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1.
Artigo em Inglês | MEDLINE | ID: mdl-32060950

RESUMO

BACKGROUND: There is no data regarding the prevalence of malignancies in patients with primary immunodeficiency (PID) in Turkey. Along with the prevalence of malignancy, we aimed to present the types of malignancy and define the underlying immune deficiency of the patients. METHOD: Between the years 1992 and 2018 years, from 5 tertiary immunology clinics, fifty-nine patients with PID who developed malignancy were included. All patients were evaluated for demographics, clinical features, and prognosis. RESULTS: The prevalence of malignancy in our cohort was detected as 0.9% (59/6392). The male to female ratio was 1.8 (38/21), and the median age of patients was 14 years (range: 1.5 - 51). The median age at diagnosis of malignancy was 10 years (range: 1.5 - 51). Ataxia-telangiectasia was the most frequent PID in patients with malignancy (n= 19, 32.2%), and non-Hodgkin lymphoma was the most common malignancy (n= 32, 51.6%). The rate of malignancy in DOCK8 deficiency (n=7/43, 16.3%) was higher than AT (n=19/193, 9.8%), WAS (n=2/22, 9.1%) and CVID (n=11/205, 5.4%). EBV quantitative PCR was positive in 16 out of 53 patients (30.2%). Three patients had secondary malignancies. Remission was achieved in 26 patients (44.1%). However, 31 patients (52.5%) died. Two patients (3.4%) are still on chemotherapy. CONCLUSION: This study is the largest cohort investigating the association of malignancy in patients with PID in Turkey. While lymphoid malignancies were the most common malignancy and observed more frequently in AT patients, the risk for malignancy was higher in patients with DOCK8 deficiency then AT.

2.
Horm Res Paediatr ; : 1-7, 2020 Jan 23.
Artigo em Inglês | MEDLINE | ID: mdl-31972562

RESUMO

BACKGROUND: Besides local reactions, systemic hypersensitivity reactions such as urticaria, anaphylaxis, serum sickness and Henoch-Schönlein purpura (HSP) have been reported during gonadotropin-releasing hormone (GnRH) analogue treatment. AIM: To present the clinical presentation of 9 cases with systemic hypersensitivity reactions to GnRH analogues and discuss the management of such reactions based on our experience. PATIENTS AND METHODS: Nine of 232 (3.8%) patients with central precocious puberty receiving GnRH analogue treatment had systemic hypersensitivity reactions in 4 years' period. Six patients had a type 1 hypersensitivity reaction (generalized hives, pruritus, and/or edema) to triptorelin acetate (TA), 2 patients to leuprolide acetate (LA), and 1 patient to both medications who also developed anaphylaxis to LA during intradermal test (IDT). Another patient on TA had skin lesions suggestive of HSP. GnRH analogue treatment was discontinued in 2 patients after discussion with the parents. Treatment was changed to another GnRH analogue preparation in 6 patients and was maintained with the same medication with antihistamines and corticosteroid premedication in 1 patient. None of the patients developed new reactions after these precautions. CONCLUSION: Systemic hypersensitivity reactions should be carefully evaluated and cross-reaction to the other GnRH analogues should be kept in mind. Discontinuation of GnRH analogue is always an option. However, if continuation of GnRH analogue is elected, we recommend switching to an alternative GnRH analogue, which should be considered only after a skin prick test (SPT) and IDT. In the lack of the possibility to perform SPT and IDT, injections may be administered under strict medical supervision in a well-equipped facility to manage anaphylaxis. We discuss additional options in situations where alternative GnRH analogues are unavailable, which enabled us to continue treatment in most cases without further problems.

3.
Int Arch Allergy Immunol ; : 1-10, 2020 Jan 03.
Artigo em Inglês | MEDLINE | ID: mdl-31901904

RESUMO

INTRODUCTION: Common variable immunodeficiency (CVID) is characterized by recurrent infections, autoimmunity, lymphoproliferation, hypogammaglobulinemia, and defective antibody production. In CVID, B-cell abnormalities were described to predict end organ involvement and prognosis. Pediatric-onset CVID is much rarer than adult CVID, and lymphocyte subset abnormalities have not been thoroughly evaluated. OBJECTIVE: We sought to determine lymphocyte subset abnormalities and their association with end organ involvement in pediatric-onset CVID patients. METHODS: The clinical manifestations and laboratory findings including absolute numbers and percentages of B-, T-, and NK cell populations were assessed in pediatric-onset CVID patients and compared to age-matched healthy controls. The patients were divided into 2 groups according to age at assessment (pediatric CVID patients: 10-16 years, n = 9; and adult CVID patients: >16 years, n = 13). The comparisons between lymphocyte subsets and organ involvement were also evaluated. RESULTS: Mean age at symptom onset was 18 (3-204) months. All CVID patients with pediatric onset had decreased levels of total and memory B cells, CD4+ T cells, CD4+CD45RA+ naive T cells, and recent thymic emigrant (RTE) cells. On the other hand, they had increases in CD8+CD45RO+ memory T cells. Interestingly, adult CVID patients demonstrated high frequencies of activated and double-negative T cells, which were unique only for this group of patients. Specific cellular abnormalities associated with the reduction in B and NK cells and increase in CD8+ T cells were found in patients with bronchiectasis. Moreover, in pediatric CVID patients, low serum IgA levels and decreased numbers of naive T and RTE cells were determined as risk factors for chronic diarrhea. CONCLUSIONS: Specific abnormalities in B- and T-lymphocyte compartments were identified in pediatric-onset CVID patients and appear to be associated with end organ manifestations.

4.
Pediatr Blood Cancer ; 67(2): e28091, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31736244

RESUMO

BACKGROUND: Regarding the difficulties in recognition and management of the malignancies in primary immune deficiencies (PIDs), we aimed to present the types, risk factors, treatment options, and prognosis of the cancers in this specific group. METHODS: Seventeen patients with PID who developed malignancies or malignant-like diseases were evaluated for demographics, clinical features, treatment, toxicity, and prognosis. RESULTS: The median age of malignancy was 12.2 years (range, 2.2-26). Lymphoma was the most frequent malignancy (n = 7), followed by adenocarcinoma (n = 3), squamous cell carcinoma (n = 2), cholangiocarcinoma (n = 1), Wilms tumor (n = 1), and acute myeloid leukemia (n = 1). Nonneoplastic lymphoproliferation mimicking lymphoma was observed in five patients. The total overall survival (OS) was 62.5% ± 12.1%. The OS for lymphoma was 62.2% ± 17.1% and found to be inferior to non-PID patients with lymphoma (P = 0.001). CONCLUSION: In patients with PIDs, malignancy may occur and negatively affect the OS. The diagnosis can be challenging in the presence of nonneoplastic lymphoproliferative disease or bone marrow abnormalities. Awareness of susceptibility to malignant transformation and early diagnosis with multidisciplinary approach can save the patients' lives.

6.
Allergy ; 2019 Oct 09.
Artigo em Inglês | MEDLINE | ID: mdl-31596517

RESUMO

BACKGROUND: Dedicator of cytokinesis 8 (DOCK8) deficiency is the main cause of the autosomal recessive hyper-IgE syndrome (HIES). We previously reported the selective loss of group 3 innate lymphoid cell (ILC) number and function in a Dock8-deficient mouse model. In this study, we sought to test whether DOCK8 is required for the function and maintenance of ILC subsets in humans. METHODS: Peripheral blood ILC1-3 subsets of 16 DOCK8-deficient patients recruited at the pretransplant stage, and seven patients with autosomal dominant (AD) HIES due to STAT3 mutations, were compared with those of healthy controls or post-transplant DOCK8-deficient patients (n = 12) by flow cytometry and real-time qPCR. Sorted total ILCs from DOCK8- or STAT3-mutant patients and healthy controls were assayed for survival, apoptosis, proliferation, and activation by IL-7, IL-23, and IL-12 by cell culture, flow cytometry, and phospho-flow assays. RESULTS: DOCK8-deficient but not STAT3-mutant patients exhibited a profound depletion of ILC3s, and to a lesser extent ILC2s, in their peripheral blood. DOCK8-deficient ILC1-3 subsets had defective proliferation, expressed lower levels of IL-7R, responded less to IL-7, IL-12, or IL-23 cytokines, and were more prone to apoptosis compared with those of healthy controls. CONCLUSION: DOCK8 regulates human ILC3 expansion and survival, and more globally ILC cytokine signaling and proliferation. DOCK8 deficiency leads to loss of ILC3 from peripheral blood. ILC3 deficiency may contribute to the susceptibility of DOCK8-deficient patients to infections.

7.
Curr Pediatr Rev ; 15(4): 245-250, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31530267

RESUMO

The life span of patients with primary and secondary immunodeficiencies has increased due to recent advances in diagnostic and therapeutic strategies. Primary immune deficiencies (PIDs) are genetic disorders that predispose patients to frequent infections, autoimmunity and malignancies. Genomic instability due to defective DNA repair processes and other unknown mechanisms in patients with PID leads to an enhanced risk of cancer. PIDs were originally described as rare diseases occurring only in infants and young children, which are associated with severe clinical symptoms. However, advances in gene sequencing technologies, have revealed that they are much more common than originally appreciated and are present in older children, adolescents, and adults. After infection, malignancy is the most prevalent cause of death in both children and adults with PIDs. The overall risk of developing cancer in patients with PID is estimated to range from 4.7 to 5.7 percent. A 1.4 to 1.6-fold excess relative risk of cancer has been reported for PIDs. Increasing awareness among physicians regarding PID and cancer may lead to earlier diagnosis which may decrease morbidity and mortality. In this paper, we review the various categories of PIDs in children and highlight their association with various malignancies. MEDLINE was searched to identify articles for inclusion. Three authors have independently screened literature search results from MEDLINE and abstracted data from studies dealing with cancers of children among primary immune deficiencies.

8.
J Clin Invest ; 129(10): 4194-4206, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31449058

RESUMO

Polymerase δ is essential for eukaryotic genome duplication and synthesizes DNA at both the leading and lagging strands. The polymerase δ complex is a heterotetramer comprising the catalytic subunit POLD1 and the accessory subunits POLD2, POLD3, and POLD4. Beyond DNA replication, the polymerase δ complex has emerged as a central element in genome maintenance. The essentiality of polymerase δ has constrained the generation of polymerase δ-knockout cell lines or model organisms and, therefore, the understanding of the complexity of its activity and the function of its accessory subunits. To our knowledge, no germline biallelic mutations affecting this complex have been reported in humans. In patients from 2 independent pedigrees, we have identified what we believe to be a novel syndrome with reduced functionality of the polymerase δ complex caused by germline biallelic mutations in POLD1 or POLD2 as the underlying etiology of a previously unknown autosomal-recessive syndrome that combines replicative stress, neurodevelopmental abnormalities, and immunodeficiency. Patients' cells showed impaired cell-cycle progression and replication-associated DNA lesions that were reversible upon overexpression of polymerase δ. The mutations affected the stability and interactions within the polymerase δ complex or its intrinsic polymerase activity. We believe our discovery of human polymerase δ deficiency identifies the central role of this complex in the prevention of replication-related DNA lesions, with particular relevance to adaptive immunity.

9.
Scand J Immunol ; 90(5): e12809, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31322747

RESUMO

We evaluated 18 DiGeorge syndrome (DGS) patients and aimed to investigate the immunological changes in this population. DGS patients with low naive CD4+ T and CD8+ T cells were defined as high-risk (HR) patients, whereas patients with normal numbers of naive CD4+ and CD8+ T cells were defined as standard risk (SR) patients. Level of serum IgM, CD3+ T cell counts and percentages of class-switched memory B cells were significantly low in HR group compared to SR ones. Severe infections and persistent hypoparathyroidism were detected significantly higher in HR group. Patients with reduced percentages of class-switched B cells had earlier onset of infection, lower blood IgM, lower CD4+ and CD8+ T counts than patients with normal class-switched memory B cells. Decreased levels of IgM were associated with low numbers of naive CD4+ and recent thymic emigrants T cells. Monitoring the immune changes of patients with DGS would be useful to predict the severe phenotype of disease.


Assuntos
Linfócitos B/imunologia , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Síndrome de DiGeorge/imunologia , Imunoglobulina M/sangue , Adolescente , Adulto , Criança , Pré-Escolar , Síndrome de DiGeorge/genética , Feminino , Humanos , Hipoparatireoidismo/diagnóstico , Switching de Imunoglobulina/imunologia , Memória Imunológica/imunologia , Lactente , Contagem de Linfócitos , Masculino
10.
Pediatr Blood Cancer ; 66(10): e27923, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31321910

RESUMO

BACKGROUND: Severe congenital neutropenia is a rare disease, and autosomal dominantly inherited ELANE mutation is the most frequently observed genetic defect in the registries from North America and Western Europe. However, in eastern countries where consanguineous marriages are common, autosomal recessive forms might be more frequent. METHOD: Two hundred and sixteen patients with severe congenital neutropenia from 28 different pediatric centers in Turkey were registered. RESULTS: The most frequently observed mutation was HAX1 mutation (n = 78, 36.1%). A heterozygous ELANE mutation was detected in 29 patients (13.4%) in our cohort. Biallelic mutations of G6PC3 (n = 9, 4.3%), CSF3R (n = 6, 2.9%), and JAGN1 (n = 2, 1%) were also observed. Granulocyte colony-stimulating factor treatment was given to 174 patients (80.6%). Two patients died with infectious complications, and five patients developed myelodysplastic syndrome/acute myeloblastic leukemia. The mean (± mean standard error) follow-up period was 129.7 ± 76.3 months, and overall survival was 96.8% (CI, 94.4-99.1%) at the age of 15 years. In Turkey, severe congenital neutropenia mostly resulted from the p W44X mutation in the HAX1 gene. CONCLUSION: In Turkey, mutation analysis should be started with HAX1, and if this is negative, ELANE and G6PC3 should be checked. Because of the very high percentage of consanguineous marriage, rare mutations should be tested in patients with a negative mutation screen.

11.
J Allergy Clin Immunol Pract ; 7(8): 2790-2800.e15, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31238161

RESUMO

BACKGROUND: LPS-responsive beige-like anchor (LRBA) deficiency presents with susceptibility to infections, autoimmunity, and lymphoproliferation. The long-term efficacy of cytotoxic T-lymphocyte-associated antigen 4-immunoglobulin (abatacept) as targeted therapy for its immune dysregulatory features remains to be established. OBJECTIVE: To determine the clinical and immunologic features of LRBA deficiency and long-term efficacy of abatacept treatment in controlling the different disease manifestations. METHODS: Twenty-two LRBA-deficient patients were recruited from different immunology centers and followed prospectively. Eighteen patients on abatacept were evaluated every 3 months for long-term clinical and immunologic responses. LRBA expression, lymphocyte subpopulations, and circulating T follicular helper cells were determined by flow cytometry. RESULTS: The mean age of the patients was 13.4 ± 7.9 years, and the follow-up period was 3.4 ± 2.3 years. Recurrent infections (n = 19 [86.4%]), immune dysregulation (n = 18 [81.8%]), and lymphoproliferation (n = 16 [72.7%]) were common clinical features. The long-term benefits of abatacept in 16 patients were demonstrated by complete control of lymphoproliferation and chronic diarrhea followed by immune dysregulation, most notably autoimmune cytopenias. Weekly or every other week administration of abatacept gave better disease control compared with every 4 weeks. There were no serious side effects related to the abatacept therapy. Circulating T follicular helper cell frequencies were found to be a reliable biomarker of disease activity, which decreased on abatacept therapy in most subjects. However, high circulating T follicular helper cell frequencies persisted in 2 patients who had a more severe disease phenotype that was relatively resistant to abatacept therapy. CONCLUSIONS: Long-term abatacept therapy is effective in most patients with LRBA deficiency.

13.
Int Arch Allergy Immunol ; 178(1): 1-9, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30404088

RESUMO

BACKGROUND AND OBJECTIVES: About 65-80% of children with IgE-mediated cow's milk allergy (CMA) can tolerate extensively heated milk. We have invested in the mass fabrication of a test product containing milk protein baked at 180°C for 30 min (SUTMEK-milk) and a milk-free placebo (SUTMEK-placebo) to carry out a standardised double-blind placebo-controlled food challenge (DBPCFC) test in patients with CMA. METHODS: We studied children with IgE-mediated CMA between 13 and 48 months of age. Specific IgEs (spIgE) to milk proteins were quantified. A DBPCFC with our bakery products was performed, and factors determining reactivity to extensively heated milk were evaluated. We also tested the applicability of SUTMEK products in baked-milk oral immunotherapy in a pilot assessment. RESULTS: We studied 15 children (8 girls, 7 boys) with a median age of 26 months (range: 13-48 months). Nine (60%) patients tolerated a challenge with extensively heated milk, while 6 (40%) were found reactive (anaphylaxis: 2, wheezing: 2, urticaria: 2). spIgE to milk, α-lactalbumin, and casein, and the wheal diameter on skin prick testing were higher in the reactive group than the tolerant groups (p = 0.001, p = 0.001, p = 0.002, and p = 0.048, respectively). Receiver-operating characteristic curve analyses yielded the following cut-off values for spIgEs that would predict a reactivity to extensively heated milk; milk: 25 kU/L (area under curve, AUC: 0.981), casein: 32 kU/L (AUC: 0.983), and α-lactalbumin: 17 kU/L (AUC: 0.981). Nine patients have tolerated well a continued daily consumption of SUTMEK-milk or -placebo for 6 months at the desired doses. CONCLUSIONS: Our bakery products were successfully used in DBPCFC studies and qualified as an acceptable tool for use in the research of interventional tolerance induction. Although spIgE appears useful in determining children at high risk of reacting to extensively heated milk, the predictive cut-off values are still far from being perfect.


Assuntos
Laticínios/efeitos adversos , Tolerância Imunológica , Imunoterapia , Hipersensibilidade a Leite/imunologia , Hipersensibilidade a Leite/terapia , Leite/efeitos adversos , Animais , Biomarcadores , Bovinos , Pré-Escolar , Feminino , Temperatura Alta , Humanos , Imunoensaio , Imunoglobulina E/sangue , Imunoglobulina E/imunologia , Lactente , Masculino , Hipersensibilidade a Leite/sangue , Hipersensibilidade a Leite/diagnóstico , Pesquisa , Sensibilidade e Especificidade
14.
J Clin Immunol ; 39(1): 37-44, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30543054

RESUMO

PURPOSE: Human signal transducer and activator of transcription 1 (STAT1) gain-of-function (GOF) mutations present with a broad range of manifestations ranging from chronic mucocutaneous candidiasis and autoimmunity to combined immunodeficiency (CID). So far, there is very limited experience with hematopoietic stem cell transplantation (HSCT) as a therapeutic modality in this disorder. Here, we describe two patients with heterozygous STAT1 GOF mutations mimicking CID who were treated with HSCT. METHODS: Data on the HSC sources, conditioning regimen, graft-versus-host disease (GvHD) and antimicrobial prophylaxis, and the post-transplant course including engraftment, GvHD, transplant-related complications, infections, chimerism, and survival were evaluated. Pre- and post-transplant immunological studies included enumeration of circulating interferon gamma (IFN-γ)- and interleukin 17 (IL-17)-expressing CD4+ T cells and analysis of IFN-ß-induced STAT1 phosphorylation in patient 1 (P1)'s T cells. RESULTS: P1 was transplanted with cord blood from an HLA-identical sibling, and P2 with bone marrow from a fully matched unrelated donor using a reduced toxicity conditioning regimen. While P1 completely recovered from her disease, P2 suffered from systemic CMV disease and secondary graft failure and died due to severe pulmonary involvement and hemorrhage. The dysregulated IFN-γ production, suppressed IL-17 response, and enhanced STAT1 phosphorylation previously found in the CD4+ T cells of P1 were normalized following transplantation. CONCLUSION: HSCT could be an alternative and curative therapeutic option for selected STAT1 GOF mutant patients with progressive life-threatening disease unresponsive to conventional therapy. Morbidity and mortality-causing complications included secondary graft failure, infections, and bleeding.


Assuntos
Mutação com Ganho de Função/genética , Doença Enxerto-Hospedeiro/genética , Fator de Transcrição STAT1/genética , Autoimunidade/genética , Linfócitos T CD4-Positivos/metabolismo , Pré-Escolar , Feminino , Transplante de Células-Tronco Hematopoéticas/métodos , Heterozigoto , Humanos , Masculino , Condicionamento Pré-Transplante/métodos
15.
Front Immunol ; 9: 543, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29599784

RESUMO

Activated phosphoinositide 3-kinase (PI3K) δ Syndrome (APDS), caused by autosomal dominant mutations in PIK3CD (APDS1) or PIK3R1 (APDS2), is a heterogeneous primary immunodeficiency. While initial cohort-descriptions summarized the spectrum of clinical and immunological manifestations, questions about long-term disease evolution and response to therapy remain. The prospective European Society for Immunodeficiencies (ESID)-APDS registry aims to characterize the disease course, identify outcome predictors, and evaluate treatment responses. So far, 77 patients have been recruited (51 APDS1, 26 APDS2). Analysis of disease evolution in the first 68 patients pinpoints the early occurrence of recurrent respiratory infections followed by chronic lymphoproliferation, gastrointestinal manifestations, and cytopenias. Although most manifestations occur by age 15, adult-onset and asymptomatic courses were documented. Bronchiectasis was observed in 24/40 APDS1 patients who received a CT-scan compared with 4/15 APDS2 patients. By age 20, half of the patients had received at least one immunosuppressant, but 2-3 lines of immunosuppressive therapy were not unusual before age 10. Response to rapamycin was rated by physician visual analog scale as good in 10, moderate in 9, and poor in 7. Lymphoproliferation showed the best response (8 complete, 11 partial, 6 no remission), while bowel inflammation (3 complete, 3 partial, 9 no remission) and cytopenia (3 complete, 2 partial, 9 no remission) responded less well. Hence, non-lymphoproliferative manifestations should be a key target for novel therapies. This report from the ESID-APDS registry provides comprehensive baseline documentation for a growing cohort that will be followed prospectively to establish prognostic factors and identify patients for treatment studies.


Assuntos
Síndromes de Imunodeficiência/tratamento farmacológico , Imunossupressores/uso terapêutico , Sistema de Registros , Sirolimo/uso terapêutico , Adolescente , Adulto , Criança , Pré-Escolar , Classe I de Fosfatidilinositol 3-Quinases , Europa (Continente) , Humanos , Pessoa de Meia-Idade , Sociedades Médicas , Adulto Jovem
16.
J Allergy Clin Immunol ; 141(3): 1036-1049.e5, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-29241729

RESUMO

BACKGROUND: Immunodysregulation polyendocrinopathy enteropathy x-linked (IPEX) syndrome is a monogenic autoimmune disease caused by FOXP3 mutations. Because it is a rare disease, the natural history and response to treatments, including allogeneic hematopoietic stem cell transplantation (HSCT) and immunosuppression (IS), have not been thoroughly examined. OBJECTIVE: This analysis sought to evaluate disease onset, progression, and long-term outcome of the 2 main treatments in long-term IPEX survivors. METHODS: Clinical histories of 96 patients with a genetically proven IPEX syndrome were collected from 38 institutions worldwide and retrospectively analyzed. To investigate possible factors suitable to predict the outcome, an organ involvement (OI) scoring system was developed. RESULTS: We confirm neonatal onset with enteropathy, type 1 diabetes, and eczema. In addition, we found less common manifestations in delayed onset patients or during disease evolution. There is no correlation between the site of mutation and the disease course or outcome, and the same genotype can present with variable phenotypes. HSCT patients (n = 58) had a median follow-up of 2.7 years (range, 1 week-15 years). Patients receiving chronic IS (n = 34) had a median follow-up of 4 years (range, 2 months-25 years). The overall survival after HSCT was 73.2% (95% CI, 59.4-83.0) and after IS was 65.1% (95% CI, 62.8-95.8). The pretreatment OI score was the only significant predictor of overall survival after transplant (P = .035) but not under IS. CONCLUSIONS: Patients receiving chronic IS were hampered by disease recurrence or complications, impacting long-term disease-free survival. When performed in patients with a low OI score, HSCT resulted in disease resolution with better quality of life, independent of age, donor source, or conditioning regimen.


Assuntos
Diabetes Mellitus Tipo 1/congênito , Diarreia , Fatores de Transcrição Forkhead , Doenças Genéticas Ligadas ao Cromossomo X , Transplante de Células-Tronco Hematopoéticas , Doenças do Sistema Imunitário/congênito , Imunossupressão , Mutação , Adolescente , Adulto , Aloenxertos , Criança , Pré-Escolar , Diabetes Mellitus Tipo 1/genética , Diabetes Mellitus Tipo 1/imunologia , Diabetes Mellitus Tipo 1/mortalidade , Diabetes Mellitus Tipo 1/terapia , Diarreia/genética , Diarreia/imunologia , Diarreia/mortalidade , Diarreia/terapia , Intervalo Livre de Doença , Feminino , Seguimentos , Fatores de Transcrição Forkhead/genética , Fatores de Transcrição Forkhead/imunologia , Doenças Genéticas Ligadas ao Cromossomo X/genética , Doenças Genéticas Ligadas ao Cromossomo X/imunologia , Doenças Genéticas Ligadas ao Cromossomo X/mortalidade , Doenças Genéticas Ligadas ao Cromossomo X/terapia , Humanos , Doenças do Sistema Imunitário/genética , Doenças do Sistema Imunitário/imunologia , Doenças do Sistema Imunitário/mortalidade , Doenças do Sistema Imunitário/terapia , Lactente , Masculino , Estudos Retrospectivos , Taxa de Sobrevida
17.
J Allergy Clin Immunol ; 141(3): 1050-1059.e10, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-28601686

RESUMO

BACKGROUND: LPS-responsive beige-like anchor protein (LRBA) and cytotoxic T lymphocyte-associated antigen 4 (CTLA4) deficiencies give rise to overlapping phenotypes of immune dysregulation and autoimmunity, with dramatically increased frequencies of circulating follicular helper T (cTFH) cells. OBJECTIVE: We sought to determine the mechanisms of cTFH cell dysregulation in patients with LRBA deficiency and the utility of monitoring cTFH cells as a correlate of clinical response to CTLA4-Ig therapy. METHODS: cTFH cells and other lymphocyte subpopulations were characterized. Functional analyses included in vitro follicular helper T (TFH) cell differentiation and cTFH/naive B-cell cocultures. Serum soluble IL-2 receptor α chain levels and in vitro immunoglobulin production by cultured B cells were quantified by using ELISA. RESULTS: cTFH cell frequencies in patients with LRBA or CTLA4 deficiency sharply decreased with CTLA4-Ig therapy in parallel with other markers of immune dysregulation, including soluble IL-2 receptor α chain, CD45RO+CD4+ effector T cells, and autoantibodies, and this was predictive of favorable clinical responses. cTFH cells in patients with LRBA deficiency were biased toward a TH1-like cell phenotype, which was partially reversed by CTLA4-Ig therapy. LRBA-sufficient but not LRBA-deficient regulatory T cells suppressed in vitro TFH cell differentiation in a CTLA4-dependent manner. LRBA-deficient TFH cells supported in vitro antibody production by naive LRBA-sufficient B cells. CONCLUSIONS: cTFH cell dysregulation in patients with LRBA deficiency reflects impaired control of TFH cell differentiation because of profoundly decreased CTLA4 expression on regulatory T cells and probably contributes to autoimmunity in patients with this disease. Serial monitoring of cTFH cell frequencies is highly useful in gauging the clinical response of LRBA-deficient patients to CTLA4-Ig therapy.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/deficiência , Antígeno CTLA-4 , Doenças do Sistema Imunitário , Linfócitos T Auxiliares-Indutores/imunologia , Proteínas Adaptadoras de Transdução de Sinal/imunologia , Antígeno CTLA-4/genética , Antígeno CTLA-4/imunologia , Criança , Feminino , Humanos , Doenças do Sistema Imunitário/genética , Doenças do Sistema Imunitário/imunologia , Doenças do Sistema Imunitário/patologia , Masculino , Linfócitos T Auxiliares-Indutores/patologia
18.
Int Arch Allergy Immunol ; 174(1): 52-56, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28950285

RESUMO

BACKGROUND: Sublingual immunotherapy (SLIT) has been successfully employed in IgE-mediated respiratory allergies. However, it is not known whether the modulation of immune responses in the sublingual area during SLIT has any deleterious effect on oral health. We sought to determine the oral health prospectively in children receiving SLIT for house dust mite allergy. MATERIAL AND METHODS: Eighteen children with allergic asthma and/or rhinitis and 31 age-matched healthy controls (HC) were included in an open-labeled trial. Oral health was evaluated by scoring the decayed, missing, and filled teeth for primary (dmft) and permanent (DMFT) dentition, and the plaque and gingival indices. Moreover, cariogenic food intake and teeth-brushing habits were also noted at baseline and at 19 months. RESULTS: The mean age of the SLIT participants was 9.5 ± 3.1 years and that of the HC was 9.2 ± 3.7 years. The mean duration of SLIT was 19.13 ± 3.81 months. At baseline, the total dmft and DMFT indices were similar in the SLIT and HC groups (p > 0.05), which demonstrated poor hygiene overall. In the within-group comparisons at the examination at 19 months, the SLIT group had a lower number of carious primary teeth and a higher number of filled primary teeth compared to the count at baseline (p = 0.027 and p = 0.058, respectively). CONCLUSION: Our study showed no detrimental effect of SLIT on oral health during a period of 19 months of follow-up. Parents should be motivated to use dental health services to prevent new caries formation since our cohort had overall poor oral hygiene at the baseline.


Assuntos
Alérgenos/administração & dosagem , Antígenos de Dermatophagoides/administração & dosagem , Asma/imunologia , Saúde Bucal , Rinite Alérgica/imunologia , Imunoterapia Sublingual/efeitos adversos , Imunoterapia Sublingual/métodos , Administração Sublingual , Alérgenos/imunologia , Animais , Antígenos de Dermatophagoides/imunologia , Criança , Feminino , Humanos , Masculino , Pyroglyphidae/imunologia
19.
Inflamm Bowel Dis ; 23(12): 2109-2120, 2017 12.
Artigo em Inglês | MEDLINE | ID: mdl-28930861

RESUMO

BACKGROUND: In contrast to adult-onset inflammatory bowel disease (IBD), where many genetic loci have been shown to be involved in complex disease etiology, early-onset IBD (eoIBD) and associated syndromes can sometimes present as monogenic conditions. As a result, the clinical phenotype and ideal disease management in these patients often differ from those in adult-onset IBD. However, due to high costs and the complexity of data analysis, high-throughput screening for genetic causes has not yet become a standard part of the diagnostic work-up of eoIBD patients. METHODS: We selected 28 genes of interest associated with monogenic IBD and performed targeted panel sequencing in 71 patients diagnosed with eoIBD or early-onset chronic diarrhea to detect causative variants. We compared these results to whole-exome sequencing (WES) data available for 25 of these patients. RESULTS: Target coverage was significantly higher in the targeted gene panel approach compared with WES, whereas the cost of the panel was considerably lower (approximately 25% of WES). Disease-causing variants affecting protein function were identified in 5 patients (7%), located in genes of the IL10 signaling pathway (3), WAS (1), and DKC1 (1). The functional effects of 8 candidate variants in 5 additional patients (7%) are under further investigation. WES did not identify additional causative mutations in 25 patients. CONCLUSIONS: Targeted gene panel sequencing is a fast and effective screening method for monogenic causes of eoIBD that should be routinely established in national referral centers.


Assuntos
Diarreia/etiologia , Predisposição Genética para Doença , Doenças Inflamatórias Intestinais/genética , Idade de Início , Criança , Pré-Escolar , Doença Crônica , Feminino , Estudo de Associação Genômica Ampla , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Lactente , Recém-Nascido , Masculino , Mutação , Sequenciamento Completo do Exoma
20.
N Engl J Med ; 377(1): 52-61, 2017 07 06.
Artigo em Inglês | MEDLINE | ID: mdl-28657829

RESUMO

BACKGROUND: Studies of monogenic gastrointestinal diseases have revealed molecular pathways critical to gut homeostasis and enabled the development of targeted therapies. METHODS: We studied 11 patients with abdominal pain and diarrhea caused by early-onset protein-losing enteropathy with primary intestinal lymphangiectasia, edema due to hypoproteinemia, malabsorption, and less frequently, bowel inflammation, recurrent infections, and angiopathic thromboembolic disease; the disorder followed an autosomal recessive pattern of inheritance. Whole-exome sequencing was performed to identify gene variants. We evaluated the function of CD55 in patients' cells, which we confirmed by means of exogenous induction of expression of CD55. RESULTS: We identified homozygous loss-of-function mutations in the gene encoding CD55 (decay-accelerating factor), which lead to loss of protein expression. Patients' T lymphocytes showed increased complement activation causing surface deposition of complement and the generation of soluble C5a. Costimulatory function and cytokine modulation by CD55 were defective. Genetic reconstitution of CD55 or treatment with a complement-inhibitory therapeutic antibody reversed abnormal complement activation. CONCLUSIONS: CD55 deficiency with hyperactivation of complement, angiopathic thrombosis, and protein-losing enteropathy (the CHAPLE syndrome) is caused by abnormal complement activation due to biallelic loss-of-function mutations in CD55. (Funded by the National Institute of Allergy and Infectious Diseases and others.).


Assuntos
Antígenos CD55/genética , Ativação do Complemento/genética , Proteínas do Sistema Complemento/metabolismo , Mutação , Enteropatias Perdedoras de Proteínas/genética , Trombose/genética , Antígenos CD55/sangue , Criança , Pré-Escolar , Ativação do Complemento/efeitos dos fármacos , Inativadores do Complemento/farmacologia , Feminino , Homozigoto , Humanos , Imunoglobulina A/sangue , Lactente , Intestino Delgado/patologia , Masculino , Linhagem , Enteropatias Perdedoras de Proteínas/complicações , Estatísticas não Paramétricas , Síndrome , Linfócitos T/metabolismo
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