European Research Council (ERC)-European Commission - 260477 European Commission - 261441 National Institute for Health Research (NIHR) Ministry of Education, Culture, Sports, Science and Technology, Japan (MEXT)-Japan Society for the Promotion of Science Ministry of Health, Labour and Welfare, Japan 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 United States Department of Health & Human Services/National Institutes of Health (NIH) - USA/NIH National Institute of Allergy & Infectious Diseases (NIAID) Postdoctoral Research Associate (PRAT) Fellowship, National Institute of General Medical Sciences(NIGMS)/NIH EU-FP7 NET4CGD UK Research & Innovation (UKRI)/Medical Research Council UK (MRC)/European Commission - MR/M012328 - MR/M012328/2 UK Research & Innovation (UKRI)/Medical Research Council UK (MRC) - MR/M012328/2 - MR/M012328/1 Institut National de la Sante et de la Recherche Medicale (Inserm) Fondation pour la Recherche Medicale - ING20130526624 la Ligue Contre le Cancer (Comite de Paris)

Recently, patient mutations that activate PI3K signaling have been linked to a primary antibody deficiency. Here, we used whole-exome sequencing and characterized the molecular defects in 4 patients from 3 unrelated families diagnosed with hypogammaglobulinemia and recurrent infections. We identified 2 different heterozygous splice site mutations that affect the same splice site in PIK3R1, which encodes the p85α subunit of PI3K. The resulting deletion of exon 10 produced a shortened p85α protein that lacks part of the PI3K p110-binding domain. The hypothetical loss of p85α-mediated inhibition of p110 activity was supported by elevated phosphorylation of the known downstream signaling kinase AKT in patient T cell blasts. Analysis of patient blood revealed that naive T and memory B cell counts were low, and T cell blasts displayed enhanced activation-induced cell death, which was corrected by addition of the PI3Kδ inhibitor IC87114. Furthermore, B lymphocytes proliferated weakly in response to activation via the B cell receptor and TLR9, indicating a B cell defect. The phenotype exhibited by patients carrying the PIK3R1 splice site mutation is similar to that of patients carrying gain-of-function mutations in PIK3CD. Our results suggest that PI3K activity is tightly regulated in T and B lymphocytes and that various defects in the PI3K-triggered pathway can cause primary immunodeficiencies.