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1.
Front Immunol ; 10: 2618, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31803180

RESUMO

Adult-onset primary immunodeficiency is characterized by recurrent infections, hypogammaglobulinemia, and poor antibody response to vaccines. In this study, we have analyzed targeted gene panel sequencing results of 270 patients diagnosed with antibody deficiency and identified five disease-associated variants in NFKB1 in five unrelated families. We detected two single base pair deletions and two single base pair insertions, causing severe protein truncations, and one missense mutation. Immunoblotting, lymphocyte stimulation, immunophenotyping, and ectopic expression assays demonstrated the functional relevance of NFKB1 mutations. Besides antibody deficiency, clinical manifestations included infections, autoimmune features, lymphoproliferation, lymphoma, Addison's disease, type 2 diabetes and asthma. Although partial clinical penetrance was observed in almost all pedigrees, all carriers presented a deficiency in certain serum immunoglobulins and the majority showed a lack of memory B cells (CD19+CD27+). Among all tested genes, NFKB1 alterations were the most common monoallelic cause of antibody deficiency in our cohort.

2.
Artigo em Inglês | MEDLINE | ID: mdl-31887391

RESUMO

BACKGROUND: Recent findings strongly support hematopoietic stem cell transplantation (HSCT) in patients with severe presentations of lipopolysaccharide-responsive beige-like anchor protein (LRBA) deficiency, but long-term follow-up and survival data for non-transplanted patients beyond previous patient reports or meta-reviews are scarce. OBJECTIVE: This international, retrospective study was conducted to elucidate the longitudinal clinical course of transplanted and non-transplanted LRBA-deficient patients. METHODS: We assessed disease burden and treatment responses with a specially developed immune deficiency and dysregulation activity (IDDA) score, reflecting the sum and severity of organ involvement and infections, days of hospitalization, supportive care requirements, and performance indices. RESULTS: Twenty-four of 76 LRBA-deficient patients from 29 centers (10 years median follow-up, range: 1-52) underwent HSCT from 2005 to 2019. Overall survival after HSCT (median follow-up 20 months) was 70.8% (17/24 patients); all deaths were due to non-specific, early, transplant-related mortality. Currently, 82.7% (43/52) of non-transplanted patients (aged 3-69 years) are alive. Of 17 HSCT survivors, seven are in complete and five in good partial remission without treatment (12/17, 70.6%). Only five of 43 non-transplanted patients (11.6%) are without immunosuppression. IDDA scores were significantly lower in patients who survived HSCT than in those receiving conventional treatment (P=0.005) or in patients who received abatacept or sirolimus as compared to other therapies, and in patients with residual LRBA expression. Higher disease burden, longer duration before HSCT, and lung involvement were associated with poor outcome. CONCLUSIONS: The life-long disease activity, implying a need for immunosuppression and risk of malignancy, must be weighed against the risks of HSCT.

3.
Artigo em Inglês | MEDLINE | ID: mdl-31857261

RESUMO

BACKGROUND: Central nervous system (CNS) disease in adult common variable immunodeficiency (CVID) is rare, and therefore diagnostic and therapeutic protocols are lacking. OBJECTIVE: To provide clinical information aiming to establish awareness and first experience-based recommendations. METHODS: We reviewed clinical manifestations, genetic and immunological characteristics, diagnostic evaluation, and treatment of patients with CVID with abnormal magnetic resonance imaging (MRI) of the CNS disease in our cohort. RESULTS: Seventeen patients with CNS manifestation and a previous diagnosis of CVID were identified. Presenting symptoms of the CNS disease included loss of sensory or motoric function, headache, or epilepsy. Contrast-enhancing lesions of the brain or solely the spinal cord were the most common findings on MRI. The prevalence of splenomegaly, lymphadenopathy, interstitial lung disease, and autoimmune cytopenia was significantly increased compared with control CVID patients. In 8 patients, a molecular defect was identified, including mutations in CTLA4, NFKB1, and CECR1. Patients with CVID with CNS involvement generally displayed lymphopenia, skewed CD4+ T-cell subsets, and increased proportions of CD21low B cells in the peripheral blood. CNS involvement usually responded well to high-dose steroids, but regularly required maintenance therapy to prevent relapse. CONCLUSION: CNS disease is a severe but rare complication in CVID disorders, particularly affecting patients with other noninfectious disease symptoms. Diagnostic evaluation needs to rule out infectious causes by all means; a genetic evaluation is recommended given the high probability of an underlying monogenic disorder. Possible treatment consists of steroids with yet to be determined optimal maintenance therapy in case of relapse.

4.
Clin Immunol ; 210: 108316, 2019 Nov 23.
Artigo em Inglês | MEDLINE | ID: mdl-31770611

RESUMO

Germline STAT3 gain-of-function (GOF) mutations have been linked to poly-autoimmunity and lymphoproliferation with variable expressivity and incomplete penetrance. Here we studied the impact of 17 different STAT3 GOF mutations on the canonical STAT3 signaling pathway and correlated the molecular results with clinical manifestations. The mutations clustered in three groups. Group 1 mutants showed altered STAT3 phosphorylation kinetics and strong basal transcriptional activity. They were associated with the highest penetrance of lymphoproliferation and autoimmunity. Group 2 mutants showed a strongly inducible transcriptional reporter activity and were clinically less penetrant. Group 3 mutants were mostly located in the DNA binding domain and showed the strongest DNA binding affinity despite a poor transcriptional reporter response. Thus, the GOF effect of STAT3 mutations is determined by a heterogeneous response pattern at the molecular level. The correlation of response pattern and clinical penetrance indicates a significant contribution of mutation-determined effects on disease manifestations.

5.
Blood ; 134(22): 1941-1950, 2019 Nov 28.
Artigo em Inglês | MEDLINE | ID: mdl-31537530

RESUMO

Immune system failure in primary antibody deficiencies (PADs) has been linked to recurrent infections, autoimmunity, and cancer, yet clinical judgment is often based on the reactivity to a restricted panel of antigens. Previously, we demonstrated that the human repertoire of carbohydrate-specific immunoglobulin G (IgG) exhibits modular organization related to glycan epitope structure. The current study compares the glycan-specific IgG repertoires between different PAD entities. Distinct repertoire profiles with extensive qualitative glycan-recognition defects were observed, which are characterized by the common loss of Galα and GalNAc reactivity and disease-specific recognition of microbial antigens, self-antigens, and tumor-associated carbohydrate antigens. Antibody repertoire analysis may provide a useful tool to elucidate the degree and the clinical implications of immune system failure in individual patients.

8.
Blood ; 134(2): 134-146, 2019 Jul 11.
Artigo em Inglês | MEDLINE | ID: mdl-31076441

RESUMO

The inflammatory responsiveness of phagocytes to exogenous and endogenous stimuli is tightly regulated. This regulation plays an important role in systemic inflammatory response syndromes (SIRSs). In SIRSs, phagocytes initially develop a hyperinflammatory response, followed by a secondary state of hyporesponsiveness, a so-called "tolerance." This hyporesponsiveness can be induced by endotoxin stimulation of Toll-like receptor 4 (TLR4), resulting in an ameliorated response after subsequent restimulation. This modification of inflammatory response patterns has been described as innate immune memory. Interestingly, tolerance can also be triggered by endogenous TLR4 ligands, such as the alarmins myeloid-related protein 8 (MRP8, S100A8) and MRP14 (S100A9), under sterile conditions. However, signaling pathways that trigger hyporesponsiveness of phagocytes in clinically relevant diseases are only barely understood. Through our work, we have now identified 2 main signaling cascades that are activated during MRP-induced tolerance of phagocytes. We demonstrate that the phosphatidylinositol 3-kinase/AKT/GSK-3ß pathway interferes with NF-κB-driven gene expression and that inhibition of GSK-3ß mimics tolerance in vivo. Moreover, we identified interleukin-10-triggered activation of transcription factors STAT3 and BCL-3 as master regulators of MRP-induced tolerance. Accordingly, patients with dominant-negative STAT3 mutations show no tolerance development. In a clinically relevant condition of systemic sterile stress, cardiopulmonary bypass surgery, we confirmed the initial induction of MRP expression and the tolerance induction of monocytes associated with nuclear translocation of STAT3 and BCL-3 as relevant mechanisms. Our data indicate that the use of pharmacological JAK-STAT inhibitors may be promising targets for future therapeutic approaches to prevent complications associated with secondary hyporesponsiveness during SIRS.

9.
Front Immunol ; 10: 568, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31057532

RESUMO

Common variable immunodeficiency (CVID) is the most frequent symptomatic primary immunodeficiency. Patients with CVID are prone to recurrent bacterial infection due to the failure of adequate immunoglobulin production. Monogenetic defects have been identified in ~25% of CVID patients. Recently, mutations in IKZF1, encoding the zinc-finger transcription factor IKAROS which is broadly expressed in hematopoietic cells, have been associated with a CVID-like phenotype. Herein we describe 11 patients with heterozygous IKZF1 variants from eight different families with autosomal dominant CVID and two siblings with an IKZF1 variant presenting with inflammatory bowel disease (IBD). This study shows that mutations affecting the DNA binding domain of IKAROS can impair the interaction with the target DNA sequence thereby preventing heterochromatin and pericentromeric localization (HC-PC) of the protein. Our results also indicate an impairment of pericentromeric localization of IKAROS by overexpression of a truncated variant, caused by an immature stop codon in IKZF1. We also describe an additional variant in TNFSF10, encoding Tumor Necrosis Factor Related Apoptosis Inducing Ligand (TRAIL), additionally presented in individuals of Family A. Our results indicate that this variant may impair the TRAIL-induced apoptosis in target cell lines and prohibit the NFκB activation by TRAIL and may act as a modifier in Family A.

10.
Front Immunol ; 10: 297, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30941118

RESUMO

Non-canonical NF-κB-pathway signaling is integral in immunoregulation. Heterozygous mutations in NFKB2 have recently been established as a molecular cause of common variable immunodeficiency (CVID) and DAVID-syndrome, a rare condition combining deficiency of anterior pituitary hormone with CVID. Here, we investigate 15 previously unreported patients with primary immunodeficiency (PID) from eleven unrelated families with heterozygous NFKB2-mutations including eight patients with the common p.Arg853* nonsense mutation and five patients harboring unique novel C-terminal truncating mutations. In addition, we describe the clinical phenotype of two patients with proximal truncating mutations. Cohort analysis extended to all 35 previously published NFKB2-cases revealed occurrence of early-onset PID in 46/50 patients (mean age of onset 5.9 years, median 4.0 years). ACTH-deficiency occurred in 44%. Three mutation carriers have deceased, four developed malignancies. Only two mutation carriers were clinically asymptomatic. In contrast to typical CVID, most patients suffered from early-onset and severe disease manifestations, including clinical signs of T cell dysfunction e.g., chronic-viral or opportunistic infections. In addition, 80% of patients suffered from (predominately T cell mediated) autoimmune (AI) phenomena (alopecia > various lymphocytic organ-infiltration > diarrhea > arthritis > AI-cytopenia). Unlike in other forms of CVID, auto-antibodies or lymphoproliferation were not common hallmarks of disease. Immunophenotyping showed largely normal or even increased quantities of naïve and memory CD4+ or CD8+ T-cells and normal T-cell proliferation. NK-cell number and function were also normal. In contrast, impaired B-cell differentiation and hypogammaglobinemia were consistent features of NFKB2-associated disease. In addition, an array of lymphocyte subpopulations, such as regulatory T cell, Th17-, cTFH-, NKT-, and MAIT-cell numbers were decreased. We conclude that heterozygous damaging mutations in NFKB2 represent a distinct PID entity exceeding the usual clinical spectrum of CVID. Impairment of the non-canonical NF-κB pathways affects function and differentiation of numerous lymphocyte-subpopulations and thus causes a heterogeneous, more severe form of PID phenotype with early-onset. Further characteristic features are multifaceted, primarily T cell-mediated autoimmunity, such as alopecia, lymphocytic organ infiltration, and in addition frequently ACTH-deficiency.

12.
Clin Immunol ; 203: 59-62, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31004792

RESUMO

Some patients diagnosed with common variable immunodeficiency (CVID) actually suffer from combined immunodeficiency (CID) and therefore may require a different, CID-adapted treatment. Several CD4 T-cell-based criteria have been proposed in the past to identify patients with CID within the cohort of adult CVID patients. In this monocentric study, we used retrospective immunological and clinical data of 238 CVID patients to compare four different proposals of how to define CID among CVID patients. We demonstrate that none of the current definitions sufficiently separates CID from CVID patients and that the relative reduction of naïve CD4 T cells <10% has the highest sensitivity of all tested markers for patients with clinical complications often associated with CID. Thus, a very low percentage of naïve CD4 T cells in any adult CVID patient should raise suspicion, but is not sufficient to define CID among CVID patients.

14.
J Allergy Clin Immunol Pract ; 7(6): 1763-1770, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30776527

RESUMO

Patient registries are instrumental for clinical research in rare diseases. They help to achieve a sufficient sample size for epidemiological and clinical research and to assess the feasibility of clinical trials. The European Society for Immunodeficiencies (ESID) registry currently comprises information on more than 25,000 patients with inborn errors of immunity (IEI). The prerequisite of a patient to be included into the ESID registry is an IEI either defined by a defect in a gene included in the disease classification of the international union of immunological societies, or verified by applying clinical criteria. Because a relevant number of patients, including those with common variable immunodeficiency (CVID), representing the largest group of patients in the registry, remain without a genetic diagnosis, consensus on classification of these patients is mandatory. Here, we present clinical criteria for a large number of IEI that were designed in expert panels with an external review. They were implemented for novel entries and verification of existing data sets from 2014, yielding a substantial refinement. For instance, 8% of adults and 27% of children with CVID (176 of 1704 patients) were reclassified to 22 different immunodeficiencies, illustrating progress in genetics, but also the previous lack of standardized disease definitions. Importantly, apart from registry purposes, the clinical criteria are also helpful to support treatment decisions in the absence of a genetic diagnosis or in patients with variants of unknown significance.

15.
Clin Immunol ; 200: 31-34, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30639166

RESUMO

This study reports on a novel activating p110δ mutation causing adult-onset hypogammaglobulinemia with lymphopenia without the classical presentation of atypical Activated phosphoinositide 3-kinase δ syndrome (ADPS-1), underlining thus the heterogeneous clinical and immunological presentation of p110δ mutated individuals and offers additional data on the role of p110δ in early and late B cell development in humans.

16.
Immunol Rev ; 287(1): 33-49, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30565239

RESUMO

Cytotoxic-T-lymphocyte-antigen-4 (CTLA-4) is a negative immune regulator constitutively expressed on regulatory T (Treg) cells and upregulated on activated T cells. CTLA-4 inhibits T cell activation by various suppressive functions including competition with CD28, regulation of the inhibitory function of Treg cells, such as transendocytosis, and the control of adhesion and motility. Intrinsic CTLA-4 signaling has been controversially discussed, but so far no distinct signaling pathway has been identified. The CTLA-4-mediated Treg suppression plays an important role in the maintenance of peripheral tolerance and the prevention of autoimmune diseases. Human CTLA-4 insufficiency is caused by heterozygous germline mutations in CTLA4 and characterized by a complex immune dysregulation syndrome. Clinical studies on CTLA4 mutation carriers showed a reduced penetrance and variable expressivity, suggesting modifying factor(s). One hundred and forty-eight CTLA4 mutation carriers have been reported; patients showed hypogammaglobulinemia, recurrent infectious diseases, various autoimmune diseases, and lymphocytic infiltration into multiple organs. The CTLA-4 expression level in Treg cells was reduced, while the frequency of Treg cells was increased in CTLA-4-insufficient patients. The transendocytosis assay is a specific functional test for the assessment of newly identified CTLA4 gene variants. Immunoglobulin substitution, corticosteroids, immunosuppressive therapy, and targeted therapy such as with CTLA-4 fusion proteins and mechanistic target of rapamycin (mTOR) inhibitors were applied; patients with life-threatening, treatment-resistant symptoms underwent hematopoietic stem cell transplantation. The fact that in humans CTLA-4 insufficiency causes severe disease taught us that the amount of CTLA-4 molecules present in/on T cells matters for immune homeostasis. However, whether the pathology-causing activated T lymphocytes in CTLA-4-insufficient patients are antigen-specific is an unsolved question. CTLA-4, in addition, has a role in autoimmune diseases and cancer. Anti-CTLA-4 drugs are employed as checkpoint inhibitors to target various forms of cancer. Thus, clinical research on human CTLA-4 insufficiency might provide us a deeper understanding of the mechanism(s) of the CTLA-4 molecule and immune dysregulation disorders.


Assuntos
Doenças Autoimunes/imunologia , Antígeno CTLA-4/genética , Sistema Imunitário , Síndromes de Imunodeficiência/imunologia , Imunoterapia/tendências , Neoplasias/imunologia , Linfócitos T Reguladores/imunologia , Homeostase , Humanos , Tolerância Imunológica , Polimorfismo Genético , Transdução de Sinais
17.
J Clin Immunol ; 39(1): 45-54, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30547383

RESUMO

Studies of chest computed tomography (CT) in patients with primary antibody deficiency syndromes (ADS) suggest a broad range of bronchial pathology. However, there are as yet no multicentre studies to assess the variety of bronchial pathology in this patient group. One of the underlying reasons is the lack of a consensus methodology, a prerequisite to jointly document chest CT findings. We aimed to establish an international platform for the evaluation of bronchial pathology as assessed by chest CT and to describe the range of bronchial pathologies in patients with antibody deficiency. Ffteen immunodeficiency centres from 9 countries evaluated chest CT scans of patients with ADS using a predefined list of potential findings including an extent score for bronchiectasis. Data of 282 patients with ADS were collected. Patients with common variable immunodeficiency disorders (CVID) comprised the largest subgroup (232 patients, 82.3%). Eighty percent of CVID patients had radiological evidence of bronchial pathology including bronchiectasis in 61%, bronchial wall thickening in 44% and mucus plugging in 29%. Bronchiectasis was detected in 44% of CVID patients aged less than 20 years. Cough was a better predictor for bronchiectasis than spirometry values. Delay of diagnosis as well as duration of disease correlated positively with presence of bronchiectasis. The use of consensus diagnostic criteria and a pre-defined list of bronchial pathologies allows for comparison of chest CT data in multicentre studies. Our data suggest a high prevalence of bronchial pathology in CVID due to late diagnosis or duration of disease.


Assuntos
Brônquios/patologia , Síndromes de Imunodeficiência/patologia , Parede Torácica/patologia , Adolescente , Adulto , Idoso , Bronquiectasia/patologia , Criança , Pré-Escolar , Imunodeficiência de Variável Comum/patologia , Feminino , Humanos , Lactente , Masculino , Espirometria/métodos , Tomografia Computadorizada por Raios X/métodos , Adulto Jovem
18.
Orphanet J Rare Dis ; 13(1): 201, 2018 11 12.
Artigo em Inglês | MEDLINE | ID: mdl-30419968

RESUMO

BACKGROUND: Common variable immunodeficiency disorders (CVID) are a group of rare innate disorders characterized by specific antibody deficiency and increased rates of infections, comorbidities and mortality. The burden of CVID in Europe has not been previously estimated. We performed a retrospective analysis of the European Society for Immunodeficiencies (ESID) registry data on the subset of patients classified by their immunologist as CVID and treated between 2004 and 2014. The registered deaths and comorbidities were used to calculate the annual average age-standardized rates of Years of Life Lost to premature death (YLL), Years Lost to Disability (YLD) and Disability Adjusted Life Years (DALY=YLL + YLD). These outcomes were expressed as a rate per 105 of the CVID cohort (the individual disease burden), and of the general population (the societal disease burden). RESULTS: Data of 2700 patients from 23 countries were analysed. Annual comorbidity rates: bronchiectasis, 21.9%; autoimmunity, 23.2%; digestive disorders, 15.6%; solid cancers, 5.5%; lymphoma, 3.8%, exceeded the prevalence in the general population by a factor of 34.0, 7.6, 8.1, 2.4 and 32.6, respectively. The comorbidities of CVID caused 8722 (6069; 12,363) YLD/105 in this cohort, whereas 44% of disability burden was attributable to infections and bronchiectasis. The total individual burden of CVID was 36,785 (33,078, 41,380) DALY/105. With estimated CVID prevalence of ~ 1/ 25,000, the societal burden of CVID ensued 1.5 (1.3, 1.7) DALY/105 of the general population. In exploratory analysis, increased mortality was associated with solid tumor, HR (95% CI): 2.69 (1.10; 6.57) p = 0.030, lymphoma: 5.48 (2.36; 12.71) p < .0001 and granulomatous-lymphocytic interstitial lung disease: 4.85 (1.63; 14.39) p = 0.005. Diagnostic delay (median: 4 years) was associated with a higher risk of death: 1.04 (1.02; 1.06) p = .0003, bronchiectasis: 1.03 (1.01; 1.04) p = .0001, solid tumor: 1.08 (1.04; 1.11) p < .0001 and enteropathy: 1.02 (1.00; 1.05) p = .0447 and stayed unchanged over four decades (p = .228). CONCLUSIONS: While the societal burden of CVID may seem moderate, it is severe to the individual patient. Delay in CVID diagnosis may constitute a modifiable risk factor of serious comorbidities and death but showed no improvement. Tools supporting timely CVID diagnosis should be developed with high priority.


Assuntos
Imunodeficiência de Variável Comum/economia , Imunodeficiência de Variável Comum/epidemiologia , Sistema de Registros , Efeitos Psicossociais da Doença , Europa (Continente)/epidemiologia , Humanos , Expectativa de Vida , Estudos Retrospectivos
19.
Front Immunol ; 9: 2012, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30250467

RESUMO

Background: Cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) is a negative immune regulator on the surface of T cells. In humans, heterozygous germline mutations in CTLA4 can cause an immune dysregulation syndrome. The phenotype comprises a broad spectrum of autoinflammatory, autoimmune, and immunodeficient features. An increased frequency of malignancies in primary immunodeficiencies is known, but their incidence in CTLA-4 insufficiency is unknown. Methods: Clinical manifestations and details of the clinical history were assessed in a worldwide cohort of 184 CTLA4 mutation carriers. Whenever a malignancy was reported, a malignancy-specific questionnaire was filled. Results: Among the 184 CTLA4 mutation carriers, 131 were considered affected, indicating a penetrance of 71.2%. We documented 17 malignancies, which amounts to a cancer prevalence of 12.9% in affected CTLA4 mutation carriers. There were ten lymphomas, five gastric cancers, one multiple myeloma, and one metastatic melanoma. Seven lymphomas and three gastric cancers were EBV-associated. Conclusion: Our findings demonstrate an elevated cancer risk for patients with CTLA-4 insufficiency. As more than half of the cancers were EBV-associated, the failure to control oncogenic viruses seems to be part of the CTLA-4-insufficient phenotype. Hence, lymphoproliferation and EBV viral load in blood should be carefully monitored, especially when immunosuppressing affected CTLA4 mutation carriers.


Assuntos
Adenocarcinoma/genética , Antígeno CTLA-4/genética , Infecções por Vírus Epstein-Barr/epidemiologia , Herpesvirus Humano 4/fisiologia , Linfoma/genética , Mutação/genética , Neoplasias Gástricas/genética , Adenocarcinoma/epidemiologia , Adolescente , Adulto , Idoso , Estudos de Coortes , Feminino , Humanos , Linfoma/epidemiologia , Masculino , Pessoa de Meia-Idade , Prevalência , Risco , Neoplasias Gástricas/epidemiologia , Adulto Jovem
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