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.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Background Myb-Like, SWIRM, and MPN domains 1 (MYSM1) is a metalloprotease that deubiquitinates the K119-monoubiquitinated form of histone 2A (H2A), a chromatin marker associated with gene ...transcription silencing. Likewise, it has been reported that murine Mysm1 participates in transcription derepression of genes, among which are transcription factors involved in hematopoietic stem cell homeostasis, hematopoiesis, and lymphocyte differentiation. However, whether MYSM1 has a similar function in human subjects remains unclear. Here we describe a patient presenting with a complete lack of B lymphocytes, T-cell lymphopenia, defective hematopoiesis, and developmental abnormalities. Objectives We sought to characterize the underlying genetic cause of this syndrome. Methods We performed genome-wide homozygosity mapping, followed by whole-exome sequencing. Results Genetic analysis revealed that this novel disorder is caused by a homozygous MYSM1 missense mutation affecting the catalytic site within the deubiquitinase JAB1/MPN/Mov34 (JAMM)/MPN domain. Remarkably, during the course of our study, the patient recovered a normal immunohematologic phenotype. Genetic analysis indicated that this improvement originated from a spontaneous genetic reversion of the MYSM1 mutation in a hematopoietic stem cell. Conclusions We here define a novel human immunodeficiency and provide evidence that MYSM1 is essential for proper immunohematopoietic development in human subjects. In addition, we describe one of the few examples of spontaneous in vivo genetic cure of a human immunodeficiency.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Background Thymic stromal lymphopoietin (TSLP) is a major proallergic cytokine that promotes TH 2 responses through dendritic cell (DC) activation. Whether it also plays a role in human autoimmune ...inflammation and associated pathways is not known. Objective In this study we investigated the potential role of several epithelium-derived factors, including TSLP, in inducing IL-23 production by human DCs. We further dissected the role of TSLP in patients with psoriasis, an IL-23–associated skin autoimmune disease. Methods The study was performed in human subjects using primary cells and tissue samples from patients with psoriasis and healthy donors. We analyzed the production of IL-23 in vitro by blood and skin DCs. We studied the function for TSLP and its interaction with other components of the inflammatory microenvironment in situ and ex vivo. Results We found that TSLP synergized with CD40 ligand to promote DC activation and pathogenic IL-23 production by primary blood and skin DCs. In situ TSLP was strongly expressed by keratinocytes of untreated psoriatic lesions but not in normal skin. Moreover, we could demonstrate that IL-4, an important component of the TH 2 inflammation seen in patients with atopic dermatitis, inhibited IL-23 production induced by TSLP and CD40 ligand in a signal transducer and activator of transcription 6–independent manner. Conclusion Our results identify TSLP as a novel player within the complex psoriasis cytokine network. Blocking TSLP in patients with psoriasis might contribute to decreasing DC activation and shutting down the production of pathogenic IL-23.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Background Chronic granulomatous disease (CGD) is a primary immunodeficiency caused by defective production of reactive oxygen species in phagocytic cells that results in life-threatening infections ...and severe inflammatory manifestations. The treatment of inflammatory manifestations remains challenging because it can be associated with an increased risk of infections. Previous studies have shown that phagocytes from patients with CGD display a defect in autophagy and a reactive oxygen species–independent activation of the inflammasome. Objective Because the intersections between autophagy and the inflammasome have been observed in patients with various diseases and microbial infections, we investigated the possible benefit of restoring the autophagy defect through rapamycin, a potent autophagy inducer, in the setting of CGD. Methods We studied 15 patients given a diagnosis of CGD and followed in our institution. All patients were free of any active infection at the time of the study. Results We show that patients with CGD present a consistent inflammatory phenotype defined by (1) increased nonclassical and intermediate monocytes, (2) a proinflammatory state of mononuclear phagocytes with increased IL-1β and TNF-α content, (3) a TH 17 bias of CD4+ T cells, (4) and an increase in IL-17A–secreting neutrophil numbers. We document the reversion of CGD inflammatory status by the mammalian target of rapamycin inhibitor rapamycin on the different immune cell subsets. We also provide evidence for the enhancement of rapamycin's inhibitory effect on IL-1β secretion by the IL-1 receptor antagonist anakinra in phagocytes of patients with CGD. Conclusion Altogether, these data open new therapeutic approaches for CGD-related inflammatory manifestations.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Background Combined immunodeficiencies (CIDs) form a heterogeneous group of inherited conditions that affect the development, function, or both of T cells. The treatment of CIDs with allogeneic ...hematopoietic stem cell transplantation (HSCT) is complicated by a high incidence of life-threatening infections and an increased risk of graft-versus-host disease (GVHD). Objective In view of the growing evidence that alloreactivity is mainly derived from human naive T cells, the selective depletion of naive T cells from allografts might constitute a way of reducing alloreactivity while maintaining memory T-cell responsiveness to pathogens. Methods Five consecutive patients with CIDs and chronic viral infections underwent an allogeneic, HLA-mismatched HSCT. Given the patients' infection status and the potential risk of severe GVHD in the mismatched setting, the CD34− fraction of the allograft was depleted of naive T cells by using magnetic CD45RA beads. Results Engraftment occurred in 4 of the 5 patients. No severe GVHD occurred. In the 4 engrafted patients viral infections were cleared within 2 months of the HSCT, and both cellular and humoral immunity were re-established within a year of the HSCT. An early T-cell response against viral pathogens was documented in 2 patients. Conclusion The present pilot study shows that clinical-grade depletion of naive T cells from an allograft through the use of magnetic CD45RA beads seems to be a feasible and efficacious option for the treatment of patients with CIDs at high risk of GVHD, infection, or both in an HLA-mismatched setting.
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...this risk is lower in patients with T-cell-repleted graft versus patients receiving T-cell-depleted transplant.2 During the posttransplant period, several prophylactic or preemptive antiviral ...treatments may be partially effective by inhibiting viral replication and thus stabilizing the viral load.3,4 However, antiviral drugs can also induce drug resistance and be responsible for organ toxicity.5 Because the transfer of donor memory T lymphocytes directed specifically against immunodominant viral antigens has been shown to control ongoing viral infections, we designed a French multicenter pilot trial (Clinicaltrials.gov: NCT01325636) with the aim of treating pediatric or adult recipients of allogeneic HSCT (regardless of the underlying disease).6-8 Inclusion criteria were as follow: (1) donor chimerism 10% or more at inclusion; (2) biological signs of infection with CMV with resistance or intolerance to conventional antiviral treatments, or CMV or ADV disease with documented organ damage; (3) graft versus host activity (<=II) controlled by corticoids (<1 mg/kg) at the time of inclusion; and (4) donor with positive CMV and/or ADV serology. Patient SAE Delay between SAE and specific T-cell infusion P1 Multivisceral failure due to disseminated CMV infectionDeath Day+7Day+31 P2 None NA P3 None NA P4 Sepsis Day+1 P5 Worsening respiratory symptoms 5 mo P6 Alveolar hemorrhage and death Day+3 P7 Gram-negative sepsis Day+12 P8 Pulmonary hypertension and intraalveolar hemorrhageDeath Day+36Day+96 P9 Multivisceral failureDeath Day+10Day+14 P10 Stage III GvHDDeath from ADV pneumonitis Day+5Day+97 P11 Intraalveolar hemorrhage, hematemesisDeath Day+14Day+25 P12 None NA P13 SepsisPneumopathy Day+23Day+48 P14 Respiratory distressDeath from PTLD Day+20Day+33 P15 Acute respiratory distress syndrome due to CMV and ADV and death Day+3 Table E3 Serious adverse event observed in treated patients GvHD, Graft versus host disease; NA, not applicable; P, patient; PTLD, posttransplant lymphoproliferative disease.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Background Signals emanating from the antigen T-cell receptor (TCR) are required for T-cell development and function. The T lymphocyte–specific protein tyrosine kinase (Lck) is a key component of the ...TCR signaling machinery. On the basis of its function, we considered LCK a candidate gene in patients with combined immunodeficiency. Objective We identify and describe a child with a T-cell immunodeficiency caused by a homozygous missense mutation of the LCK gene (c.1022T>C) resulting from uniparental disomy. Methods Genetic, molecular, and functional analyses were performed to characterize the Lck deficiency, and the associated clinical and immunologic phenotypes are reported. Results The mutant LCK protein (p.L341P) was weakly expressed with no kinase activity and failed to reconstitute TCR signaling in LCK-deficient T cells. The patient presented with recurrent respiratory tract infections together with predominant early-onset inflammatory and autoimmune manifestations. The patient displayed CD4+ T-cell lymphopenia and low levels of CD4 and CD8 expression on the T-cell surface. The residual T lymphocytes had an oligoclonal T-cell repertoire and exhibited a profound TCR signaling defect, with only weak tyrosine phosphorylation signals and no Ca2+ mobilization in response to TCR stimulation. Conclusion We report a new form of T-cell immunodeficiency caused by a LCK gene defect, highlighting the essential role of Lck in human T-cell development and responses. Our results also point out that defects in the TCR signaling cascade often result in abnormal T-cell differentiation and functions, leading to an important risk factor for inflammation and autoimmunity.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Background Defects in phagocytic nicotinamide adenine dinucleotide phosphate oxidase 2 (NOX2) function cause chronic granulomatous disease (CGD), a primary immunodeficiency characterized by ...dysfunctional microbicidal activity and chronic inflammation. Objective We sought to study the effect of chronic inflammation on the hematopoietic compartment in patients and mice with X-linked chronic granulomatous disease (X-CGD). Methods We used immunostaining and functional analyses to study the hematopoietic compartment in patients with CGD. Results An analysis of bone marrow cells from patients and mice with X-CGD revealed a dysregulated hematopoiesis characterized by increased numbers of hematopoietic progenitor cells (HPCs) at the expense of repopulating hematopoietic stem cells (HSCs). In patients with X-CGD, there was a clear reduction in the proportion of HSCs in bone marrow and peripheral blood, and they were also more rapidly exhausted after in vitro culture. In mice with X-CGD, increased cycling of HSCs, expansion of HPCs, and impaired long-term engraftment capacity were found to be associated with high concentrations of proinflammatory cytokines, including IL-1β. Treatment of wild-type mice with IL-1β induced enhanced cell-cycle entry of HSCs, expansion of HPCs, and defects in long-term engraftment, mimicking the effects observed in mice with X-CGD. Inhibition of cytokine signaling in mice with X-CGD reduced HPC numbers but had only minor effects on the repopulating ability of HSCs. Conclusions Persistent chronic inflammation in patients with CGD is associated with hematopoietic proliferative stress, leading to a decrease in the functional activity of HSCs. Our observations have clinical implications for the development of successful autologous cell therapy approaches.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
The CEC count was persistently higher at day 30 in patients with VE (median = 98/mL; range: 1-548) as compared to patients without VE (median = 4/mL; range: 2-52; P = .002) (Fig 1, A). ...the ...increase of CEC counts was significantly higher in patients with VE during the first month post-transplant (median δD0-D30 = 92; range: 16.5-547; P = .007) as compared to patients without (Fig 1, B).  No vascular event (n = 23) Vascular event (n = 11) Total patients (n = 34) Sex ratio female/male 9/14 3/8 12/22 Age: median (range) 3 y (0.5-14 y) 0.9 y (0.25-9 y) 3 and 5 y (0.25-14 y) Diagnosis    SCID 6 2 8 CID 8 5 13 HLH 5 3 8 Neutrophil disorders 3 1 5 Donor    Matched sibling donor 7 0 7 MUD 7 5 12 MMUD 4 2 6 Haploidentical donor 5 4 9 Defibrotide conditioning regimen 8 9 17 Bu/Flu/ATG 16 6 22 Bu/Flu/ThioTEPA/ATG 6 5 11 Mel/Flu/Alemtuzumab 1 0 1 Graft characteristics    In vitro T-depletion 5 6 11 No in vitro T-depletion 18 5 23 CD34 cell dose (106/kg) 8.2 (1.4-24.2) 13 (5-24.2) 10.5 (1.4-24.2) Engraftment day 19 (9-49) 18.5 (13-31) 19 (9-49) Rejection 2 1 3 GVHD 8 3 11 Grade 1-2 6 1 7 Grade 3-4 2 2 4 Time onset (days) 16.5 (2-60) 27 (10-47) 17 (2-60) CMV systemic replication 4 3 7 Severe sepsis 2 1 3 Duration of hospitalization post-HSCT (days) 78 (38-212) 92 (56-155) 83 (38-212) Death 3 5 8 Table I Hematopoietic transplantation characteristics For CD34 number, engraftment, time of onset of GVHD, and duration of post-HSCT hospitalization, median time is indicated with range in brackets.ATG, Antithymocyte globulin; Bu, busulfan; CID, combined immunodeficiency; CMV, cytomegalovirus; Flu, fludarabine; HLH, hemophagocytic lymphohistiocytosis; Mel, Melphalan; MMUD, mismatched unrelated donor; MUD, matched unrelated donor; SCID, severe combined immunodeficiency.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Background Telomeres represent the tips of linear chromosomes. In human subjects telomere maintenance deficiency leads to dyskeratosis congenita (DC), a rare genetic disorder characterized by ...progressive bone marrow failure, accelerated aging, and cancer predisposition. Hoyeraal-Hreidarsson syndrome (HH) is a severe variant of DC in which an early onset of bone marrow failure leading to combined immunodeficiency is associated with microcephaly, cerebellar hypoplasia, and growth retardation. Objectives Limited information is available on the cellular and molecular phenotypes of cells from patients with HH. We analyzed fibroblasts and whole blood cells from 5 patients with HH, 3 of them of unknown molecular origin. Methods Telomere length, cellular senescence rate, telomerase activity, telomeric aberration, and DNA repair pathways were investigated. Results Although patients’ cells exhibit dysfunctional telomeres, sharp differences in the telomeric aberrations and telomere lengths were noted among these patients. In some patients the dysfunctional telomere phenotype was unprecedented and associated with either normal telomere length or with telomeric aberrations akin to fragile telomeres. This result is of particular importance because the molecular diagnosis of these patients is primarily based on telomere length, which therefore misses a subset of patients with telomere dysfunction. Conclusion These observations provide the notions that (1) various telomere defects can lead to similar clinical features, (2) telomere dysfunction in cells from patients with DC/HH is not always associated with short telomeres, and (3) additional factors, likely involved in telomere protection rather than in length regulation, are responsible for a subset of DC/HH.
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