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1.
J Clin Immunol ; 2019 Nov 23.
Artigo em Inglês | MEDLINE | ID: mdl-31760574

RESUMO

Blau syndrome (BS) is an auto-inflammatory granulomatous disease that possibly involves abnormal response to interferon gamma (IFNγ) due to exaggerated nucleotide-binding oligomerization domain containing 2 (NOD2) activity. Mendelian susceptibility to mycobacterial diseases (MSMD) is an infectious granulomatous disease that is caused by impaired production of or response to IFNγ. We report a mother and daughter who are both heterozygous for NOD2c.2264C˃T variant and dominant-negative IFNGR1818del4 mutation. The 17-year-old patient displayed an altered form of BS and milder form of MSMD, whereas the 44-year-old mother was completely asymptomatic. This experiment of nature supports the notion that IFNγ is an important driver of at least some BS manifestations and that elucidation of its involvement in the disease immunopathogenesis may identify novel therapeutic targets.

2.
Clin Ther ; 2019 Sep 26.
Artigo em Inglês | MEDLINE | ID: mdl-31564514

RESUMO

PURPOSE: Immunoglobulin substitution therapy is an essential therapeutic approach for patients with primary antibody deficiencies. Different methods of administration, including intravenous immunoglobulin (IVIG) or subcutaneous immunoglobulin (SCIG) preparations, provide effective and tolerable treatment and enable the adjustment of therapy to patients' needs. A new 20% SCIG represents a new therapeutic option and a new route of administration using rapid-push application. The aim of the Czech Hizentra Noninterventional Study With Rapid Push (CHHINSTRAP) is to evaluate patient satisfaction with as well as the tolerability and efficacy of nonmedical switch to 20% SCIG from previous treatment with IVIG or SCIG and rapid push as a new way to administer SCIG. CHHINSTRAP is the first Phase IV, noninterventional, open-label, prospective, multicentric study of this type conducted in Central and Eastern Europe. METHODS: Primary end points, including efficacy, adverse effects, convenience of use, and overall satisfaction, were evaluated by Treatment Satisfaction Questionnaire for Medication version II. Secondary end points, such as serum IgG trough levels, infusion duration, number of application sites, frequency of infections, related hospital admissions, and antibiotic consumption, were obtained from patients at each follow-up visit. FINDINGS: Together, 50 eligible patients with primary antibody deficiency were switched from SCIG or IVIG to an equivalent dose of 20% SCIG and were followed up for 12 months during 5 consecutive visits. The results indicate that patients switched from previous IVIG or SCIG preparations had significantly higher serum trough IgG levels and a lower incidence of infections and related events, such as hospital admissions or consumption of antibiotics. These findings were also reflected in gradually increasing convenience of use and overall satisfaction reported by patients. Apart from duration of application, no differences were found between patients previously receiving SCIG or IVIG. Moreover, our study found a high level of safety of 20% SCIG rapid push, which was comparable to other preparations and application methods. IMPLICATIONS: On the basis of the results of CHHINSTRAP study, we conclude that 20% SCIG is a tolerable and effective immunoglobulin preparation, representing a new therapeutic approach in patients with primary antibody deficiencies. Its efficacy and tolerability have been found in patients on nonmedical switch from previous treatment with IVIG or SCIG. (Clin Ther. 2019;XX:XXX-XXX) © 2019 Elsevier HS Journals, Inc.

3.
Acta Diabetol ; 2019 Sep 30.
Artigo em Inglês | MEDLINE | ID: mdl-31570993

RESUMO

AIMS: The development of the immune phenotype in patients with type 1 diabetes (T1D) during the first year following disease onset remains poorly described, and studies analysing the longitudinal development of a complex set of immunological and metabolic parameters are missing. Thus, we aim to provide such complex view in a cohort of 38 children with new onset T1D who were prospectively followed for 1 year. METHODS: All subjects were tested for a set of immunological parameters (complete blood count; serum immunoglobulins; and T, B and dendritic cells), HbA1c and daily insulin dose at baseline and at 6 and 12 months after T1D diagnosis. A mixed meal tolerance test was administered to each of the subjects 12 months after diagnosis, and the C-peptide area under the curve (AUC) was noted and was then tested for association with all immunological parameters. RESULTS: A gradual decrease in leukocytes (adjusted p = 0.0012) was reflected in a significant decrease in neutrophils (adjusted p = 0.0061) over the post-onset period, whereas Tregs (adjusted p = 0.0205) and originally low pDCs (adjusted p < 0.0001) increased. The expression of the receptor for BAFF (BAFFR) on B lymphocytes (adjusted p = 0.0127) markedly increased after onset. No immunological parameters were associated with C-peptide AUC; however, we observed a linear increase in C-peptide AUC with the age of the patients (p < 0.0001). CONCLUSIONS: Our study documents substantial changes in the innate and adaptive immune system over the first year after disease diagnosis but shows no association between immunological parameters and residual beta-cell activity. The age of patients remains the best predictor of C-peptide AUC, whereas the role of the immune system remains unresolved.

4.
J Autoimmun ; 105: 102294, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31256920

RESUMO

BACKGROUND: The aberrant recognition of self-nucleic acids by the innate immune system contributes to the pathology of several autoimmune diseases. Although microbial DNA and, in certain instances, self-DNA that is released from damaged cells are primarily recognized by Toll-like receptor 9 (TLR9), recent evidence suggests that other cytosolic sequence-nonspecific DNA sensors contribute to DNA recognition. In this study, we focused on the sensing of microbial and host DNA in type 1 diabetes (T1D) patients. METHODS: Peripheral blood mononuclear cells (PBMCs) and monocytes from pediatric patients with T1D and from healthy donors were stimulated with microbial DNA (CpG) or with self-DNA (DNA contained within neutrophil extracellular traps, NETs). The production of cytokines was measured by flow cytometry and multiplex bead assays. The internalization of microbial DNA and its colocalization with STING was detected by image cytometry. Furthermore, the involvement of the TBK1 kinase was investigated by detecting its phosphorylation with phospho-flow cytometry or by using a TBK1 inhibition assay. RESULTS: We observed a prominent proinflammatory response in T1D PBMCs, especially pDCs and monocytes, to microbial DNA in comparison to that in controls. We further confirmed that monocytes could bind and internalize DNA and respond by releasing proinflammatory cytokines in a more pronounced manner in T1D patients than those in controls. Surprisingly, this cytokine production was not affected by TLR9 blockade, suggesting the involvement of intracellular receptors in DNA recognition. We further identified TBK1 and STING as two crucial molecules in the DNA-sensing pathway that were involved in CpG-DNA sensing by T1D cells. A similar DNA-sensing pathway that was dependent on intracellular DNA sensors and the STING-TBK1 interaction was employed in response to NETs, which were used to model self-DNA. CONCLUSIONS: Here, we show that there were significant differences in DNA sensing in T1D patients compared to that in controls. We demonstrate that monocytes from T1D patients are able to sense microbial- and self-DNA, leading to proinflammatory cytokine secretion through the adaptor protein STING and the TBK1 kinase.

5.
PLoS One ; 14(7): e0219987, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31356620

RESUMO

BACKGROUND: The recognition of active inflammation in the central nervous system (CNS) in the absence of infectious agents is challenging. The present study aimed to determine the diagnostic relevance of five selected chemo/cytokines in the recognition of CNS inflammation and in the context of traditional cerebrospinal fluid (CSF) biomarkers (white blood cell [WBC] counts, oligoclonal bands, protein levels, CSF/serum albumin ratios) and clinical diagnoses. METHODS: C-C and C-X-C motif ligands (CCL2, CXCL8, 10 and 13) and interleukin (IL) 6 levels in the CSF and serum from 37 control and 87 symptomatic children with ten different (mostly noninfectious) inflammatory CNS disorders (16 of which had follow-up samples after recovery) were determined using Luminex multiple bead technology and software. Nonparametric tests were used; p < 0.05 was considered statistically significant. Receiver operating characteristic curves were constructed to analyze controls and 1) all symptomatic samples or 2) symptomatic samples without CSF pleocytosis. RESULTS: Compared with the control CSF samples, levels of all investigated chemo/cytokines were increased in symptomatic CSF samples, and only IL-6 remained elevated in recovery samples (p ≤ 0.001). CSF CXCL-13 levels (> 10.9 pg/mL) were the best individual discriminatory criterion to differentiate neuroinflammation (specificity/sensitivity: 97/72% and 97/61% for samples without pleocytosis), followed by CSF WBC counts (specificity/sensitivity: 97/62%). The clinical utility of the remaining CSF chemo/cytokine levels was determined in descending order of sensitivities corresponding to thresholds that ensured 97% specificity for neuroinflammation in samples without pleocytosis (pg/mL; sensitivity %): IL-6 (3.8; 34), CXCL8 (32; 26), CXCL10 (317; 24) and CCL2 (387; 10). Different diagnosis-related patterns of CSF chemo/cytokines were observed. CONCLUSIONS: The increased CSF level of CXCL13 was the marker with the greatest predictive utility for the general recognition of neuroinflammation among all of the individually investigated biomarkers. The potential clinical utility of chemo/cytokines in the differential diagnosis of neuroinflammatory diseases was identified.

6.
Int Arch Allergy Immunol ; : 1-9, 2018 Nov 20.
Artigo em Inglês | MEDLINE | ID: mdl-30458444

RESUMO

BACKGROUND: Common variable immunodeficiency (CVID) is one of the most frequent primary immunodeficiencies and is characterized by disturbed immunoglobulin production and dysregulation of the immune system. Results of previous studies suggest a higher prevalence of bronchial asthma (BA) in CVID patients than in the general population. We initiated this study to evaluate lung functions and identify risk factors for BA and bronchial hyperresponsiveness (BHR) in patients with CVID. METHODS: Twenty-three patients with CVID were included in this study. In all of them, spirometry and a metacholine bronchoprovocation test were performed. We also investigated the role of atopy, eosinophilic inflammation, and potential risk factors such as gender, age, or immunoglobulin levels at the time of diagnosis. RESULTS: BHR was confirmed in 12 patients (52%), all of whom had normal FEV1 and FEV1/FVC. However, BHR-positive patients had significantly decreased MEF25. BHR-positive patients had also more symptoms related to bronchial obstruction, with 8 of them (35%) being suspected of having BA at the end of the study. A higher prevalence of BHR was found in females, with a relative risk of 2.89. CONCLUSIONS: An increased prevalence of BHR and BA was detected in CVID patients compared to the general population. BA may develop despite the disturbed immunoglobulin production, and the majority of patients display nonatopic and noneosinophilic properties. These results suggest a limited role of atopy and eosinophilic inflammation in the pathogenesis of BA in CVID patients.

8.
Front Immunol ; 9: 1730, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30083170

RESUMO

DiGeorge syndrome is an immunodeficiency characterized by thymic dysplasia resulting in T cell lymphopenia. Most patients suffer from increased susceptibility to infections and heightened prevalence of autoimmune disorders, such as autoimmune thrombocytopenia. B cells in DiGeorge syndrome show impaired maturation, with low switched-memory B cells and a wide spectrum of antibody deficiencies or dysgammaglobulinemia, presumably due to impaired germinal center responses. We set out to evaluate circulating follicular helper T cells (cTFHs) in DiGeorge syndrome, as markers of T-B interaction in the germinal centers in a cohort of 17 patients with partial DiGeorge and 21 healthy controls of similar age. cTFHs were characterized as CXCR5+CD45RA- CD4+ T cells using flow cytometry. We verify previous findings that the population of memory CD4+ T cells is relatively increased in diGeorge patients, corresponding to low naïve T cells and impaired T cell production in the thymus. The population of CXCR5+ memory CD4+ T cells (cTFHs) was significantly expanded in patients with DiGeorge syndrome, but only healthy controls and not DiGeorge syndrome patients showed gradual increase of CXCR5 expression on cTFHs with age. We did not observe correlation between cTFHs and serum IgG levels or population of switched memory B cells. There was no difference in cTFH numbers between DiGeorge patients with/without thrombocytopenia and with/without allergy. Interestingly, we show strong decline of PD1 expression on cTFHs in the first 5 years of life in DiGeorge patients and healthy controls, and gradual increase of PD1 and ICOS expression on CD4- T cells in healthy controls later in life. Thus, here, we show that patients with DiGeorge syndrome have elevated numbers of cTFHs, which, however, do not correlate with autoimmunity, allergy, or production of immunoglobulins. This relative expansion of cTFH cells may be a result of impaired T cell development in patients with thymic dysplasia.

9.
Allergy ; 73(11): 2122-2136, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30043993

RESUMO

The 2017 International Union of Immunological Societies (IUIS) classification recognizes 3 hyper-IgE syndromes (HIES), including the prototypic Job's syndrome (autosomal dominant STAT3-loss of function) and autosomal recessive PGM3 and SPINK5 syndromes. Early diagnosis of PID can direct life-saving or transformational interventions; however, it remains challenging owing to the rarity of these conditions. This can result in diagnostic delay and worsen prognosis. Within increasing access to "clinical-exome" testing, clinicians need to be aware of the implication and rationale for genetic testing, including the benefits and limitations of current therapies. Extreme elevation of serum IgE has been associated with a growing number of PID syndromes including the novel CARD11 and ZNF341 deficiencies. Variable elevations in IgE are associated with defects in innate, humoral, cellular and combined immunodeficiency syndromes. Barrier compromise can closely phenocopy these conditions. The aim of this article was to update readers on recent developments at this important interface between allergy and immunodeficiency, highlighting key clinical scenarios which should draw attention to possible immunodeficiency associated with extreme elevation of IgE, and outline initial laboratory assessment and management.

10.
J Clin Immunol ; 2018 Jun 22.
Artigo em Inglês | MEDLINE | ID: mdl-29934865

RESUMO

PURPOSE: Signal transducer and activator of transcription 1 gain-of-function (STAT1 GOF) mutations are the most common cause of chronic mucocutaneous candidiasis (CMC). We aim to report the effect of oral ruxolitinib, the Janus kinase (JAK) family tyrosine kinase inhibitor, on clinical and immune status of a 12-year-old boy with severe CMC due to a novel STAT1 GOF mutation. METHODS: Clinical features and laboratory data were analyzed, particularly lymphocyte subsets, ex vivo IFNγ- and IFNα-induced STAT1, 3, 5 phosphorylation dynamics during the course of JAK1/2 inhibition therapy, and Th17-related, STAT1- and STAT3-inducible gene expression before and during the treatment. Sanger sequencing was used to detect the STAT1 mutation. Literature review of ruxolitinib in treatment of CMC is appended. RESULTS: A novel STAT1 GOF mutation (c.617T > C; p.L206P), detected in a child with recalcitrant CMC, was shown to be reversible in vitro with ruxolitinib. Major clinical improvement was achieved after 8 weeks of ruxolitinib treatment, while sustained suppression of IFNγ- and IFNα-induced phosphorylation of STAT1, STAT3, and STAT5, as well as increased STAT3-inducible and Th17-related gene expression, was demonstrated ex vivo. Clinical relapse and spike of all monitored phosphorylated STAT activity was registered shortly after unplanned withdrawal, decreasing again after ruxolitinib reintroduction. No increase of peripheral CD4+ IL17+ T cells was detected after 4 months of therapy. No adverse effects were noted. CONCLUSION: JAK1/2 inhibition with ruxolitinib represents a viable option for treatment of refractory CMC, if HSCT is not considered. However, long-term administration is necessary, as the effect is not sustained after treatment discontinuation.

11.
Artigo em Inglês | MEDLINE | ID: mdl-29729943

RESUMO

BACKGROUND: Cytotoxic T-lymphocyte antigen 4 (CTLA-4) is a negative immune regulator. Heterozygous CTLA4 germline mutations can cause a complex immune dysregulation syndrome in human subjects. OBJECTIVE: We sought to characterize the penetrance, clinical features, and best treatment options in 133 CTLA4 mutation carriers. METHODS: Genetics, clinical features, laboratory values, and outcomes of treatment options were assessed in a worldwide cohort of CTLA4 mutation carriers. RESULTS: We identified 133 subjects from 54 unrelated families carrying 45 different heterozygous CTLA4 mutations, including 28 previously undescribed mutations. Ninety mutation carriers were considered affected, suggesting a clinical penetrance of at least 67%; median age of onset was 11 years, and the mortality rate within affected mutation carriers was 16% (n = 15). Main clinical manifestations included hypogammaglobulinemia (84%), lymphoproliferation (73%), autoimmune cytopenia (62%), and respiratory (68%), gastrointestinal (59%), or neurological features (29%). Eight affected mutation carriers had lymphoma, and 3 had gastric cancer. An EBV association was found in 6 patients with malignancies. CTLA4 mutations were associated with lymphopenia and decreased T-, B-, and natural killer (NK) cell counts. Successful targeted therapies included application of CTLA-4 fusion proteins, mechanistic target of rapamycin inhibitors, and hematopoietic stem cell transplantation. EBV reactivation occurred in 2 affected mutation carriers after immunosuppression. CONCLUSIONS: Affected mutation carriers with CTLA-4 insufficiency can present in any medical specialty. Family members should be counseled because disease manifestation can occur as late as 50 years of age. EBV- and cytomegalovirus-associated complications must be closely monitored. Treatment interventions should be coordinated in clinical trials.

12.
Ann Rheum Dis ; 77(4): 612-619, 2018 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-29358286

RESUMO

OBJECTIVES: To characterise the clinical features, immune manifestations and molecular mechanisms in a recently described autoinflammatory disease caused by mutations in TRNT1, a tRNA processing enzyme, and to explore the use of cytokine inhibitors in suppressing the inflammatory phenotype. METHODS: We studied nine patients with biallelic mutations in TRNT1 and the syndrome of congenital sideroblastic anaemia with immunodeficiency, fevers and developmental delay (SIFD). Genetic studies included whole exome sequencing (WES) and candidate gene screening. Patients' primary cells were used for deep RNA and tRNA sequencing, cytokine profiling, immunophenotyping, immunoblotting and electron microscopy (EM). RESULTS: We identified eight mutations in these nine patients, three of which have not been previously associated with SIFD. Three patients died in early childhood. Inflammatory cytokines, mainly interleukin (IL)-6, interferon gamma (IFN-γ) and IFN-induced cytokines were elevated in the serum, whereas tumour necrosis factor (TNF) and IL-1ß were present in tissue biopsies of patients with active inflammatory disease. Deep tRNA sequencing of patients' fibroblasts showed significant deficiency of mature cytosolic tRNAs. EM of bone marrow and skin biopsy samples revealed striking abnormalities across all cell types and a mix of necrotic and normal-appearing cells. By immunoprecipitation, we found evidence for dysregulation in protein clearance pathways. In 4/4 patients, treatment with a TNF inhibitor suppressed inflammation, reduced the need for blood transfusions and improved growth. CONCLUSIONS: Mutations of TRNT1 lead to a severe and often fatal syndrome, linking protein homeostasis and autoinflammation. Molecular diagnosis in early life will be crucial for initiating anti-TNF therapy, which might prevent some of the severe disease consequences.

13.
Front Immunol ; 9: 3135, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30723478

RESUMO

Background: Common variable immunodeficiency disorder (CVID) is one of the most frequent inborn errors of immunity, increased occurrence of malignancies, particularly lymphomas, and gastric cancers, has long been noted among CVID patients. Multifactorial etiology, including immune dysregulation, infections, chronic inflammation, or genetic background, is suggested to contribute to tumor development. Here, we present the results of the first Czech nationwide study focused on epidemiology, immunology and genetic background in a cohort of CVID patients who also developed tumors Methods: The cohort consisted of 295 CVID patients followed for 3,070 patient/years. Standardized incidence ratio (SIR) was calculated to determine the risk of cancer, and Risk ratio (RR) was established to evaluate the significance of comorbidities. Moreover, immunophenotyping, including immunoglobulin levels and lymphocyte populations, was assessed. Finally, Whole exome sequencing (WES) was performed in all patients with lymphoma to investigate the genetic background. Results: Twenty-five malignancies were diagnosed in 22 patients in a cohort of 295 CVID patients. SIR was more than 6 times greater in comparison to the general population. The most common neoplasias were gastric cancers and lymphomas. History of Immune thrombocytopenic purpura (ITP) was established as a potential risk factor, with over 3 times higher risk of cancer development. The B cell count at diagnosis of lymphoma was reduced in the lymphoma group; moreover, post-treatment B and T cell lymphopenia, associated with poorer outcome, was found in a majority of the patients. Intriguingly, no NK cell depression was observed after the chemotherapy. WES revealed heterogeneous genetic background among CVID patients with tumors, identifying gene variants associated with primary immunodeficiencies (such as CTLA4, PIK3CD, PMS2) and/or increased cancer susceptibility (including BRCA1, RABEP1, EP300, KDM5A). Conclusions: The incidence of malignancy in our CVID cohort was found to be more than 6 times greater compared to the general population. Gastric cancers and lymphomas were the most frequently diagnosed tumors. ITP was identified as a risk factor for malignancy in CVID patients. WES analysis confirmed a wide genetic heterogeneity among CVID patients. The identified causative or modifying gene variants pointed to errors in mechanisms contributing to both immunodeficiency and malignancy.


Assuntos
Imunodeficiência de Variável Comum/complicações , Imunodeficiência de Variável Comum/epidemiologia , Neoplasias/epidemiologia , Neoplasias/etiologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais , República Tcheca/epidemiologia , Suscetibilidade a Doenças/imunologia , Feminino , Predisposição Genética para Doença , Humanos , Imunofenotipagem , Incidência , Masculino , Pessoa de Meia-Idade , Neoplasias/terapia , Vigilância da População , Prevalência , Medição de Risco , Fatores de Risco , Sequenciamento Completo do Exoma , Adulto Jovem
14.
Blood ; 130(21): 2307-2316, 2017 11 23.
Artigo em Inglês | MEDLINE | ID: mdl-28972011

RESUMO

Pathogenic gain-of-function variants in the genes encoding phosphoinositide 3-kinase δ (PI3Kδ) lead to accumulation of transitional B cells and senescent T cells, lymphadenopathy, and immune deficiency (activated PI3Kδ syndrome [APDS]). Knowing the genetic etiology of APDS afforded us the opportunity to explore PI3Kδ inhibition as a precision-medicine therapy. Here, we report in vitro and in vivo effects of inhibiting PI3Kδ in APDS. Treatment with leniolisib (CDZ173), a selective PI3Kδ inhibitor, caused dose-dependent suppression of PI3Kδ pathway hyperactivation (measured as phosphorylation of AKT/S6) in cell lines ectopically expressing APDS-causative p110δ variants and in T-cell blasts derived from patients. A clinical trial with 6 APDS patients was conducted as a 12-week, open-label, multisite, within-subject, dose-escalation study of oral leniolisib to assess safety, pharmacokinetics, and effects on lymphoproliferation and immune dysregulation. Oral leniolisib led to a dose-dependent reduction in PI3K/AKT pathway activity assessed ex vivo and improved immune dysregulation. We observed normalization of circulating transitional and naive B cells, reduction in PD-1+CD4+ and senescent CD57+CD4- T cells, and decreases in elevated serum immunoglobulin M and inflammatory markers including interferon γ, tumor necrosis factor, CXCL13, and CXCL10 with leniolisib therapy. After 12 weeks of treatment, all patients showed amelioration of lymphoproliferation with lymph node sizes and spleen volumes reduced by 39% (mean; range, 26%-57%) and 40% (mean; range, 13%-65%), respectively. Thus, leniolisib was well tolerated and improved laboratory and clinical parameters in APDS, supporting the specific inhibition of PI3Kδ as a promising new targeted therapy in APDS and other diseases characterized by overactivation of the PI3Kδ pathway. This trial was registered at www.clinicaltrials.gov as #NCT02435173.


Assuntos
Classe I de Fosfatidilinositol 3-Quinases/antagonistas & inibidores , Síndromes de Imunodeficiência/tratamento farmacológico , Síndromes de Imunodeficiência/enzimologia , Terapia de Alvo Molecular , Inibidores de Proteínas Quinases/farmacologia , Piridinas/farmacologia , Pirimidinas/farmacologia , Animais , Quimiocinas/sangue , Criança , Pré-Escolar , Classe I de Fosfatidilinositol 3-Quinases/imunologia , Classe I de Fosfatidilinositol 3-Quinases/metabolismo , Demografia , Relação Dose-Resposta a Droga , Feminino , Humanos , Imunoglobulina M/sangue , Síndromes de Imunodeficiência/imunologia , Síndromes de Imunodeficiência/patologia , Lactente , Linfonodos/efeitos dos fármacos , Linfonodos/patologia , Ativação Linfocitária/efeitos dos fármacos , Masculino , Mutação/genética , Tamanho do Órgão , Fenótipo , Piridinas/farmacocinética , Pirimidinas/farmacocinética , Ratos , Baço/efeitos dos fármacos , Baço/patologia , Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologia , Serina-Treonina Quinases TOR/antagonistas & inibidores , Serina-Treonina Quinases TOR/metabolismo , Transfecção
15.
Immunol Lett ; 189: 94-100, 2017 09.
Artigo em Inglês | MEDLINE | ID: mdl-28414179

RESUMO

BACKGROUND: Lately, mounting evidence has shown that B cells play an important role in the pathogenesis of type 1 diabetes (T1D). Here, we present alterations in B cell subsets including BAFF receptor (BAFFR) expression in cohorts of patients with type 1 diabetes (T1D) and their relatives. PATIENTS AND METHODS: B cells were studied in 438 patients with T1D (158 at disease onset and 280 with long-term disease), 136 first-degree relatives and 53 healthy controls. The B cell panel included transitional, naïve, MZ-like, switched memory B cells and plasmablasts. We also measured serum BAFF levels as well as BAFFR expression on both B and T cells. Moreover, the effect of BAFF on T and B lymphocytes was analysed in vitro. RESULTS: We observed a significant decrease in the proportion of transitional B cells in the patients with T1D, accompanied by an increased proportion of plasmablasts, especially in recent-onset patients and their relatives. While the BAFF serum levels did not differ in the patients with T1D, BAFFR-expressing B and especially T cell numbers were reduced in the T1D cohort, with the exception of patients with recent-onset disease who exhibited a significant increase in the number of BAFFR-expressing T cells. T cell activation and B cell proliferation were more pronounced after activation with BAFF in the T1D cohort compared to controls. CONCLUSION: The B cell panel in patients with T1D is characterized by significantly reduced populations of B cells in their early stages of development with a shift towards plasma cells. The dynamics of BAFFR-expressing B and T cells and the more pronounced responsiveness of the T1D T cells to BAFF point to the role of BAFF and T and B cell cooperation in the development of T1D.


Assuntos
Fator Ativador de Células B/metabolismo , Receptor do Fator Ativador de Células B/metabolismo , Subpopulações de Linfócitos B/imunologia , Diferenciação Celular , Diabetes Mellitus Tipo 1/imunologia , Plasmócitos/imunologia , Linfócitos T/imunologia , Adolescente , Adulto , Receptor do Fator Ativador de Células B/genética , Comunicação Celular , Células Cultivadas , Criança , Pré-Escolar , Feminino , Regulação da Expressão Gênica , Humanos , Lactente , Recém-Nascido , Masculino , Adulto Jovem
16.
Horm Res Paediatr ; 88(2): 160-166, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28253502

RESUMO

BACKGROUND: Germline STAT3 gain-of-function (GOF) mutations cause multiple endocrine and haematologic autoimmune disorders, lymphoproliferation, and growth impairment. As the JAK-STAT pathway is known to transduce the growth hormone (GH) signalling, and STAT3 interacts with STAT5 in growth regulation, we hypothesised that short stature in STAT3 GOF mutations results mostly from GH insensitivity via involving activation of STAT5. CASE REPORT: A boy with a novel STAT3 c.2144C>T (p.Pro715Leu) mutation presented with short stature (-2.60 SD at 5.5 years). He developed diabetes mellitus at 11 months, generalised lympho-proliferation, autoimmune thyroid disease, and immune bicytopenia in the subsequent years. At 5.5 years, his insulin-like growth factor-1 (IGF-I) was 37 µg/L (-2.22 SD) but stimulated GH was 27.7 µg/L. Both a standard IGF-I generation test (GH 0.033 mg/kg/day sc; 4 days) and a high-dose prolonged IGF-I generation test (GH 0.067 mg/kg/day sc; 14 days) failed to significantly increase IGF-I levels (37-46 and 72-87 µg/L, respectively). The boy underwent haematopoietic stem cell transplantation at 6 years due to severe neutropenia and massive lymphoproliferation, but unfortunately deceased 42 days after transplantation from reactivated generalised adenoviral infection. CONCLUSIONS: Our findings confirm the effect of STAT3 GOF mutation on the downstream activation of STAT5 resulting in partial GH insensitivity. 
.


Assuntos
Doenças Autoimunes/genética , Transtornos do Crescimento/genética , Hormônio do Crescimento Humano/metabolismo , Mutação , Fator de Transcrição STAT3/genética , Transdução de Sinais/genética , Doenças Autoimunes/metabolismo , Criança , Pré-Escolar , Evolução Fatal , Transtornos do Crescimento/metabolismo , Humanos , Lactente , Recém-Nascido , Masculino , Fator de Transcrição STAT3/metabolismo , Gêmeos
18.
Sci Rep ; 7: 39710, 2017 01 05.
Artigo em Inglês | MEDLINE | ID: mdl-28054583

RESUMO

Common variable immunodeficiency (CVID) is a heterogeneous group of diseases. Our aim was to define sub-groups of CVID patients with similar phenotypes and clinical characteristics. Using eight-color flow cytometry, we analyzed both B- and T-cell phenotypes in a cohort of 88 CVID patients and 48 healthy donors. A hierarchical clustering of probability binning "bins" yielded a separate cluster of 22 CVID patients with an abnormal phenotype. We showed coordinated proportional changes in naïve CD4+ T-cells (decreased), intermediate CD27- CD28+ CD4+ T-cells (increased) and CD21low B-cells (increased) that were stable for over three years. Moreover, the lymphocytes' immunophenotype in this patient cluster exhibited features of profound immunosenescence and chronic activation. Thrombocytopenia was only found in this cluster (36% of cases, manifested as Immune Thrombocytopenia (ITP) or Evans syndrome). Clinical complications more frequently found in these patients include lung fibrosis (in 59% of cases) and bronchiectasis (55%). The degree of severity of these symptoms corresponded to more deviation from normal levels with respect to CD21low B-cells, naïve CD4+ and CD27− CD28+ CD4+ T-cells. Next-generation sequencing did not reveal any common genetic background. We delineate a subgroup of CVID patients with activated and immunosenescent immunophenotype of lymphocytes and distinct set of clinical complications without common genetic background.


Assuntos
Linfócitos B/imunologia , Linfócitos T CD4-Positivos/imunologia , Imunodeficiência de Variável Comum/imunologia , Pulmão/patologia , Púrpura Trombocitopênica Idiopática/imunologia , Adolescente , Adulto , Idoso , Separação Celular , Estudos de Coortes , Feminino , Fibrose , Citometria de Fluxo , Humanos , Imunossenescência , Ativação Linfocitária , Masculino , Pessoa de Meia-Idade , Fenótipo , Adulto Jovem
19.
Clin Immunol ; 176: 77-86, 2017 03.
Artigo em Inglês | MEDLINE | ID: mdl-28104464

RESUMO

BACKGROUND: Mutations in PIK3CD and PIK3R1 cause activated PI3K-δ syndrome (APDS) by dysregulation of the PI3K-AKT pathway. METHODS: We studied precursor and peripheral B-cell differentiation and apoptosis via flowcytometry. Furthermore, we performed AKT-phosphorylation assays and somatic hypermutations (SHM) and class switch recombination (CSR) analysis. RESULTS: We identified 13 patients of whom 3 had new mutations in PIK3CD or PIK3R1. Patients had low total B-cell numbers with increased frequencies of transitional B cells and plasmablasts, while the precursor B-cell compartment in bone marrow was relatively normal. Basal AKT phosphorylation was increased in lymphocytes from APDS patients and natural effector B cells where most affected. PI3K mutations resulted in altered SHM and CSR and increased apoptosis. CONCLUSIONS: The B-cell compartment in APDS patients is affected by the mutations in PI3K. There is reduced differentiation beyond the transitional stage, increased AKT phosphorylation and increased apoptosis. This B-cell phenotype contributes to the clinical phenotype.


Assuntos
Agamaglobulinemia/genética , Agamaglobulinemia/imunologia , Linfócitos B/imunologia , Diferenciação Celular/genética , Classe I de Fosfatidilinositol 3-Quinases/genética , Fosfatidilinositol 3-Quinases/genética , Adolescente , Adulto , Diferenciação Celular/imunologia , Criança , Pré-Escolar , Feminino , Humanos , Switching de Imunoglobulina/genética , Switching de Imunoglobulina/imunologia , Infecção/genética , Ativação Linfocitária/genética , Ativação Linfocitária/imunologia , Masculino , Mutação/genética , Mutação/imunologia , Fosforilação/genética , Plasmócitos/imunologia , Células Precursoras de Linfócitos B/imunologia , Proteínas Proto-Oncogênicas c-akt/genética , Recidiva , Transdução de Sinais/genética , Hipermutação Somática de Imunoglobulina/genética , Hipermutação Somática de Imunoglobulina/imunologia , Adulto Jovem
20.
J Allergy Clin Immunol ; 139(2): 597-606.e4, 2017 02.
Artigo em Inglês | MEDLINE | ID: mdl-27555459

RESUMO

BACKGROUND: Activated phosphoinositide 3-kinase δ syndrome (APDS) is a recently described combined immunodeficiency resulting from gain-of-function mutations in PIK3CD, the gene encoding the catalytic subunit of phosphoinositide 3-kinase δ (PI3Kδ). OBJECTIVE: We sought to review the clinical, immunologic, histopathologic, and radiologic features of APDS in a large genetically defined international cohort. METHODS: We applied a clinical questionnaire and performed review of medical notes, radiology, histopathology, and laboratory investigations of 53 patients with APDS. RESULTS: Recurrent sinopulmonary infections (98%) and nonneoplastic lymphoproliferation (75%) were common, often from childhood. Other significant complications included herpesvirus infections (49%), autoinflammatory disease (34%), and lymphoma (13%). Unexpectedly, neurodevelopmental delay occurred in 19% of the cohort, suggesting a role for PI3Kδ in the central nervous system; consistent with this, PI3Kδ is broadly expressed in the developing murine central nervous system. Thoracic imaging revealed high rates of mosaic attenuation (90%) and bronchiectasis (60%). Increased IgM levels (78%), IgG deficiency (43%), and CD4 lymphopenia (84%) were significant immunologic features. No immunologic marker reliably predicted clinical severity, which ranged from asymptomatic to death in early childhood. The majority of patients received immunoglobulin replacement and antibiotic prophylaxis, and 5 patients underwent hematopoietic stem cell transplantation. Five patients died from complications of APDS. CONCLUSION: APDS is a combined immunodeficiency with multiple clinical manifestations, many with incomplete penetrance and others with variable expressivity. The severity of complications in some patients supports consideration of hematopoietic stem cell transplantation for severe childhood disease. Clinical trials of selective PI3Kδ inhibitors offer new prospects for APDS treatment.


Assuntos
Classe I de Fosfatidilinositol 3-Quinases/genética , Síndromes de Imunodeficiência/genética , Transtornos Linfoproliferativos/genética , Mutação/genética , Infecções Respiratórias/genética , Adolescente , Adulto , Animais , Antibioticoprofilaxia , Criança , Pré-Escolar , Classe I de Fosfatidilinositol 3-Quinases/antagonistas & inibidores , Estudos de Coortes , Inibidores Enzimáticos/uso terapêutico , Feminino , Transplante de Células-Tronco Hematopoéticas , Infecções por Herpesviridae/genética , Infecções por Herpesviridae/mortalidade , Infecções por Herpesviridae/terapia , Humanos , Imunoglobulinas Intravenosas/uso terapêutico , Síndromes de Imunodeficiência/mortalidade , Síndromes de Imunodeficiência/terapia , Lactente , Cooperação Internacional , Transtornos Linfoproliferativos/mortalidade , Transtornos Linfoproliferativos/terapia , Masculino , Camundongos , Pessoa de Meia-Idade , Recidiva , Infecções Respiratórias/mortalidade , Infecções Respiratórias/terapia , Inquéritos e Questionários , Análise de Sobrevida , Adulto Jovem
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