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.
Background Activated phosphoinositide 3-kinase δ syndrome (APDS) 2 (p110δ-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 (p85α, p55α, and p50α) 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 δ inhibitors are possible treatment options.
Background We investigated 7 male patients (from 5 different families) presenting with profound lymphopenia, hypogammaglobulinemia, fluctuating monocytopenia and neutropenia, a poor immune response ...to vaccine antigens, and increased susceptibility to bacterial and varicella zoster virus infections. Objective We sought to characterize the genetic defect involved in a new form of X-linked immunodeficiency. Methods We performed genetic analyses and an exhaustive phenotypic and functional characterization of the lymphocyte compartment. Results We observed hemizygous mutations in the moesin (MSN) gene (located on the X chromosome and coding for MSN) in all 7 patients. Six of the latter had the same missense mutation, which led to an amino acid substitution (R171W) in the MSN four-point-one, ezrin, radixin, moesin domain. The seventh patient had a nonsense mutation leading to a premature stop codon mutation (R533X). The naive T-cell counts were particularly low for age, and most CD8+ T cells expressed the senescence marker CD57. This phenotype was associated with impaired T-cell proliferation, which was rescued by expression of wild-type MSN. MSN-deficient T cells also displayed poor chemokine receptor expression, increased adhesion molecule expression, and altered migration and adhesion capacities. Conclusion Our observations establish a causal link between an ezrin-radixin-moesin protein mutation and a primary immunodeficiency that could be referred to as X-linked moesin-associated immunodeficiency.
SMB cell subset Low (n = 30) Normal (n = 13) P value MZB cell subset Low (n = 17) Normal (n = 13) P value Normal (n = 13) Upper respiratory tract infections 13 11 NS 11 NS Lower respiratory tract ...infections 11 12 NS 9 NS Pneumonia 10 8 NS 2 .017 Bronchiectasis 6 3 NS 0 .041 Autoimmune diseases 2 3 NS 0 NS Splenomegaly 3 2 NS 0 NS Gastroenteritis 3 1 NS 6 .02 Invasive acute infection 4 1 NS 2 NS IgRT 17 6 .0008 11 NS No response to vaccines 9/14 3/11 NS 1/9 NS Normal CD40+IL4-induced proliferation 11/16 10/12 NS 9/9 NS Normal CD40 class-switch recombination 11/16 6/10 NS 9/9 NS Normal BAFF-induced proliferation 6/13 7/12 NS 2/6 NS Normal CpG-induced proliferation 6/13 8/12 NS 3/6 NS Normal anti-A/B allohemagglutinins 2/10 3/9 NS 5/7 NS Table II Characteristics of patients as a function of their SMB and MZB cell counts BAFF, B-cell activating factor; NS, not significant.Low SMB and MZB cell counts were defined as being at least 2 SDs below the age-adjusted normal value (NS, P > .05). Characteristic No. (%) or median (min; max) Sex: male 20 (45.4) Age at onset (y) 1.77 (0.06; 5.9) Age at diagnosis (y) 5.15 (0.33; 17.3) Age at last follow-up (y) 14.46 (4.17; 35.87) Time between symptom onset and diagnosis years 3.00 (0.0; 13.23) Follow-up period (y) 6.29 (0.23; 27.09) Patients with another case in their family 13 (29.5) IgG deficiency 6 (13.6) IgG and IgA deficiency 9 (20.4) IgG and IgM deficiency 3 (6.8) IgA and IgM deficiency 1 (2.2) IgG, IgA, and IgM deficiency 25 (56.8) Patients with upper respiratory tract infections 35 (79.5) Patients with lower respiratory tract infections 33 (75) * Repeated acute bronchitis 17 (38.6) * Pneumonia 20 (45.5) * Bronchiectasis 9 (20.4) Patients with gastroenteritis 10 (22.7) Patients with autoimmune diseases 5 (11.4) Patients with splenomegaly 5 (11.4) Patients with lymphoma 1 (2.2) Table E1 Demographic, clinical, and biological characteristics of patients
Background Immunoglobulin class-switch recombination defects (CSR-D) are rare primary immunodeficiencies characterized by impaired production of switched immunoglobulin isotypes and normal or ...elevated IgM levels. They are caused by impaired T:B cooperation or intrinsic B cell defects. However, many immunoglobulin CSR-Ds are still undefined at the molecular level. Objective This study's objective was to delineate new causes of immunoglobulin CSR-Ds and thus gain further insights into the process of immunoglobulin class-switch recombination (CSR). Methods Exome sequencing in 2 immunoglobulin CSR-D patients identified variations in the INO80 gene. Functional experiments were performed to assess the function of INO80 on immunoglobulin CSR. Results We identified recessive, nonsynonymous coding variations in the INO80 gene in 2 patients affected by defective immunoglobulin CSR. Expression of wild-type INO80 in patients' fibroblastic cells corrected their hypersensitivity to high doses of γ-irradiation. In murine CH12-F3 cells, the INO80 complex accumulates at Sα and Eμ regions of the IgH locus, and downregulation of INO80 as well as its partners Reptin and Pontin impaired CSR. In addition, Reptin and Pontin were shown to interact with activation-induced cytidine deaminase. Finally, an abnormal separation of sister chromatids was observed upon INO80 downregulation in CH12-F3 cells, pinpointing its role in cohesin activity. Conclusion INO80 deficiency appears to be associated with defective immunoglobulin CSR. We propose that the INO80 complex modulates cohesin function that may be required during immunoglobulin switch region synapsis.
BENTA disease is genetically linked to germline-encoded, gain-of-function mutations in caspase recruitment domain 11 (CARD11), a scaffolding protein largely expressed in lymphocytes and required for ...antigen receptor (AgR)-induced NF-κB activation.3,4 Like somatic mutations found in approximately 10% of diffuse large B-cell lymphomas, CARD11 mutations in patients with BENTA fall within or immediately adjacent to the coiled-coil (CC) domain.5 CC mutations likely abrogate the requirement for AgR-triggered phosphorylation of the inhibitory linker domain, which supports the "open" conformational change necessary for BCL10-MALT1 recruitment and downstream signal transduction via the IκB kinase complex.6 We recently encountered 3 new patients with disease symptoms suggesting BENTA, including moderate, polyclonal B-cell lymphocytosis with a markedly diminished memory B-cell compartment (Table I). The CARD domain is critical for BCL10 interaction and downstream TCR signaling, as well as regulatory T-cell development.7 This mutation was previously reported in 1 case of diffuse large B-cell lymphoma,8 and identified in an unbiased screen for gain-of-function CARD11 mutants capable of activating NF-κB and promoting human diffuse large B-cell lymphoma tumor growth in vitro.6 Indeed, we confirmed that transfection of the C49Y CARD11 mutant into the CARD11-deficient Jurkat T-cell line JPM50.6 resulted in spontaneous protein aggregation, colocalization with MALT1 and active IκB kinase,9 and constitutive NF-κB activation in the absence of AgR stimulation, comparable to other BENTA mutants described (Fig 1, C and D).
Background The capacity of CD8+ T cells to control infections and mediate antitumor immunity requires the development and survival of effector and memory cells. IL-21 has emerged as a potent inducer ...of CD8+ T-cell effector function and memory development in mouse models of infectious disease. However, the role of IL-21 and associated signaling pathways in protective CD8+ T-cell immunity in human subjects is unknown. Objective We sought to determine which signaling pathways mediate the effects of IL-21 on human CD8+ T cells and whether defects in these pathways contribute to disease pathogenesis in patients with primary immunodeficiencies caused by mutations in components of the IL-21 signaling cascade. Methods Human primary immunodeficiencies resulting from monogenic mutations provide a unique opportunity to assess the requirement for particular molecules in regulating human lymphocyte function. Lymphocytes from patients with loss-of-function mutations in signal transducer and activator of transcription 1 (STAT1) , STAT3 , or IL-21 receptor (IL21R) were used to assess the respective roles of these genes in human CD8+ T-cell differentiation in vivo and in vitro. Results Mutations in STAT3 and IL21R , but not STAT1 , led to a decrease in multiple memory CD8+ T-cell subsets in vivo , indicating that STAT3 signaling, possibly downstream of IL-21R, regulates the memory cell pool. Furthermore, STAT3 was important for inducing the lytic machinery in IL-21–stimulated naive CD8+ T cells. However, this defect was overcome by T-cell receptor engagement. Conclusion The IL-21R/STAT3 pathway is required for many aspects of human CD8+ T-cell behavior but in some cases can be compensated by other signals. This helps explain the relatively mild susceptibility to viral disease observed in STAT3- and IL-21R–deficient subjects.
Background The molecular mechanism of class-switch recombination (CSR) in human subjects has not been fully elucidated. The CSR-induced mutations occurring in the switch region of the IgM gene ...(Smu-SHMs) in in vitro CSR-activated and in vivo switched B cells have been analyzed in mice but not in human subjects. Objective We sought to better characterize the molecular mechanism of CSR in human subjects. Methods Smu-SHMs were analyzed in vitro and in vivo by using healthy control subjects and patients with molecularly defined CSR defects. Results We found that Smu-SHMs can be induced in vitro by means of CSR activation in human subjects. We also found large amounts of Smu-SHMs in in vivo class-switched memory B cells, smaller (although significant) amounts in unswitched memory B cells, and very low amounts in naive B cells. In class-switched memory B cells a high frequency of Smu-SHMs was found throughout the Smu. In unswitched memory B cells, the Smu-SHM frequency was significantly decreased in the 5′ part of the Smu. The difference between switched and unswitched B cells suggests that the extension of somatic hypermutation (SHM) to the 5′ upstream region of the Smu might be associated with the effective induction of CSR. The analysis of the pattern of mutations within and outside the WRCY/RGYW (W, A/T; R, A/G; and Y, C/T) motifs, as well as the Smu-SHMs, in CD27+ B cells from CD40 ligand (CD40L)–, activation-induced cytidine deaminase (AID)–, and uracil-DNA glycosylase (UNG)–deficient patients revealed the dependence of Smu-SHM on CD40L, AID, UNG, and the mismatch repair system in human subjects. Conclusion CD40L-, AID-, UNG-, and mismatch repair system–dependent Smu-SHMs and extension to the 5′ region of Smu are necessary to accomplish effective CSR in human subjects.
Next-generation DNA sequencing has accelerated the genetic characterization of many human primary immunodeficiency diseases (PIDs). These discoveries can be lifesaving for the affected patients and ...also provide a unique opportunity to study the effect of specific genes on human immune function. In the past 18 months, a number of independent groups have begun to define novel PIDs caused by defects in the caspase recruitment domain family, member 11 (CARD11) –B-cell chronic lymphocytic leukemia/lymphoma 10 (BCL10) –mucosa-associated lymphoid tissue lymphoma translocation gene 1 (MALT1 CBM) signalosome complex. The CBM complex forms an essential molecular link between the triggering of cell-surface antigen receptors and nuclear factor κB activation. Germline mutations affecting the CBM complex are now recognized as the cause of novel combined immunodeficiency phenotypes, which all share abnormal nuclear factor κB activation and dysregulated B-cell development as defining features. For this “Current perspectives” article, we have engaged experts in both basic biology and clinical immunology to capture the worldwide experience in recognizing and managing patients with PIDs caused by CBM complex mutations.
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