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1.
Immunol Lett ; 266: 106839, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38309375

RESUMO

The X-linked chronic granulomatous disease (X-CGD), a rare genetic disease characterised by recurrent infections, is caused by mutations of NOX2. Significant proportions of X-CGD patients display signs of immune dysregulation. Regulatory T cells (Tregs) are CD4+T lymphocytes that expand in active inflammation and prevent autoimmune disorders. Here we asked whether X-CGD is associated to Treg dysfunctions in adult patients. To this aim, the frequency of Tregs was analysed through intracellular flow cytometry in a cohort of adult X-CGD patients, carriers and controls. We found that Tregs were significantly expanded and activated in blood of adult X-CGD patients, and this was associated with activation of conventional CD4+T cells (Tconvs). T cell activation was characterised by accumulation of intracellular ROS, not derived from NOX2 but likely produced by cellular metabolism. The higher TNF production by Tconvs in X-CGD patients might contribute to the expansion of Tregs through the TNFR2 receptor. In summary, our data indicate that Tregs expand in adult X-CGD in response to immune activation, and that the increase of NOX2-independent ROS content is a feature of activated T cells.


Assuntos
Doença Granulomatosa Crônica , Adulto , Humanos , Doença Granulomatosa Crônica/genética , Doença Granulomatosa Crônica/metabolismo , Linfócitos T Reguladores , NADPH Oxidases/genética , NADPH Oxidases/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Mutação
2.
J Clin Immunol ; 44(2): 47, 2024 Jan 17.
Artigo em Inglês | MEDLINE | ID: mdl-38231401

RESUMO

PURPOSE: Inborn errors of immunity (IEI) represent a heterogeneous group of rare genetically determined diseases. In some cases, patients present with complex or atypical phenotypes, not fulfilling the accepted diagnostic criteria for IEI and, thus, at high risk of misdiagnosis or diagnostic delay. This study aimed to validate a platform that, through the opinion of immunologist experts, improves the diagnostic process and the level of care of patients with atypical/complex IEI. METHODS: Here, we describe the functioning of the IEI-Virtual Consultation System (VCS), an innovative platform created by the Italian Immunodeficiency Network (IPINet). RESULTS: In the validation phase, from January 2020 to June 2021, 68 cases were entered on the IEI-VCS platform. A final diagnosis was achieved in 35/68 cases (51%, 95% CI 38.7 to 64.2). In 22 out of 35 solved cases, the diagnosis was confirmed by genetic analysis. In 3/35 cases, a diagnosis of secondary immunodeficiency was made. In the remaining 10 cases, an unequivocal clinical and immunological diagnosis was obtained, even though not substantiated by genetic analysis. CONCLUSION: From our preliminary study, the VCS represents an innovative and useful system to improve the diagnostic process of patients with complex unsolved IEI disorders, with benefits both in terms of reduction of time of diagnosis and access to the required therapies. These results may help the functioning of other international platforms for the management of complex cases.


Assuntos
Diagnóstico Tardio , Doenças Raras , Humanos , Fenótipo , Encaminhamento e Consulta , Itália
3.
Front Immunol ; 14: 1229674, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37781361

RESUMO

Background and aims: Wiskott-Aldrich syndrome (WAS) is an X-linked recessive primary immunodeficiency disorder characterized by severe eczema, recurrent infections, and micro-thrombocytopenia. Allogeneic hematopoietic stem cell transplantation (HSCT) is a potentially curative therapeutic option for patients with classic form. The risk of developing post-transplant tumors appears to be higher in patients with WAS than in other inborn errors of immunity (IEIs), but the actual incidence is not well defined, due to the scarcity of published data. Methods: Herein, we describe a 10-year-old patient diagnosed with WAS, treated with HSCT in the first year of life, who subsequently developed two rare solid tumors, kaposiform hemangioendothelioma and desmoid tumor. A review of the literature on post-HSCT tumors in WAS patients has been performed. Results: The patient received diagnosis of classic WAS at the age of 2 months (Zhu score = 3), confirmed by WAS gene sequencing, which detected the nonsense hemizygous c.37C>T (Arg13X) mutation. At 9 months, patient underwent HSCT from a matched unrelated donor with an adequate immune reconstitution, characterized by normal lymphocyte subpopulations and mitogen proliferation tests. Platelet count significantly increased, even though platelet count never reached reference values. A mixed chimerism was also detected, with a residual WASP- population on monocytes (27.3%). The patient developed a kaposiform hemangioendothelioma at the age of 5. A second abdominal tumor was identified, histologically classified as a desmoid tumor when he reached the age of 10 years. Both hematopoietic and solid tumors were identified in long-term WAS survivors after HSCT. Conclusion: Here, we describe the case of a patient with WAS who developed two rare solid tumors after HSCT. An active surveillance program for the risk of tumors is necessary in the long-term follow-up of post-HSCT WAS patients.


Assuntos
Fibromatose Agressiva , Transplante de Células-Tronco Hematopoéticas , Sarcoma de Kaposi , Síndrome de Wiskott-Aldrich , Masculino , Humanos , Lactente , Criança , Síndrome de Wiskott-Aldrich/diagnóstico , Síndrome de Wiskott-Aldrich/terapia , Síndrome de Wiskott-Aldrich/genética , Fibromatose Agressiva/etiologia , Sarcoma de Kaposi/etiologia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos
4.
J Clin Immunol ; 43(8): 2192-2207, 2023 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-37837580

RESUMO

GATA2 deficiency is a rare disorder encompassing a broadly variable phenotype and its clinical picture is continuously evolving. Since it was first described in 2011, up to 500 patients have been reported. Here, we describe a cohort of 31 Italian patients (26 families) with molecular diagnosis of GATA2 deficiency. Patients were recruited contacting all the Italian Association of Pediatric Hematology and Oncology (AIEOP) centers, the Hematology Department in their institution and Italian societies involved in the field of vascular anomalies, otorhinolaryngology, dermatology, infectious and respiratory diseases. Median age at the time of first manifestation, molecular diagnosis and last follow-up visit was 12.5 (age-range, 2-52 years), 18 (age-range, 7-64 years) and 22 years (age-range, 3-64), respectively. Infections (39%), hematological malignancies (23%) and undefined cytopenia (16%) were the most frequent symptoms at the onset of the disease. The majority of patients (55%) underwent hematopoietic stem cell transplantation. During the follow-up rarer manifestations emerged. The clinical penetrance was highly variable, with the coexistence of severely affected pediatric patients and asymptomatic adults in the same pedigree. Two individuals remained asymptomatic at the last follow-up visit. Our study highlights new (pilonidal cyst/sacrococcygeal fistula, cholangiocarcinoma and gastric adenocarcinoma) phenotypes and show that lymphedema may be associated with null/regulatory mutations. Countrywide studies providing long prospective follow-up are essential to unveil the exact burden of rarer manifestations and the natural history in GATA2 deficiency.


Assuntos
Deficiência de GATA2 , Transplante de Células-Tronco Hematopoéticas , Adolescente , Adulto , Criança , Pré-Escolar , Humanos , Pessoa de Meia-Idade , Adulto Jovem , Deficiência de GATA2/diagnóstico , Deficiência de GATA2/genética , Deficiência de GATA2/terapia , Estudos de Associação Genética , Itália/epidemiologia , Estudos Prospectivos
5.
Cancer Med ; 12(13): 14663-14673, 2023 07.
Artigo em Inglês | MEDLINE | ID: mdl-37264737

RESUMO

BACKGROUND/OBJECTIVES: Ataxia telangiectasia (A-T) is a multiorgan disorder with increased vulnerability to cancer. Despite this increased cancer risk, there are no widely accepted guidelines for cancer surveillance in people affected by A-T. We aimed to understand the current international practice regarding cancer surveillance in A-T and agreed-upon approaches to develop cancer surveillance in A-T. DESIGN/METHODS: We used a consensus development method, the e-Delphi technique, comprising three rounds. Round 1 consisted of a Delphi questionnaire and a survey that collected the details of respondents' professional background, experience, and current practice of cancer surveillance in A-T. Rounds 2 and 3 were designed based on previous rounds and modified according to the comments made by the panellists. The pre-specified consensus threshold was ≥75% agreement. RESULTS: Thirty-five expert panellists from 13 countries completed the study. The survey indicated that the current practice of cancer surveillance varies widely between experts and centres'. Consensus was reached that evidence-based guidelines are needed for cancer surveillance in people with A-T, with separate recommendations for adults and children. Statements relating to the tests that should be included, the age for starting and stopping cancer surveillance and the optimal surveillance interval were also agreed upon, although in some areas, the consensus was that further research is needed. CONCLUSION: The international expert consensus statement confirms the need for evidence-based cancer surveillance guidelines in A-T, highlights key features that the guidelines should include, and identifies areas of uncertainty in the expert community. This elucidates current knowledge gaps and will inform the design of future clinical trials.


Assuntos
Ataxia Telangiectasia , Neoplasias , Adulto , Criança , Humanos , Ataxia Telangiectasia/complicações , Ataxia Telangiectasia/diagnóstico , Consenso , Técnica Delfos , Inquéritos e Questionários
6.
Allergy Asthma Clin Immunol ; 19(1): 32, 2023 Apr 20.
Artigo em Inglês | MEDLINE | ID: mdl-37081481

RESUMO

Job's syndrome, or autosomal dominant hyperimmunoglobulin E syndrome (AD-HIES, STAT3-Dominant Negative), is a rare inborn error of immunity (IEI) with multi-organ involvement and long-life post-infective damage. Longitudinal registries are of primary importance in improving our knowledge of the natural history and management of these rare disorders. This study aimed to describe the natural history of 30 Italian patients with AD-HIES recorded in the Italian network for primary immunodeficiency (IPINet) registry. This study shows the incidence of manifestations present at the time of diagnosis versus those that arose during follow up at a referral center for IEI. The mean time of diagnostic delay was 13.7 years, while the age of disease onset was < 12 months in 66.7% of patients. Respiratory complications, namely bronchiectasis and pneumatoceles, were present at diagnosis in 46.7% and 43.3% of patients, respectively. Antimicrobial prophylaxis resulted in a decrease in the incidence of pneumonia from 76.7% to 46.7%. At the time of diagnosis, skin involvement was present in 93.3% of the patients, including eczema (80.8%) and abscesses (66.7%). At the time of follow-up, under therapy, the prevalence of complications decreased: eczema and skin abscesses reduced to 63.3% and 56.7%, respectively. Antifungal prophylaxis decreased the incidence of mucocutaneous candidiasis from 70% to 56.7%. During the SARS-CoV-2 pandemic, seven patients developed COVID-19. Survival analyses showed that 27 out of 30 patients survived, while three patients died at ages of 28, 39, and 46 years as a consequence of lung bleeding, lymphoma, and sepsis, respectively. Analysis of a cumulative follow-up period of 278.7 patient-years showed that early diagnosis, adequate management at expertise centers for IEI, prophylactic antibiotics, and antifungal therapy improve outcomes and can positively influence the life expectancy of patients.

7.
Blood Transfus ; 21(3): 227-234, 2023 05.
Artigo em Inglês | MEDLINE | ID: mdl-35969137

RESUMO

BACKGROUND: In neonates, antibody-mediated destruction of neutrophils may occur as a consequence of auto- or isoimmune disorders. There are few studies on this topic, and particularly on neonatal alloimmune neutropenia (NAN). MATERIALS AND METHODS: We retrospectively evaluated the clinical and molecular/serological findings of 83 neutropenic infants referred to our Reference Laboratory for diagnostic evaluation of NAN, from 2008 to 2021. We also genotyped 260 Italian healthy subjects for the four principal human neutrophil antigens (HNA). RESULTS: The diagnosis of NAN was confirmed in 31 cases. The other 52 cases were autoimmune neutropenia (n=21), neutropenia caused by maternal neutrophil autoantibodies (n=8), neutropenia of non-immune origin (n=17), and cases in which a diagnosis could not be reached (n=6). The median age at neutropenia onset and absolute neutrophil count (ANC) were significantly lower in NAN than in non-NAN cases (1 vs 30 days, p<0.005; 330 vs 580/µL, p=0.003, respectively). About 74% of NAN cases developed neutropenia within the first week of life and laboratory investigations were required within 2 weeks. In five patients the neutropenia was discovered at the end of the first month of life and they were referred to our laboratory 1-2 months later when neutropenia had already resolved. Infections were seen in 19% of NAN cases. The median time to resolution of NAN was 31 days. About 50% of NAN cases were due to alloantibodies against HNA-1b, the most frequent allele of HNA-1 in the Italian population (allele frequency 0.63). In five cases of NAN the mothers had an HNA-1 null phenotype, a frequency higher than that observed in our Italian cohort. DISCUSSION: NAN should be considered by clinicians in infants with neutropenia onset within 5-7 days of life, even though there can be other reasons for a low ANC. If neutropenia is detected later, benign neutropenia seems more likely, although persistence of maternal alloantibodies cannot be ruled out.


Assuntos
Isoanticorpos , Neutropenia , Recém-Nascido , Lactente , Humanos , Estudos Retrospectivos , Isoantígenos/genética , Neutrófilos , Neutropenia/diagnóstico , Neutropenia/epidemiologia , Neutropenia/genética
8.
Eur J Immunol ; 52(7): 1171-1189, 2022 07.
Artigo em Inglês | MEDLINE | ID: mdl-35562849

RESUMO

Common variable immunodeficiency (CVID) is the most frequent primary antibody deficiency whereby follicular helper T (Tfh) cells fail to establish productive responses with B cells in germinal centers. Here, we analyzed the frequency, phenotype, transcriptome, and function of circulating Tfh (cTfh) cells in CVID patients displaying autoimmunity as an additional phenotype. A group of patients showed a high frequency of cTfh1 cells and a prominent expression of PD-1 and ICOS as well as a cTfh mRNA signature consistent with highly activated, but exhausted, senescent, and apoptotic cells. Plasmatic CXCL13 levels were elevated in this group and positively correlated with cTfh1 cell frequency and PD-1 levels. Monoallelic variants in RTEL1, a telomere length- and DNA repair-related gene, were identified in four patients belonging to this group. Their blood lymphocytes showed shortened telomeres, while their cTfh were more prone to apoptosis. These data point toward a novel pathogenetic mechanism in CVID, whereby alterations in DNA repair and telomere elongation might predispose to antibody deficiency. A Th1, highly activated but exhausted and apoptotic cTfh phenotype was associated with this form of CVID.


Assuntos
Imunodeficiência de Variável Comum , Apoptose/genética , Imunodeficiência de Variável Comum/genética , Humanos , Receptor de Morte Celular Programada 1/genética , Células T Auxiliares Foliculares , Linfócitos T Auxiliares-Indutores
9.
J Clin Immunol ; 42(5): 935-946, 2022 07.
Artigo em Inglês | MEDLINE | ID: mdl-35445287

RESUMO

COVID-19 manifestations range from asymptomatic to life-threatening infections. The outcome in different inborn errors of immunity (IEI) is still a matter of debate. In this retrospective study, we describe the experience of the of the Italian Primary Immunodeficiencies Network (IPINet). Sixteen reference centers for adult or pediatric IEI were involved. One hundred fourteen patients were enrolled including 35 pediatric and 79 adult patients. Median age was 32 years, and male-to-female ratio was 1.5:1. The most common IEI were 22q11.2 deletion syndrome in children (26%) and common variable immunodeficiency (CVID) in adults (65%). Ninety-one patients did not require hospital admission, and among these, 33 were asymptomatic. Hospitalization rate was 20.17%. Older age (p 0.004) and chronic lung disease (p 0.0008) represented risk factors for hospitalization. Hospitalized patients mainly included adults suffering from humoral immunodeficiencies requiring immunoglobulin replacement therapy and as expected had lower B cell counts compared to non-hospitalized patients. Infection fatality rate in the whole cohort was 3.5%. Seroconversion was observed is 86.6% of the patients evaluated and in 83.3% of CVID patients. 16.85% of the patients reported long-lasting COVID symptoms. All but one patient with prolonged symptoms were under IgRT. The fatality rate observed in IEI was slightly similar to the general population. The age of the patients who did not survive was lower compared to the general population, and the age stratified mortality in the 50-60 age range considerable exceeded the mortality from 50 to 60 age group of the Italian population (14.3 vs 0.6%; p < 0.0001). We hypothesize that this is due to the fact that comorbidities in IEI patients are very common and usually appear early in life.


Assuntos
COVID-19 , Imunodeficiência de Variável Comum , Adulto , COVID-19/complicações , COVID-19/epidemiologia , Criança , Imunodeficiência de Variável Comum/epidemiologia , Feminino , Hospitalização , Humanos , Masculino , Estudos Retrospectivos , SARS-CoV-2 , Síndrome Pós-COVID-19 Aguda
10.
Front Immunol ; 13: 845496, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35371100

RESUMO

Background: Severe skeletal muscle damage has been recently reported in patients with SARS-CoV-2 infection and as a rare vaccination complication. Case summary: On Apr 28, 2021 a 68-year-old man who was previously healthy presented with an extremely severe rhabdomyolysis that occurred nine days following the first dose of SARS-CoV-2 ChAdOx1 nCov-19 vaccination. He had no risk factors, and denied any further assumption of drugs except for fermented red rice, and berberine supplement. The clinical scenario was complicated by a multi organ failure involving bone marrow, liver, lung, and kidney. For the rapid increase of the inflammatory markers, a cytokine storm was suspected and multi-target biologic immunosuppressive therapy was started, consisting of steroids, anakinra, and eculizumab, which was initially successful resulting in close to normal values of creatine phosphokinase after 17 days of treatment. Unfortunately, 48 days after the vaccination an accelerated phase of deterioration, characterized by severe multi-lineage cytopenia, untreatable hypotensive shock, hypoglycemia, and dramatic increase of procalcitonin (PCT), led to patient death. Conclusion: Physicians should be aware that severe and fatal rhabdomyolysis may occur after SARS-CoV2 vaccine administration.


Assuntos
COVID-19 , Rabdomiólise , Trombocitopenia , Idoso , Vacinas contra COVID-19/efeitos adversos , ChAdOx1 nCoV-19 , Humanos , Masculino , Insuficiência de Múltiplos Órgãos/etiologia , RNA Viral , Rabdomiólise/etiologia , SARS-CoV-2 , Vacinação/efeitos adversos
11.
J Clin Med ; 11(5)2022 Feb 25.
Artigo em Inglês | MEDLINE | ID: mdl-35268351

RESUMO

The epigenome bridges environmental factors and the genome, fine-tuning the process of gene transcription. Physiological programs, including the development, maturation and maintenance of cellular identity and function, are modulated by intricate epigenetic changes that encompass DNA methylation, chromatin remodeling, histone modifications and RNA processing. The collection of genome-wide DNA methylation data has recently shed new light into the potential contribution of epigenetics in pathophysiology, particularly in the field of immune system and host defense. The study of patients carrying mutations in genes encoding for molecules involved in the epigenetic machinery has allowed the identification and better characterization of environment-genome interactions via epigenetics as well as paving the way for the development of new potential therapeutic options. In this review, we summarize current knowledge of the role of epigenetic modifications in the immune system and outline their potential involvement in the pathogenesis of inborn errors of immunity.

12.
J Clin Immunol ; 42(4): 783-797, 2022 05.
Artigo em Inglês | MEDLINE | ID: mdl-35257272

RESUMO

Ataxia telangiectasia (AT) is a rare neurodegenerative genetic disorder due to bi-allelic mutations in the Ataxia Telangiectasia Mutated (ATM) gene. The aim of this paper is to better define the immunological profile over time, the clinical immune-related manifestations at diagnosis and during follow-up, and to attempt a genotype-phenotype correlation of an Italian cohort of AT patients. Retrospective data of 69 AT patients diagnosed between December 1984 and November 2019 were collected from the database of the Italian Primary Immunodeficiency Network. Patients were classified at diagnosis as lymphopenic (Group A) or non-lymphopenic (Group B). Fifty eight out of 69 AT patients (84%) were genetically characterized and distinguished according to the type of mutations in truncating/truncating (TT; 27 patients), non-truncating (NT)/T (28 patients), and NT/NT (5 patients). In 3 patients, only one mutation was detected. Data on age at onset and at diagnosis, cellular and humoral compartment at diagnosis and follow-up, infectious diseases, signs of immune dysregulation, cancer, and survival were analyzed and compared to the genotype. Lymphopenia at diagnosis was related per se to earlier age at onset. Progressive reduction of cellular compartment occurred during the follow-up with a gradual reduction of T and B cell number. Most patients of Group A carried bi-allelic truncating mutations, had a more severe B cell lymphopenia, and a reduced life expectancy. A trend to higher frequency of interstitial lung disease, immune dysregulation, and malignancy was noted in Group B patients. Lymphopenia at the onset and the T/T genotype are associated with a worst clinical course. Several mechanisms may underlie the premature and progressive immune decline in AT subjects.


Assuntos
Ataxia Telangiectasia , Linfopenia , Ataxia Telangiectasia/diagnóstico , Ataxia Telangiectasia/genética , Proteínas Mutadas de Ataxia Telangiectasia/genética , Humanos , Mutação/genética , Estudos Retrospectivos , Linfócitos T
13.
Heart Fail Clin ; 18(1): 155-164, 2022 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-34776076

RESUMO

DiGeorge syndrome (DGS), also known as "22q11.2 deletion syndrome" (22q11DS) (MIM # 192430 # 188400), is a genetic disorder caused by hemizygous microdeletion of the long arm of chromosome 22. In the last decades, the introduction of fluorescence in situ hybridization assays, and in selected cases the use of multiplex ligation-dependent probe amplification, has allowed the detection of chromosomal microdeletions that could not be previously identified using standard karyotype analysis. The aim of this review is to address cardiovascular and systemic involvement in children with DGS, provide genotype-phenotype correlations, and discuss their medical management and therapeutic options.


Assuntos
Síndrome de DiGeorge , Cardiopatias Congênitas , Síndrome de Marfan , Deleção Cromossômica , Síndrome de DiGeorge/diagnóstico , Síndrome de DiGeorge/genética , Síndrome de DiGeorge/terapia , Humanos , Hibridização in Situ Fluorescente , Cariotipagem
15.
J Allergy Clin Immunol Pract ; 9(9): 3237-3248, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34273582

RESUMO

Since its outbreak in late December 2019 in Wuhan, coronavirus disease 2019 pandemic has posed a therapeutic challenge for the world population, with a plenty of clinical pictures and a broad spectrum of severity of the manifestations. In spite of initial speculations on a direct role of primary or acquired immune deficiency in determining a worse disease outcome, recent studies have provided evidence that specific immune defects may either serve as an experimentum naturae entailing this risk or may not be relevant enough to impact the host defense against the virus. Taken together, these observations may help unveil pathogenetic mechanisms of the infection and suggest new therapeutic strategies. Thus, in this review, we summarize current knowledge regarding the mechanisms of immune response against severe acute respiratory syndrome coronavirus 2 infection and clinical manifestations with a special focus on children and patients presenting with congenital or acquired immune deficiency.


Assuntos
COVID-19 , Síndromes de Imunodeficiência , Criança , Surtos de Doenças , Humanos , Pandemias , SARS-CoV-2
17.
J Clin Immunol ; 41(4): 756-768, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33464451

RESUMO

Human nude SCID is a rare autosomal recessive inborn error of immunity (IEI) characterized by congenital athymia, alopecia, and nail dystrophy. Few cases have been reported to date. However, the recent introduction of newborn screening for IEIs and high-throughput sequencing has led to the identification of novel and atypical cases. Moreover, immunological alterations have been recently described in patients carrying heterozygous mutations. The aim of this paper is to describe the extended phenotype associated with FOXN1 homozygous, compound heterozygous, or heterozygous mutations. We collected clinical and laboratory information of a cohort of 11 homozygous, 2 compound heterozygous, and 5 heterozygous patients with recurrent severe infections. All, except one heterozygous patient, had signs of CID or SCID. Nail dystrophy and alopecia, that represent the hallmarks of the syndrome, were not always present, while almost 50% of the patients developed Omenn syndrome. One patient with hypomorphic compound heterozygous mutations had a late-onset atypical phenotype. A SCID-like phenotype was observed in 4 heterozygous patients coming from the same family. A spectrum of clinical manifestations may be associated with different mutations. The severity of the clinical phenotype likely depends on the amount of residual activity of the gene product, as previously observed for other SCID-related genes. The severity of the manifestations in this heterozygous family may suggest a mechanism of negative dominance of the specific mutation or the presence of additional mutations in noncoding regions.


Assuntos
Fatores de Transcrição Forkhead/genética , Heterozigoto , Homozigoto , Mutação , Fenótipo , Imunodeficiência Combinada Severa/diagnóstico , Imunodeficiência Combinada Severa/etiologia , Linhagem Celular , Pré-Escolar , Análise Mutacional de DNA , Gerenciamento Clínico , Feminino , Fatores de Transcrição Forkhead/química , Estudos de Associação Genética , Loci Gênicos , Predisposição Genética para Doença , Transplante de Células-Tronco Hematopoéticas , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Masculino , Modelos Moleculares , Conformação Molecular , Linhagem , Imunodeficiência Combinada Severa/terapia , Relação Estrutura-Atividade , Resultado do Tratamento
19.
Int Rev Immunol ; 40(3): 159-170, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33063546

RESUMO

The complement system is a multi-functional system representing the first line host defense against pathogens in innate immune response, through three different pathways. Impairment of its function, consisting in deficiency or excessive deregulated activation, may lead to severe systemic infections or autoimmune disorders. These diseases may be inherited or acquired. Despite many diagnostic tools are currently available, ranging from traditional, such as hemolytic or ELISA based assays, to innovative ones, like next generation sequencing techniques, these diseases are often not recognized. As for therapeutic aspects, strategies based on the use of targeted drugs are now widespread. The aim of this review is to present an updated overview of complement system pathophysiology, clinical implications of its dysfunction and to summarize diagnostic and therapeutic approaches.


Assuntos
Proteínas do Sistema Complemento , Imunidade Inata , Fenômenos Fisiológicos Celulares , Humanos
20.
Immunol Invest ; 50(2-3): 295-303, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-32397775

RESUMO

Ataxia-Telangiectasia (A-T) is characterized by cerebellar neurodegeneration and immunodeficiency. Recent studies suggest that very low glucocorticoids (GCs) doses may help improve A-T neurological phenotype in some patients. Interestingly, in GCs studies an unexpected improvement of lymphocytes proliferation in some A-T patients has been observed. GCs are able to upregulate IL-7 Rα expression and rescue it from the recycling. In this study, we compared several immunological functions, including PBMC proliferative responses, cell activation events and IL-7/IL-7 Rα axis functionality, with the neurological behavior during an in-vivo GCs treatment between the most Responder patient to GC and the Non-Responder at all. During in-vivo GC treatment, we observed an increase of lymphocyte proliferation upon stimulation with PHA or IL-7 only in the Responder. This finding paralleled the increase in the surface expression of IL-7 R and up-regulation of the CD69 T-cell activation marker. Internalization and recycling of IL-7 R occurred properly only in the Responder. Microarray analysis revealed a remarkable difference in the DE-genes levels among Responder and Non-Responder, mostly concerning miRNAs and Multiple Complex families. Our findings suggest that the improvement of lymphocyte functionality, which correlates to the neurological behavior, is mediated through an effect of GCs on the IL-7/IL-7 Rα axis.


Assuntos
Anti-Inflamatórios/uso terapêutico , Ataxia Telangiectasia/tratamento farmacológico , Transtornos de Deficit da Atenção e do Comportamento Disruptivo/tratamento farmacológico , Betametasona/uso terapêutico , Interleucina-7/metabolismo , Linfócitos/imunologia , Receptores de Interleucina-7/metabolismo , Administração Oral , Pré-Escolar , Feminino , Humanos , Ativação Linfocitária/efeitos dos fármacos , Masculino , Análise em Microsséries , Transdução de Sinais/efeitos dos fármacos
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