The patients, aged between 5 and 12 years, exhibited the phenotypic variability associated with TMEM173-activating mutations,2-4 with lung disease and systemic inflammation being the major features ...in patient 1 (P1) and patient 3 (P3), while in patient 2 (P2) skin involvement was most prominent (Fig 1; see Supplemental Text and Table E1 in this article's Online Repository at www.jacionline.org). Modest and incomplete downregulation of ISG was recently described in splenic B cells of mice treated with tofacitinib, a JAK1/3 inhibitor, with differential signaling effects suggesting currently poorly understood facets of IFN regulation.9 In this regard, our kinetic ex vivo experiments provide insights into the rapid dynamic changes in IFN signaling secondary to JAK1 blockade.
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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 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.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Background Primary immunodeficiencies are a rare group of inborn diseases characterized by a broad clinical and genetic heterogeneity. Substantial advances in the identification of the underlying ...molecular mechanisms can be achieved through the study of patients with increased susceptibility to specific infections and immune dysregulation. We evaluated 3 siblings from a consanguineous family presenting with EBV-associated B-cell lymphoproliferation at an early age (12, 7½, and 14 months, respectively) and profound naive T-cell lymphopenia. Objective On the basis of the hypothesis of a rare inborn immunodeficiency of autosomal recessive inheritance, we sought to characterize the underlying genetic defect. Methods We performed genome-wide homozygosity mapping, followed by whole-exome sequencing. Results We identified a homozygous inherited missense mutation in the gene encoding Coronin-1A (CORO1A) in the 3 siblings. This mutation, p. V134M, results in the substitution of an evolutionarily conserved amino acid within the β-propeller domain, which abrogates almost completely the protein expression in the patients' cells. In addition to a significant diminution of naive T-cell numbers, we found impaired development of a diverse T-cell repertoire, near-to-absent invariant natural killer T cells, and severely diminished mucosal-associated invariant T cell numbers. Conclusions Our findings define a new clinical entity of a primary immunodeficiency with increased susceptibility to EBV-induced lymphoproliferation in patients associated with hypomorphic Coronin-1A mutation.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Background Most children with primary immunodeficiencies (PIDs) now reach adulthood. However, few studies have evaluated their health status and health-related quality of life (HRQoL). Objective To ...investigate long-term morbidity, the French Reference Center for PIDs initiated a prospective multicenter cohort: the French Childhood Immune Deficiency Long-term Cohort. The data collected were used to assess the physical health condition of patients who reached adulthood and the effect on their quality of life. Methods Patients were asked to complete health status questionnaires. A severity score (grade 1 mild to grade 4 life-threatening) was assigned to each health condition. The HRQoL of patients was compared with age- and sex-matched French normal values by using the 36-item Short-Form Survey (SF-36) HRQoL questionnaire. Results Among 329 participants, the mean age at evaluation was 27.6 years, with a 21-year mean follow-up after diagnosis; 43% reported at least 1 grade 4 health condition, and 86% reported at least 1 grade 3 (severe) or 4 health condition. Twenty-five (7.6%) patients had been treated for cancer. Compared with the French normal values, adults with PIDs scored significantly lower for all HRQoL domains. HRQoL was strongly associated with the burden of health conditions. The association with grade 4 or grade 3-4 health conditions was highly significant for all physical and mental domains. Conclusion Adults with PIDs diagnosed during childhood experienced a heavy burden of health conditions, which affected their HRQoL. Our results emphasize the need to closely monitor this vulnerable population.
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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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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
...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 The inclusion of severe combined immunodeficiency (SCID) in a Europe-wide screening program is currently debated. Objective In making a case for inclusion in the French newborn screening ...program, we explored the costs incurred and potentially saved by early management of SCID. Methods For test costs, a microcosting study documented the resources used in a laboratory piloting a newborn screening test on Guthrie cards using the T-cell receptor excision circle quantification method. For treatment costs, patients with SCID admitted to the national reference center for primary immunodeficiency in France between 2006 and 2010 were included. Costs of admission were estimated from actual national production costs. We estimated the costs for patients who underwent early versus delayed hematopoietic stem cell transplantation (HSCT; age, ≤3 vs >3 months, respectively). Results The unit cost of the test varied between €4.69 and €6.79 for 33,800 samples per year, depending on equipment use and saturation. Of the 30 patients included, 27 underwent HSCT after age 3 months. At 1 year after HSCT, 10 of these had died, and all 3 patients undergoing early transplantation survived. The medical costs for HSCT after 3 months were €195,776 (interquartile range, €165,884-€257,160) versus €86,179 (range, €59,014-€272,577) when performed before 3 months of age. In patients undergoing late transplantation, active infection contributed to high cost and poor outcome. Conclusion Early detection of SCID could reduce the cost of treatment by €50,000-100,000 per case. Assuming a €5 unit cost per test, the incidence required to break even is 1:20,000; however, if the survival advantage of HSCT before 3 months is confirmed, universal screening is likely to be cost-effective.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Background PRKDC encodes for DNA-dependent protein kinase catalytic subunit (DNA-PKcs), a kinase that forms part of a complex (DNA-dependent protein kinase DNA-PK) crucial for DNA double-strand break ...repair and V(D)J recombination. In mice DNA-PK also interacts with the transcription factor autoimmune regulator (AIRE) to promote central T-cell tolerance. Objective We sought to understand the causes of an inflammatory disease with granuloma and autoimmunity associated with decreasing T- and B-cell counts over time that had been diagnosed in 2 unrelated patients. Methods Genetic, molecular, and functional analyses were performed to characterize an inflammatory disease evocative of a combined immunodeficiency. Results We identified PRKDC mutations in both patients. These patients exhibited a defect in DNA double-strand break repair and V(D)J recombination. Whole-blood mRNA analysis revealed a strong interferon signature. On activation, memory T cells displayed a skewed cytokine response typical of TH 2 and TH 1 but not TH 17. Moreover, mutated DNA-PKcs did not promote AIRE-dependent transcription of peripheral tissue antigens in vitro . The latter defect correlated in vivo with production of anti–calcium-sensing receptor autoantibodies, which are typically found in AIRE-deficient patients. In addition, 9 months after bone marrow transplantation, patient 1 had Hashimoto thyroiditis, suggesting that organ-specific autoimmunity might be linked to nonhematopoietic cells, such as AIRE-expressing thymic epithelial cells. Conclusion Deficiency of DNA-PKcs, a key AIRE partner, can present as an inflammatory disease with organ-specific autoimmunity, suggesting a role for DNA-PKcs in regulating autoimmune responses and maintaining AIRE-dependent tolerance in human subjects.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
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