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1.
J Exp Med ; 2019 Sep 19.
Artigo em Inglês | MEDLINE | ID: mdl-31537641

RESUMO

Infection of T cells by Epstein-Barr virus (EBV) causes chronic active EBV infection (CAEBV) characterized by T cell lymphoproliferative disorders (T-LPD) of unclear etiology. Here, we identified two homozygous biallelic loss-of-function mutations in PIK3CD and TNFRSF9 in a patient who developed a fatal CAEBV. The mutation in TNFRSF9 gene coding CD137/4-1BB, a costimulatory molecule expressed by antigen-specific activated T cells, resulted in a complete loss of CD137 expression and impaired T cell expansion toward CD137 ligand-expressing cells. Isolated as observed in one sibling, CD137 deficiency resulted in persistent EBV-infected T cells but without clinical manifestations. The mutation in PIK3CD gene that encodes the catalytic subunit p110δ of the PI3K significantly reduced its kinase activity. Deficient T cells for PIK3CD exhibited reduced AKT signaling, while calcium flux, RAS-MAPK activation, and proliferation were increased, suggestive of an imbalance between the PLCγ1 and PI3K pathways. These skewed signals in T cells may sustain accumulation of EBV-infected T cells, a process controlled by the CD137-CD137L pathway, highlighting its critical role in immunity to EBV.

2.
Front Immunol ; 10: 1936, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31440263

RESUMO

The complement system is crucial for defense against pathogens and the removal of dying cells or immune complexes. Thus, clinical indications for possible complete complement deficiencies include, among others, recurrent mild or serious bacterial infections as well as autoimmune diseases (AID). The diagnostic approach includes functional activity measurements of the classical (CH50) and alternative pathway (AP50) and the determination of the C3 and C4 levels, followed by the quantitative analysis of individual components or regulators. When biochemical analysis reveals the causal abnormality of the complement deficiency (CD), molecular mechanisms remains frequently undetermined. Here, using direct sequencing analysis of the coding region we report the pathogenic variants spectrum that underlie the total or subtotal complement deficiency in 212 patients. We identified 107 different hemizygous, homozygous, or compound heterozygous pathogenic variants in 14 complement genes [C1Qß (n = 1), C1r (n = 3), C1s (n = 2), C2 (n = 12), C3 (n = 5), C5 (n = 12), C6 (n = 9), C7 (n = 17), C8 ß (n = 7), C9 (n = 3), CFH (n = 7), CFI (n = 18), CFP (n = 10), CFD (n = 2)]. Molecular analysis identified 17 recurrent pathogenic variants in 6 genes (C2, CFH, C5, C6, C7, and C8). More than half of the pathogenic variants identified in unrelated patients were also found in healthy controls from the same geographic area. Our study confirms the strong association of meningococcal infections with terminal pathway deficiency and highlights the risk of pneumococcal and auto-immune diseases in the classical and alternative pathways. Results from this large genetic investigation provide evidence of a restricted number of molecular mechanisms leading to complement deficiency and describe the clinical potential adverse events of anti-complement therapy.

3.
Proc Natl Acad Sci U S A ; 116(33): 16463-16472, 2019 Aug 13.
Artigo em Inglês | MEDLINE | ID: mdl-31346092

RESUMO

Heterozygous in-frame mutations in coding regions of human STAT3 underlie the only known autosomal dominant form of hyper IgE syndrome (AD HIES). About 5% of familial cases remain unexplained. The mutant proteins are loss-of-function and dominant-negative when tested following overproduction in recipient cells. However, the production of mutant proteins has not been detected and quantified in the cells of heterozygous patients. We report a deep intronic heterozygous STAT3 mutation, c.1282-89C>T, in 7 relatives with AD HIES. This mutation creates a new exon in the STAT3 complementary DNA, which, when overexpressed, generates a mutant STAT3 protein (D427ins17) that is loss-of-function and dominant-negative in terms of tyrosine phosphorylation, DNA binding, and transcriptional activity. In immortalized B cells from these patients, the D427ins17 protein was 2 kDa larger and 4-fold less abundant than wild-type STAT3, on mass spectrometry. The patients' primary B and T lymphocytes responded poorly to STAT3-dependent cytokines. These findings are reminiscent of the impaired responses of leukocytes from other patients with AD HIES due to typical STAT3 coding mutations, providing further evidence for the dominance of the mutant intronic allele. These findings highlight the importance of sequencing STAT3 introns in patients with HIES without candidate variants in coding regions and essential splice sites. They also show that AD HIES-causing STAT3 mutant alleles can be dominant-negative even if the encoded protein is produced in significantly smaller amounts than wild-type STAT3.

4.
BMC Infect Dis ; 19(1): 302, 2019 Apr 03.
Artigo em Inglês | MEDLINE | ID: mdl-30943907

RESUMO

BACKGROUND: Staphylococcus aureus has emerged as a leading cause of invasive severe diseases with a high rate of morbidity and mortality worldwide. The wide spectrum of clinical manifestations and outcome observed in staphylococcal illness may be a consequence of both microbial factors and variability of the host immune response. CASE PRESENTATION: A 14-years old child developed limb ischemia with gangrene following S. aureus bloodstream infection. Histopathology revealed medium-sized arterial vasculitis. The causing strain belonged to the emerging clone CC1-MSSA and numerous pathogenesis-related genes were identified. Patient's genotyping revealed functional variants associated with severe infections. A combination of virulence and host factors might explain this unique severe form of staphylococcal disease. CONCLUSION: A combination of virulence and genetic host factors might explain this unique severe form of staphylococcal disease.


Assuntos
Infecções Estafilocócicas/diagnóstico , Staphylococcus aureus/genética , Vasculite/diagnóstico , Adolescente , Amputação , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Encéfalo/diagnóstico por imagem , Cefotaxima/farmacologia , Cefotaxima/uso terapêutico , Clindamicina/farmacologia , Clindamicina/uso terapêutico , Humanos , Perna (Membro)/cirurgia , Imagem por Ressonância Magnética , Masculino , Meticilina/farmacologia , Choque Séptico/diagnóstico , Choque Séptico/tratamento farmacológico , Infecções Estafilocócicas/complicações , Infecções Estafilocócicas/microbiologia , Staphylococcus aureus/efeitos dos fármacos , Staphylococcus aureus/isolamento & purificação , Vasculite/complicações , Vasculite/microbiologia
5.
Clin Immunol ; 202: 33-39, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30946917

RESUMO

PURPOSE: Severe combined immunodeficiency (SCID) refers to a group of genetic disorders characterized by greatly compromised cellular and humoral immunity. Children with SCID are asymptomatic at birth, but they die from infections within the first months of life if not treated. Quantification of T-cell receptor excision circles is an extremely sensitive screening method for detecting newborns who may have SCID.The goal of the DEPISTREC study was to evaluate the feasibility of nationwide newborn screening for severe T-cell lymphopenia in France as well as its economic and clinical utility. METHODS: The test universally used for neonatal screening for SCID was the quantification of TRECs on Guthrie cards. We compared a group of 190,517 babies from 48 maternities across the country who underwent newborn SCID screening with a control group of 1.4 million babies out of whom 28 were diagnosed with SCID without such screening during the course of the study. RESULTS: Within the screening group, 62 babies were found to be lymphopenic, including three with SCID. The cost of screening ranged from 4.7€ to €8.15 per newborn. The average 18-month cost was €257,574 vs €204,697 in the control group. CONCLUSIONS: In this large-scale study, we demonstrate that routine SCID screening is feasible and effective. This screening offers the additional benefit of aiding in the diagnosis of non-SCID lymphopenia. Economic evaluation allowed us to calculate the cost per test. Newborn screening may also prevent death by SCID before any curative treatment can be administered. The difference in cost between screened and control children could not be ascertained because of the very low numbers and death of one of the children tested.

6.
Blood ; 134(1): 9-21, 2019 Jul 04.
Artigo em Inglês | MEDLINE | ID: mdl-30940614

RESUMO

Evans syndrome (ES) is a rare severe autoimmune disorder characterized by the combination of autoimmune hemolytic anemia and immune thrombocytopenia. In most cases, the underlying cause is unknown. We sought to identify genetic defects in pediatric ES (pES), based on a hypothesis of strong genetic determinism. In a national, prospective cohort of 203 patients with early-onset ES (median [range] age at last follow-up: 16.3 years ([1.2-41.0 years]) initiated in 2004, 80 nonselected consecutive individuals underwent genetic testing. The clinical data were analyzed as a function of the genetic findings. Fifty-two patients (65%) received a genetic diagnosis (the M+ group): 49 carried germline mutations and 3 carried somatic variants. Thirty-two (40%) had pathogenic mutations in 1 of 9 genes known to be involved in primary immunodeficiencies (TNFRSF6, CTLA4, STAT3, PIK3CD, CBL, ADAR1, LRBA, RAG1, and KRAS), whereas 20 patients (25%) carried probable pathogenic variants in 16 genes that had not previously been reported in the context of autoimmune disease. Lastly, no genetic abnormalities were found in the remaining 28 patients (35%, the M- group). The M+ group displayed more severe disease than the M- group, with a greater frequency of additional immunopathologic manifestations and a greater median number of lines of treatment. Six patients (all from the M+ group) died during the study. In conclusion, pES was potentially genetically determined in at least 65% of cases. Systematic, wide-ranging genetic screening should be offered in pES; the genetic findings have prognostic significance and may guide the choice of a targeted treatment.

7.
JCI Insight ; 52019 Apr 25.
Artigo em Inglês | MEDLINE | ID: mdl-31021819

RESUMO

Bi-allelic inactivating mutations in DOCK8 cause a combined immunodeficiency characterised by severe pathogen infections, eczema, allergies, malignancy and impaired humoral responses. These clinical features result from functional defects in most lymphocyte lineages. Thus, DOCK8 plays a key role in immune cell function. Hematopoietic stem cell transplantation (HSCT) is curative for DOCK8 deficiency. While previous reports have described clinical outcomes for DOCK8 deficiency following HSCT, the effect on lymphocyte reconstitution and function has not been investigated. Our study determined whether defects in lymphocyte differentiation and function in DOCK8-deficient patients were restored following HSCT. DOCK8-deficient T and B lymphocytes exhibited aberrant activation and effector function in vivo and in vitro. Frequencies of αß T and MAIT cells were reduced while γδT cells were increased in DOCK8-deficient patients. HSCT improved, abnormal lymphocyte function in DOCK8-deficient patients. Elevated total and allergen-specific IgE in DOCK8-deficient patients decreased over time following HSCT. Our results document the extensive catalogue of cellular defects in DOCK8-deficient patients, and the efficacy of HSCT to correct these defects, concurrent with improvements in clinical phenotypes. Overall, our findings provide mechanisms at a functional cellular level for improvements in clinical features of DOCK8 deficiency post-HSCT, identify biomarkers that correlate with improved clinical outcomes, and inform the general dynamics of immune reconstitution in patients with monogenic immune disorders following HSCT.

9.
Biol Blood Marrow Transplant ; 25(7): 1363-1373, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30876929

RESUMO

Allogeneic hematopoietic stem cell transplantation (HSCT) is a potentially curative treatment for some inherited disorders, including selected primary immunodeficiencies (PIDs). In the absence of a well-matched donor, HSCT from a haploidentical family donor (HIFD) may be considered. In adult recipients high-dose post-transplant cyclophosphamide (PTCY) is increasingly used to mitigate the risks of graft failure and graft-versus-host disease (GVHD). However, data on the use of PTCY in children (and especially those with inherited disorders) are scarce. We reviewed the outcomes of 27 children transplanted with an HIFD and PTCY for a PID (n = 22) or osteopetrosis (n = 5) in a single center. The median age was 1.5 years (range, .2 to 17). HSCT with PTCY was a primary procedure (n = 21) or a rescue procedure after graft failure (n = 6). The conditioning regimen was myeloablative in most primary HSCTs and nonmyeloablative in rescue procedures. After a median follow-up of 25.6 months, 24 of 27 patients had engrafted. Twenty-one patients are alive and have been cured of the underlying disease. The 2-year overall survival rate was 77.7%. The cumulative incidences of acute GVHD grade ≥ II, chronic GVHD, and autoimmune disease were 45.8%, 24.2%, and 29.6%, respectively. There were 2 cases of grade III acute GVHD and no extensive cGVHD. The cumulative incidences of blood viral replication and life-threatening viral events were 58% and 15.6%, respectively. There was evidence of early T cell immune reconstitution. In the absence of an HLA-identical donor, HIFD HSCT with PTCY is a viable option for patients with life-threatening inherited disorders.

10.
J Allergy Clin Immunol Pract ; 7(6): 1986-1995.e3, 2019 Jul - Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30878710

RESUMO

BACKGROUND: Autosomal-dominant signal transducer and activator of transcription 3 (STAT3) deficiency predisposes to recurrent bacterial pneumonia, complicated by bronchiectasis and cavitations. Aspergillosis is a major cause of morbidity in these patients. However, its diagnosis, classification, and treatment are challenging. OBJECTIVE: We aimed to assess the prevalence and describe the clinical, mycological, and radiological presentation and related therapy and outcome of Aspergillus infections of the respiratory tract in the STAT3-deficient patients of the National French cohort. METHODS: We performed a retrospective study of all pulmonary aspergillosis cases in STAT3-deficient patients (n = 74). Clinical and mycological data were collected up to October 2015 and imaging was centralized. RESULTS: Twenty-one episodes of pulmonary aspergillosis in 13 (17.5%) STAT3-deficient patients were identified. The median age at first episode was 13 years (interquartile range, 10-26 years). Ninety percent of patients had previous bronchiectasis or cavitations. Infections were classified as follows: 5 single aspergilloma, 9 chronic cavity pulmonary aspergillosis, 5 allergic bronchopulmonary aspergillosis-like disease, and 2 mixed forms of concomitant allergic bronchopulmonary aspergillosis-like disease and chronic cavity pulmonary aspergillosis. No invasive aspergillosis cases were identified. Aspergillus species were isolated in 71% of episodes and anti-Aspergillus antibodies in 93%. Eleven episodes were breakthrough infections. Antifungal treatment was prolonged, with a median of 13 months, and 6 patients (7 episodes) required surgery, with a high rate of postsurgical complications. One patient died and 6 had a relapse. CONCLUSIONS: Chronic and allergic forms of aspergillosis occurred in 17.5% of STAT3-deficient patients, mostly in lung cavities. Almost half had recurrences, despite prolonged antifungal treatment and/or surgery.

11.
Clin Immunol ; 201: 30-34, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30776520

RESUMO

Severe combined immunodeficiencies (SCID) comprise a group of genetic diseases characterized by abrogated development of T lymphocytes. In some case reports of atypical SCID patients elevated proportions of γδ T lymphocytes have been reported. However, it is unknown whether these γδ T cells modulate or reflect the patient's clinical phenotype. We investigated the frequency of elevated γδ T cell proportions and associations with clinical disease manifestations in a cohort of 76 atypical SCID patients. Increased proportions of γδ T lymphocytes were present in approximately 60% of these patients. Furthermore, we identified positive correlations between elevated proportions of γδ T cells and the occurrence of CMV infections and autoimmune cytopenias. We discuss that CMV infections might trigger an expansion of γδ T lymphocytes, which could drive the development of autoimmune cytopenias. We advocate that atypical SCID patients should be screened for elevated proportions of γδ T lymphocytes, CMV infection and autoimmune cytopenias.

14.
J Clin Immunol ; 39(1): 55-64, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30552536

RESUMO

PURPOSE: Progressive multifocal leukoencephalopathy (PML) is a rare but severe demyelinating disease caused by the polyomavirus JC (JCV) in immunocompromised patients. We report a series of patients with primary immune deficiencies (PIDs) who developed PML. METHODS: Retrospective observational study including PID patients with PML. Clinical, immunological, imaging features, and outcome are provided for each patient. RESULTS: Eleven unrelated patients with PIDs developed PML. PIDs were characterized by a wide range of syndromic or genetically defined defects, mostly with combined B and T cell impairment. Genetic diagnosis was made in 7 patients. Before the development of PML, 10 patients had recurrent infections, 7 had autoimmune and/or inflammatory manifestations, and 3 had a history of malignancies. Immunologic investigations showed CD4+ lymphopenia (median 265, range 50-344) in all cases. Six patients received immunosuppressive therapy in the year before PML onset, including prolonged steroid therapy in 3 cases, rituximab in 5 cases, anti-TNF-α therapy, and azathioprine in 1 case each. Despite various treatments, all but 1 patient died after a median of 8 months following PML diagnosis. CONCLUSION: PML is a rare but fatal complication of PIDs. Many cases are secondary to immunosuppressive therapy warranting careful evaluation before initiation subsequent immunosuppression during PIDs.

16.
J Clin Invest ; 2018 Dec 06.
Artigo em Inglês | MEDLINE | ID: mdl-30521495

RESUMO

ARHGEF1 is a RhoA-specific guanine nucleotide exchange factor expressed in hematopoietic cells. We used whole-exome sequencing to identify compound heterozygous mutations in ARHGEF1, resulting in the loss of ARHGEF1 protein expression in two primary-antibody-deficient siblings presenting with recurrent severe respiratory tract infections and bronchiectasis. Both ARHGEF1-deficient patients showed an abnormal B cell immunophenotype, with a deficiency in marginal-zone and memory B cells and an increased frequency of transitional B cells. Furthermore, the patients' blood contained immature myeloid cells. Analysis of a mediastinal lymph node from one patient highlighted the small size of the germinal centres and an abnormally high plasma cell content. On the molecular level, T and B lymphocytes from both patients displayed low RhoA activity and low steady-state actin polymerization (even after stimulation of lysophospholipid receptors). As a consequence of disturbed regulation of the RhoA downstream target ROCK, the patients' lymphocytes failed to efficiently restrain AKT phosphorylation. Enforced ARHGEF1 expression or drug-induced activation of RhoA in patients' cells corrected the impaired actin polymerization and AKT regulation. Our results indicate that ARHGEF1 activity in human lymphocytes is involved in controlling actin cytoskeleton dynamics, restraining PI3K/AKT signalling, and confining B lymphocytes and myelocytes within their dedicated functional environment.

17.
Artigo em Inglês | MEDLINE | ID: mdl-30391550

RESUMO

BACKGROUND: Biallelic variations in the DOCK8 gene cause a combined immunodeficiency with eczema, recurrent bacterial and viral infections, and malignancy. Natural disease outcome is dismal, but allogeneic hematopoietic stem cell transplantation (HSCT) can cure the disease. OBJECTIVE: To determine outcome of HSCT for DOCK8 deficiency and define possible outcome variables. METHODS: We performed a retrospective study of the results of HSCT in a large international cohort of DOCK8 deficient patients. RESULTS: We identified 81 patients from 22 centers transplanted at a median age of 9.7 years (range: 0.7-27.2) between 1995 and 2015. After median follow-up of 26 months (3-135), 68 of 81 patients are alive (84%). Severe acute (III-IV) or chronic graft versus host disease (GVHD) occurred in 11% and 10% respectively. Causes of death wereinfections (n=5), GVHD (5), multi-organ failure (2) and pre-existent lymphoma (1). Survival after matched related (n=40) or unrelated (35) HSCT was 89% and 81%, respectively. Reduced toxicity conditioning based on either treosulfan or reduced-dose busulfan resulted in superior survival compared to fully myeloablative busulfan-based regimens (97% vs. 78%; p=0.049). 96% of patients aged <8 years at HSCT survived, compared to 78% of those ≥8 years (p=0.06). Of 73 patients with chimerism data available, 65 (89%) had >90% donor T-cell chimerism at last follow-up. Not all disease manifestations responded equally well to HSCT: eczema, infections and Mollusca resolved better than food allergies or failure to thrive. CONCLUSION: HSCT is curative in most DOCK8 deficient patients, confirming this approach as the treatment of choice. HSCT using a reduced toxicity regimen may offer the best chance for survival.

18.
PLoS One ; 13(10): e0205826, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30365510

RESUMO

Mutations in interleukin-10 receptor (IL-10R) genes are one cause of very early-onset inflammatory bowel disease with perianal lesions, which can be cured by hematopoietic stem cell transplantation. Using a functional test, which assesses responsiveness of peripheral monocytes to IL-10, we identified three unrelated Portuguese patients carrying two novel IL-10RB mutations. In the three patients, sequencing of genomic DNA identified the same large deletion of exon 3 which precluded protein expression. This mutation was homozygous in two patients born from consanguineous families and heterozygous in the third patient born from unrelated parents. Microsatellite analysis of the IL10RB genomic region revealed a common haplotype in the three Portuguese families pointing to a founder deletion inherited from a common ancestor 400 years ago. In the third patient, surface expression of IL-10R was normal but signaling in response to IL-10 was impaired. Complementary DNA sequencing and next-generation sequencing of IL10RB locus with custom-made probes revealed a ≈ 6 Kb duplication encompassing the exon 6 which leads to a frameshift mutation and a loss of the TYK2-interacting Box 2 motif. Altogether, we describe two novel copy number variations in IL10RB, one with founder effect and one preserving cell surface expression but abolishing signaling.

20.
Pediatr Dermatol ; 35(6): e375-e377, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30189467

RESUMO

Transporter associated with antigen processing (TAP) is essential for the stabilization and surface expression of major histocompatibility complex class I molecules of all nucleated cells. TAP deficiency syndrome, also known as bare lymphocyte syndrome type I, is a rare primary immunodeficiency disorder. We report a case of TAP1 deficiency revealed by skin lesions long before the occurrence of respiratory infectious manifestations.


Assuntos
Membro 2 da Subfamília B de Transportadores de Cassetes de Ligação de ATP/genética , Granuloma/patologia , Imunodeficiência Combinada Severa/diagnóstico , Dermatopatias/etiologia , Pré-Escolar , Feminino , Antígenos de Histocompatibilidade Classe I , Humanos , Mutação , Pele/patologia
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