RESUMO
INTRODUCTION: The signal transducer and activator of transcription (STAT1) gain-of-function (GOF) syndrome accounts for most cases of chronic mucocutaneous candidiasis but is characterized by a broader clinical phenotype that may include bacterial, viral, or invasive fungal infections, autoimmunity, autoinflammatory manifestations, vascular complications, or malignancies. The severity of lymphopenia may vary and influence the infectious morbidity. METHODS: In our cohort of seven STAT1-GOF patients, we investigated the mechanisms that may determine T lymphopenia, we characterized the interferon gene signature (IGS) and analyzed the effect of ruxolitinib in reverting the immune dysregulation. RESULTS: STAT1-GOF patients exhibited increased T lymphocyte apoptosis that was significantly augmented in both resting conditions and following stimulation with mitogens and IFNα, as evaluated by flow cytometry by Annexin V/ Propidium iodide assay. The JAK inhibitor ruxolitinib significantly reduced the IFNα-induced hyperphosphorylation of STAT1 and reverted the stimulation-induced T-cell apoptosis, in vitro. In two adult STAT1-GOF patients, the JAKinib treatment ameliorated chronic mucocutaneous candidiasis and lymphopenia. Most STAT1-GOF patients, particularly those who had autoimmunity, presented increased IGS that significantly decreased in the two patients during ruxolitinib treatment. CONCLUSION: In STAT1-GOF patients, T lymphocyte apoptosis is increased, and T lymphopenia may determine higher risk of severe infections. The JAKinib target therapy should be evaluated to treat severe chronic candidiasis and lymphopenia, and to downregulate the IFNs in patients with autoinflammatory or autoimmune manifestations.
Assuntos
Candidíase Mucocutânea Crônica , Inibidores de Janus Quinases , Linfopenia , Nitrilas , Pirazóis , Pirimidinas , Trombocitopenia , Adulto , Humanos , Mutação com Ganho de Função , Inibidores de Janus Quinases/uso terapêutico , Candidíase Mucocutânea Crônica/tratamento farmacológico , Candidíase Mucocutânea Crônica/genética , Interferons , Fator de Transcrição STAT1/metabolismoRESUMO
Granulomatous lymphocytic interstitial lung disease (GLILD) represents a fatal immune dysregulatory complication in common variable immunodeficiency (CVID). Evidence-based diagnostic guidelines are lacking, and GLILD treatment consists in immunosuppressive drugs; nonetheless, therapeutical strategies are heterogeneous and essentially based on experts' opinions and data from small case series or case reports.We aimed to evaluate the efficacy and safety of first-line Rituximab monotherapy for CVID-related GLILD, by assessing symptoms and quality of life alterations, immunological parameters, pulmonary function tests, and lung computed tomography.All six GLILD patients received Rituximab infusions as a first-line treatment. Rituximab was administered at 375 mg/m2 monthly for six infusions followed by maintenance every 3 months; none of the patients experienced severe adverse events. Symptom burden and quality of life significantly improved in treated patients compared to a control group of CVID patients without GLILD. Rituximab treatment indirectly caused a trend toward reduced T-cell activation and exhaustion markers sCD25 and sTIM-3. Lung function improved in treated patients, with statistically significant increases in TLC and DLCO. Lung CT scan findings expressed by means of Baumann scoring system displayed a reduction in the entire cohort.In conclusion, first-line monotherapy with Rituximab displayed high efficacy in disease remission in all treated patients, with improvement of symptoms and amelioration of quality of life, as well as restoration of PFTs and lung CT scan findings.
Assuntos
Imunodeficiência de Variável Comum , Doenças Pulmonares Intersticiais , Humanos , Rituximab/uso terapêutico , Imunodeficiência de Variável Comum/complicações , Imunodeficiência de Variável Comum/diagnóstico , Imunodeficiência de Variável Comum/tratamento farmacológico , Doenças Pulmonares Intersticiais/diagnóstico , Doenças Pulmonares Intersticiais/tratamento farmacológico , Doenças Pulmonares Intersticiais/etiologia , Qualidade de Vida , PulmãoRESUMO
PURPOSE: Binding of the B cell activating factor (BAFF) to its receptor (BAFFR) activates in mature B cells many essential pro-survival functions. Null mutations in the BAFFR gene result in complete BAFFR deficiency and cause a block in B cell development at the transition from immature to mature B cells leading therefore to B lymphopenia and hypogammaglobulinemia. In addition to complete BAFFR deficiency, single nucleotide variants encoding BAFFR missense mutations were found in patients suffering from common variable immunodeficiency (CVID), autoimmunity, or B cell lymphomas. As it remained unclear to which extent such variants disturb the activity of BAFFR, we performed genetic association studies and developed a cellular system that allows the unbiased analysis of BAFFR variants regarding oligomerization, signaling, and ectodomain shedding. METHODS: In addition to genetic association studies, the BAFFR variants P21R, A52T, G64V, DUP92-95, P146S, and H159Y were expressed by lentiviral gene transfer in DG-75 Burkitt's lymphoma cells and analyzed for their impacts on BAFFR function. RESULTS: Binding of BAFF to BAFFR was affected by P21R and A52T. Spontaneous oligomerization of BAFFR was disturbed by P21R, A52T, G64V, and P146S. BAFF-dependent activation of NF-κB2 was reduced by P21R and P146S, while interactions between BAFFR and the B cell antigen receptor component CD79B and AKT phosphorylation were impaired by P21R, A52T, G64V, and DUP92-95. P21R, G64V, and DUP92-95 interfered with phosphorylation of ERK1/2, while BAFF-induced shedding of the BAFFR ectodomain was only impaired by P21R. CONCLUSION: Although all variants change BAFFR function and have the potential to contribute as modifiers to the development of primary antibody deficiencies, autoimmunity, and lymphoma, P21R is the only variant that was found to correlate positively with CVID.
Assuntos
Receptor do Fator Ativador de Células B , Imunodeficiência de Variável Comum , Humanos , Fator Ativador de Células B/genética , Fator Ativador de Células B/metabolismo , Receptor do Fator Ativador de Células B/genética , Receptor do Fator Ativador de Células B/metabolismo , Linfócitos B , Imunodeficiência de Variável Comum/genética , Imunodeficiência de Variável Comum/metabolismo , Ligantes , Transdução de SinaisRESUMO
INTRODUCTION: Autoimmunity is a common feature in CVID patients. To date the mechanisms leading to the development of such complications are not fully elucidated. MATERIALS AND METHODS: Data from 122 CVID patients subdivided in three groups based on the absence of autoimmunity (n-AI) or the presence of hematologic autoimmune phenomena (Cy-AI) or non-hematologic autoimmune phenomena (n-Cy-AI) were evaluated. RESULTS: We identified a total of 128 autoimmune manifestations in 55/122 patients (45.1%). 30/122 (24.6%) patients presented hematologic autoimmune phenomena while 29/122 (23.8%) presented gastrointestinal autoimmune involvement. Immune thrombocytopenia was the most common manifestation (27/122; 22.1%), followed by autoimmune hemolytic anemia (18/122; 14.8%) and autoimmune enteropathy (17/122; 13.9%). Cy-AI patients displayed higher CD4+ effector memory and terminally differentiated CD8+ cells with lower percentages of naïve and recent thymic emigrants (RTEs) CD4+ cells and a significant expansion of the CD19hiCD21low population. CONCLUSIONS: CVID patients developing autoimmune cytopenias display characteristic immune phenotypic features.
Assuntos
Imunodeficiência de Variável Comum , Púrpura Trombocitopênica Idiopática , Autoimunidade , Linfócitos T CD4-Positivos , Humanos , ImunofenotipagemRESUMO
Dedicator of Cytokinesis 8 (DOCK8) deficiency is a rare form of autosomal recessive combined immunodeficiency. The effect of DOCK8 deficiency on Natural Killer cell biology has not been fully elucidated yet. Thus, we undertook a detailed phenotypic and functional evaluation of NK cells from seven patients with DOCK8 deficiency. Patients' immature CD56bright NK cells were defective in IFN-γ secretion, while their mature CD56dim NK cells showed impaired cytotoxicity, partially rescued upon rIL-2 addition. Cross-linking of NK cell receptors revealed a specific defect in the CD3 zeta chain-dependent activation pathway in DOCK8 deficiency. Lack of DOCK8, but not of WASP, impaired CCR7 expression on human CD56bright NK cells, a critical receptor for their migration to secondary lymph nodes. Evaluation of a patient's lymph node showed a severe reduction in NK cells that showed increased intracellular expression of CCR7. Our data suggest that DOCK8 deficiency variably affects NK cell homeostasis in humans.
Assuntos
Citocinese , Fatores de Troca do Nucleotídeo Guanina , Células Matadoras Naturais , Receptores CCR7 , Antígeno CD56/metabolismo , Fatores de Troca do Nucleotídeo Guanina/genética , Fatores de Troca do Nucleotídeo Guanina/metabolismo , Humanos , Células Matadoras Naturais/metabolismo , Receptores CCR7/genética , Receptores CCR7/metabolismo , Proteína da Síndrome de Wiskott-AldrichRESUMO
PURPOSE: Jacobsen syndrome (JS) is a rare form of genetic disorder that was recently classified as a syndromic immunodeficiency. Available detailed immunological data from JS patients are limited. METHODS: Clinical and immunological presentation of twelve pediatric patients with JS by means of revision of clinical records, flow cytometry, real-time PCR, and lymphocyte functional testing were collected. RESULTS: Recurrent infections were registered in 6/12 patients (50%), while bleeding episodes in 2/12 (16.7%). White blood cell and absolute lymphocyte counts were reduced in 8/12 (66.7%) and 7/12 (58.3%) patients, respectively. Absolute numbers of CD3+ and CD4+ T cells were reduced in 8/12 (66.7%) and 7/12 (58.3%), respectively. Of note, recent thymic emigrants (RTE) were reduced in all tested patients (9/9), with T-cell receptor excision circle analysis (TRECs) showing a similar trend in 8/9 patients; naïve CD4+ T cells were low only in 5/11 patients (45.4%). Interestingly, B-cell counts, IgM memory B cells, and IgM serum levels were reduced in 10/12 (83.3%) patients. Natural killer (NK) cell counts were mostly normal but the percentages of CD16+CD56low/- cells were expanded in 7/7 patients tested. The observed immunological alterations did not correlate with patients' age. Finally, responses to proliferative stimuli were normal at presentation for all patients, although they may deteriorate over time. CONCLUSIONS: Our data suggest that patients affected with JS may display important numeric and maturational alterations in the T-, B-, and NK-cell compartments. These findings suggest that JS patients should be regularly monitored from an immunological point of view.
Assuntos
Síndrome da Deleção Distal 11q de Jacobsen , Linfócitos B , Criança , Citometria de Fluxo , Humanos , Células Matadoras Naturais , Contagem de LinfócitosRESUMO
BACKGROUND: X-linked agammaglobulinemia (XLA) is the prototype of primary humoral immunodeficiencies. Long-term follow-up studies regarding disease-related complications and outcome are scarce. OBJECTIVE: Our aim was to describe the natural history of XLA. METHODS: A nationwide multicenter study based on the Italian Primary Immunodeficiency Network registry was established in 2000 in Italy. Affected patients were enrolled by documenting centers, and the patients' laboratory, clinical, and imaging data were recorded on an annual base. RESULTS: Data on the patients (N = 168) were derived from a cumulative follow-up of 1370 patient-years, with a mean follow-up of 8.35 years per patient. The mean age at diagnosis decreased after establishment of the Italian Primary Immunodeficiency Network registry (84 months before vs 23 months after). Respiratory, skin, and gastrointestinal manifestations were the most frequent clinical symptoms at diagnosis and during long-term follow-up. Regular immunoglobulin replacement treatment reduced the incidence of invasive infections. Affected patients developed chronic lung disease over time (47% after 40 years of follow-up) in the presence of chronic sinusitis (84%). Malignancies were documented in a minority of cases (3.7%). Overall survival for affected patients was significantly reduced when compared with that for the healthy male Italian population, and it further deteriorated in the presence of chronic lung disease. CONCLUSIONS: This is the first detailed long-term follow-up study for patients with XLA, revealing that although immunoglobulin replacement treatment reduces the incidence of invasive infections, it does not appear to influence the development of chronic lung disease. The overall survival of affected patients is reduced. Further studies are warranted to improve patients' clinical management and increase awareness among physicians.
Assuntos
Agamaglobulinemia/epidemiologia , Doenças Genéticas Ligadas ao Cromossomo X/epidemiologia , Infecções/epidemiologia , Pneumopatias/epidemiologia , Sinusite/epidemiologia , Adolescente , Adulto , Agamaglobulinemia/mortalidade , Criança , Pré-Escolar , Seguimentos , Doenças Genéticas Ligadas ao Cromossomo X/mortalidade , Humanos , Lactente , Recém-Nascido , Itália/epidemiologia , Masculino , Pessoa de Meia-Idade , Análise de Sobrevida , Adulto JovemRESUMO
Mutations affecting the non-canonical pathway of NF-κB were recently identified to underlie a form of common variable immunodeficiency strongly associated with autoimmunity. Although intrinsic B-cell abnormalities explain most of the humoral defects of this disease, detailed data on the impact of NFKB2 on follicular helper (Tfh) and regulatory (Tregs) T cells are scarce. Here, we show that Tfh, CXCR5+, and CXCR5- Treg cell subsets were significantly reduced in patients heterozygous for a truncating mutation of NFKB2. Plasma CXCL13 levels were reduced, underlining an important role for NFKB2 in regulating the germinal center (GC) response. Proinflammatory IFNγ, IL-17 and IL-10 cytokine production by CD4 T cells was lower in the mutated patients, but the production of IL-4 and IL-21 was not altered. Taken together, our findings show that NFKB2 influences the quality and efficiency of human GC reaction, by affecting not only the B cells but also GC-relevant T cell subsets.
Assuntos
Imunodeficiência de Variável Comum/imunologia , Centro Germinativo/imunologia , Subunidade p52 de NF-kappa B/genética , Linfócitos T Auxiliares-Indutores/imunologia , Linfócitos T Reguladores/imunologia , Adolescente , Adulto , Autoimunidade , Diferenciação Celular , Proliferação de Células , Células Cultivadas , Criança , Imunodeficiência de Variável Comum/genética , Citocinas/metabolismo , Feminino , Humanos , Masculino , NF-kappa B/genética , NF-kappa B/metabolismo , Deleção de Sequência/genética , Transdução de Sinais , Adulto JovemRESUMO
This study provides evidence for the first time for APDS-1 presenting as MAS/HLH, with evident clinical implications in patient's management and prognosis.
Assuntos
Classe I de Fosfatidilinositol 3-Quinases/genética , Linfo-Histiocitose Hemofagocítica/diagnóstico , Síndrome de Ativação Macrofágica/diagnóstico , Doenças da Imunodeficiência Primária/diagnóstico , Criança , Humanos , Linfo-Histiocitose Hemofagocítica/genética , Síndrome de Ativação Macrofágica/genética , Masculino , Mutação , Doenças da Imunodeficiência Primária/genéticaRESUMO
Primary immunodeficiencies (PIDs) are heterogeneous disorders, characterized by variable clinical and immunological features. National PID registries offer useful insights on the epidemiology, diagnosis, and natural history of these disorders. In 1999, the Italian network for primary immunodeficiencies (IPINet) was established. We report on data collected from the IPINet registry after 20 years of activity. A total of 3352 pediatric and adult patients affected with PIDs are registered in the database. In Italy, a regional distribution trend of PID diagnosis was observed. Based on the updated IUIS classification of 2019, PID distribution in Italy showed that predominantly antibody deficiencies account for the majority of cases (63%), followed by combined immunodeficiencies with associated or syndromic features (22.5%). The overall age at diagnosis was younger for male patients. The minimal prevalence of PIDs in Italy resulted in 5.1 per 100.000 habitants. Mortality was similar to other European registries (4.2%). Immunoglobulin replacement treatment was prescribed to less than one third of the patient cohort. Collectively, this is the first comprehensive description of the PID epidemiology in Italy.
Assuntos
Doenças da Imunodeficiência Primária/epidemiologia , Adolescente , Adulto , Criança , Pré-Escolar , Bases de Dados Factuais , Feminino , Geografia Médica , História do Século XX , História do Século XXI , Humanos , Lactente , Recém-Nascido , Itália/epidemiologia , Masculino , Vigilância da População , Prevalência , Doenças da Imunodeficiência Primária/diagnóstico , Doenças da Imunodeficiência Primária/história , Doenças da Imunodeficiência Primária/terapia , Prognóstico , Sistema de Registros , Adulto JovemRESUMO
This study provides evidence for a novel role for NFKB2 in human B cell development in the bone marrow and in the periphery, leading to progressive peripheral B cell deficiency not always combined with autoimmune phenomena, broadening thus the clinical spectrum of NFKB2 mutated CVID disease and implying an essential role for NFKB2 in early human B cell development.
Assuntos
Imunodeficiência de Variável Comum/genética , Linfopoese/genética , Subunidade p52 de NF-kappa B/genética , Células Precursoras de Linfócitos B/imunologia , Adulto , Linfócitos B/imunologia , Imunodeficiência de Variável Comum/imunologia , Mutação da Fase de Leitura , Humanos , MasculinoRESUMO
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.
Assuntos
Agamaglobulinemia/genética , Classe I de Fosfatidilinositol 3-Quinases/genética , Linfopenia/genética , Doenças da Imunodeficiência Primária/genética , Adulto , Agamaglobulinemia/imunologia , Linfócitos B/citologia , Linfócitos B/imunologia , Classe I de Fosfatidilinositol 3-Quinases/imunologia , Feminino , Mutação com Ganho de Função , Humanos , Linfopenia/imunologia , Linfopoese , Doenças da Imunodeficiência Primária/imunologiaRESUMO
PURPOSE: Selective IgA deficiency (SIgAD) is the most common humoral primary immunodeficiency. Long-term follow-up data in large cohort of pediatric patients are scarce. METHODS: We report on a single-center cohort of 184 pediatric patients affected with selective IgA deficiency and describe the characteristics at diagnosis and during follow-up. RESULTS: Respiratory infections were the most common clinical finding leading to the initial diagnosis (62%). Positive family history for antibody deficiencies (selective IgA deficiency, common variable immunodeficiency) led to SIgAD diagnosis in 16% of cases. During follow-up, while the incidence of respiratory infections was not particularly high, gastrointestinal symptoms were reported in 27% of patients. Allergic manifestations were found in 23% at diagnosis and an additional 16% of patients during follow-up, leading to a prevalence of atopy of 39% among SIgAD patients. Autoimmune manifestations, excluding celiac disease, were found in 9% of affected patients during follow-up. Celiac disease was found in a high prevalence (14%). Increase of serum IgA levels to partial deficiency (9%) and normal serum levels for age (4%) was observed during follow-up. A small percentage of patients (2%) progressed to common variable immunodeficiency (CVID). CONCLUSIONS: In conclusion, this is the first study to describe a large single-center pediatric cohort of patients affected with SIgAD, revealing that overall most patients do well with regard to infections. Many develop CD, at a rate much higher than the general population. A few normalize their IgA levels. A few progress to CVID. Thus, careful follow-up is suggested to diagnose and treat potential complications earlier for avoiding potential morbidities.
Assuntos
Deficiência de IgA/epidemiologia , Adolescente , Doença Celíaca/epidemiologia , Criança , Pré-Escolar , Estudos de Coortes , Feminino , Humanos , Hipersensibilidade/epidemiologia , Deficiência de IgA/diagnóstico , Itália , Estudos Longitudinais , Masculino , Infecções Respiratórias/epidemiologiaRESUMO
NFKB1, a component of the canonical NF-κB pathway, was recently reported to be mutated in a limited number of CVID patients. CVID-associated mutations in NFKB2 (non-canonical pathway) have previously been shown to impair NK cell cytotoxic activity. Although a biological function of NFKB1 in non-human NK cells has been reported, the role of NFKB1 mutations for human NK cell biology and disease has not been investigated yet. We decided therefore to evaluate the role of monoallelic NFKB1 mutations in human NK cell maturation and functions. We show that NFKB1 mutated NK cells present impaired maturation, defective cytotoxicity and reduced IFN-γ production upon in vitro stimulation. Furthermore, human IL-2 activated NFKB1 mutated NK cells fail to up-regulate the expression of the activating marker NKp44 and show reduced proliferative capacity. These data suggest that NFKB1 plays an essential novel role for human NK cell maturation and effector functions.
Assuntos
Células Matadoras Naturais/imunologia , Subunidade p50 de NF-kappa B/imunologia , Linhagem Celular Tumoral , Citotoxicidade Imunológica/imunologia , Feminino , Humanos , Interferon gama/imunologia , Interleucina-2/imunologia , Células K562 , Masculino , NF-kappa B/imunologiaRESUMO
B cell developmental defects in CVID were recently described in a limited number of cases. To date, a detailed correlation between this maturational defect and the clinical presentation of affected patients has not been reported. In this study, we correlated bone marrow B cell evaluation, peripheral B and T lymphocyte subsets and clinical findings in 15 CVID patients. Early B cell developmental defects were observed in one third of patients. Combined bone marrow and peripheral lymphocytes evaluation allowed to further subdivide CVID patients in three groups with shared clinical features at diagnosis and during follow-up. These data broaden the number of CVID patients with early B cell developmental defects and, together with the peripheral lymphocytes evaluation, offer insight into the related clinical features in affected patients.
Assuntos
Linfócitos B/imunologia , Células da Medula Óssea/imunologia , Imunodeficiência de Variável Comum/imunologia , Ativação Linfocitária/imunologia , Linfócitos T/imunologia , Adolescente , Adulto , Doenças Autoimunes/etiologia , Doenças Autoimunes/imunologia , Subpopulações de Linfócitos B/imunologia , Medula Óssea , Bronquiectasia/etiologia , Bronquiectasia/imunologia , Imunodeficiência de Variável Comum/complicações , Feminino , Citometria de Fluxo , Humanos , Masculino , Pessoa de Meia-Idade , Recidiva , Infecções Respiratórias/etiologia , Infecções Respiratórias/imunologia , Esplenomegalia/etiologia , Esplenomegalia/imunologia , Subpopulações de Linfócitos T/imunologia , Adulto JovemAssuntos
Agamaglobulinemia/diagnóstico , Linfócitos B/imunologia , COVID-19/diagnóstico , Síndromes de Imunodeficiência/diagnóstico , Pulmão/diagnóstico por imagem , Miastenia Gravis/diagnóstico , SARS-CoV-2/fisiologia , Linfócitos T/imunologia , Timoma/diagnóstico , Neoplasias do Timo/diagnóstico , Pressão Positiva Contínua nas Vias Aéreas , Evolução Fatal , Humanos , Masculino , Pessoa de Meia-Idade , Tomografia Computadorizada por Raios XAssuntos
Síndrome Linfoproliferativa Autoimune/etiologia , Mutação em Linhagem Germinativa , Homozigoto , Receptor fas/deficiência , Síndrome Linfoproliferativa Autoimune/diagnóstico , Síndrome Linfoproliferativa Autoimune/metabolismo , Síndrome Linfoproliferativa Autoimune/terapia , Biomarcadores , Suscetibilidade a Doenças , Predisposição Genética para Doença , Transplante de Células-Tronco Hematopoéticas , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Linfócitos T/imunologia , Linfócitos T/metabolismoRESUMO
Senescent fibroblasts, which are present in chronic ulcers, are the reason for the wound becoming chronic. In this study, we introduce full-thickness micro skin grafts in the ulcer, a surgical technique known as a 'nested graft', which gave encouraging results leading to complete wound healing in all patients. The assessment of fibroblast cultures taken from the wound before and after treatment and comparison with fibroblasts from healthy skin showed that the fibroblasts taken from the ulcer after the nested graft treatment acquire morpho-functional characteristics overlapping those of fibroblasts from healthy skin. This surgical approach is, therefore, able to lead to the healing of chronic ulcers through the de-senescence of the fibroblasts.