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.
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.
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.
Background Chronic granulomatous disease (CGD) is a rare phagocytic disorder that results in not only infections but also potentially severe inflammatory manifestations that can be difficult to ...diagnose and treat. Objective To describe inflammatory manifestations in a single-center cohort of patients with CGD. Methods Medical records of patients treated at Necker-Enfants Malades Hospital (Paris, France) between 1968 and 2009 and registered at the French National Reference Center for Primary Immunodeficiencies (CEREDIH) were retrospectively reviewed. Results In a study population of 98 patients, a total of 221 inflammatory episodes were recorded in 68 individuals (69.4%). The incidence rate of inflammatory episodes was 0.15 per person-year (0.18 in patients with X-linked XL CGD and 0.08 in patients with autosomal-recessive AR CGD). The most commonly affected organs were the gastrointestinal tract (in 88.2% of the patients), lungs (26.4%), the urogenital tract (17.6%), and eyes (8.8%). Inflammation at other sites (the skin, central nervous system, and tympanum) and autoimmune manifestations (lupus, arthritis, etc) were recorded in 19.1% and 10.3% of the patients, respectively. Granuloma was found in 50% of the 44 histological analyses reviewed. The risk of inflammatory episodes was 2-fold higher in patients with XL-CGD than in patients with AR-CGD (relative risk, 2.22; 95% CI, 1.43-3.46). Conclusions Patients with XL-CGD have a higher risk of developing inflammatory episodes than do patients with AR-CGD. Although the most commonly affected organ is the gastrointestinal tract, other sites can be involved, making the management of patients with CGD a complex, multidisciplinary task.
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.
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.
...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.
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.
Background Ataxia-telangiectasia (A-T) is a rare genetic disease caused by germline biallelic mutations in the ataxia-telangiectasia mutated gene (ATM) that result in partial or complete loss of ATM ...expression or activity. The course of the disease is characterized by neurologic manifestations, infections, and cancers. Objective We studied A-T progression and investigated whether manifestations were associated with the ATM genotype. Methods We performed a retrospective cohort study in France of 240 patients with A-T born from 1954 to 2005 and analyzed ATM mutations in 184 patients, along with neurologic manifestations, infections, and cancers. Results Among patients with A-T, the Kaplan-Meier 20-year survival rate was 53.4%; the prognosis for these patients has not changed since 1954. Life expectancy was lower among patients with mutations in ATM that caused total loss of expression or function of the gene product (null mutations) compared with that seen in patients with hypomorphic mutations because of earlier onset of cancer (mainly hematologic malignancies). Cancer (hazard ratio, 2.7; 95% CI, 1.6-4.5) and respiratory tract infections (hazard ratio, 2.3; 95% CI, 1.4-3.8) were independently associated with mortality. Cancer (hazard ratio, 5.8; 95% CI, 2.9-11.6) was a major risk factor for mortality among patients with null mutations, whereas respiratory tract infections (hazard ratio, 4.1; 95% CI, 1.8-9.1) were the leading cause of death among patients with hypomorphic mutations. Conclusion Morbidity and mortality among patients with A-T are associated with ATM genotype. This information could improve our prognostic ability and lead to adapted therapeutic strategies.
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.