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1.
Front Immunol ; 10: 2322, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31611883

RESUMO

Ataxia-telangiectasia (AT) and Nijmegen breakage syndrome (NBS) belong to a group of primary immunodeficiency diseases (PI) characterized by premature aging, cerebral degeneration, immunoglobulin deficiency and higher cancer susceptibility. Despite the fact that oxidative stress has been demonstrated in vitro and in animal models of AT and NBS, the involvement of redox homeostasis disorders is still unclear in the in vivo phenotype of AT and NBS patients. Our study is the first to compare both enzymatic and non-enzymatic antioxidants as well as oxidative damage between AT and NBS subjects. Twenty two Caucasian children with AT and twelve patients with NBS were studied. Enzymatic and non-enzymatic antioxidants - glutathione peroxidase (GPx), catalase (CAT), superoxide dismutase-1 (SOD) and uric acid (UA); redox status-total antioxidant capacity (TAC) and ferric reducing ability of plasma (FRAP); and oxidative damage products-8-hydroxy-2'-deoxyguanosine (8-OHdG), advanced glycation end products (AGE), advanced oxidation protein products (AOPP), 4-hydroxynonenal (4-HNE) protein adducts, and 8-isoprostanes (8-isop) were evaluated in serum or plasma samples. We showed that CAT, SOD and UA were significantly increased, while TAC and FRAP levels were statistically lower in the plasma of AT patients compared to controls. In NBS patients, only CAT activity was significantly elevated, while TAC was significantly decreased as compared to healthy children. We also showed higher oxidative damage to DNA (↑8-OHdG), proteins (↑AGE, ↑AOPP), and lipids (↑4-HNE, ↑8-isop) in both AT and NBS patients. Interestingly, we did not demonstrate any significant differences in the antioxidant defense and oxidative damage between AT and NBS patients. However, in AT children, we showed a positive correlation between 8-OHdG and the α-fetoprotein level as well as a negative correlation between 8-OHdG and IgA. In NBS, AGE was positively correlated with IgM and negatively with the IgG level. Summarizing, we demonstrated an imbalance in cellular redox homeostasis and higher oxidative damage in AT and NBS patients. Despite an increase in the activity/concentration of some antioxidants, the total antioxidant capacity is overwhelmed in children with AT and NBS and predisposes them to more considerable oxidative damage. Oxidative stress may play a major role in AT and NBS phenotype.

2.
Pediatrics ; 142(3)2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30068713

RESUMO

BACKGROUND: The capsular group B meningococcal vaccine (4CMenB) is recommended for children with complement deficiencies, asplenia, and splenic dysfunction; however, data on the immunogenicity of 4CMenB in these "at-risk" children are missing. METHODS: Participants aged 2 to 17 years in Italy, Spain, Poland, the United Kingdom, and Russia with complement deficiencies, asplenia, or splenic dysfunction received 2 doses of 4CMenB 2 months apart, as did healthy children in the control group. Exogenous and endogenous human complement serum bactericidal activity (SBA) was determined at baseline and 1 month after the second immunization against 4 test strains: H44/76 (assessing vaccine antigen factor H binding protein), 5/99 (Neisserial adhesion A), NZ98/254 (Porin A), and M10713 (Neisserial heparin binding antigen). RESULTS: Of 239 participants (mean age 10.3 years, 45% female), 40 children were complement deficient (9 eculizumab therapy, 4 terminal-chain deficiencies, 27 "other"), 112 children had asplenia or splenic dysfunction (8 congenital asplenia, 8 functional asplenia, 96 splenectomy), and 87 children were in the control group. After immunization, the proportions of complement-deficient participants with exogenous complement SBA titers ≥1:5 were 87% (H44/76), 95% (5/99), 68% (NZ98/254), and 73% (M10713), compared with 97%, 100%, 86%, and 94%, respectively, for asplenic children and 98%, 99%, 83%, and 99% for children in the control group. When testing with endogenous complement, strain-specific bactericidal activity was evident in only 1 eculizumab-treated participant and 1 terminal chain complement-deficient participant. CONCLUSIONS: 4CMenB administration is similarly immunogenic in healthy children and those with asplenia or splenic dysfunction. The significance of the trend to lower responses of SBA titers in complement-deficient children (especially those with terminal chain complement deficiency or those on eculizumab therapy) must be determined by ongoing surveillance for vaccine failures.

3.
Adv Med Sci ; 63(1): 173-178, 2018 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-29128760

RESUMO

PURPOSE: The objective of this study was to evaluate thevitamin D concentration in patients with recurrent respiratory infections with or without immunoglobulin G, A or M (IgG, IgA, IgM) deficiency, and to find a correlation between the vitamin D concentration and the response to hepatitis B vaccination. MATERIALS AND METHOD: The study involved 730 patients with recurrent respiratory infections. The concentration of 25-hydroxyvitamin D (25(OH)D), immunoglobulins G, A and M, anti-HBs was determined. RESULTS: The tests showed that 11% of patients presented IgG levels below the age related reference values. Children with reduced IgG concentration were also found to have significantly lower vitamin D concentrations in comparison to children with normal IgG. Vitamin D deficiency was observed in schoolchildren between 7 and 18 years of age. No correlation was found between 25(OH)D concentration and Hbs antibody levels. CONCLUSIONS: An investigation of a large group of patients who have recurrent infection found patients with IgG deficiency to whom special proceeding have to be performed: 1. Significantly lower vitamin D concentration observed in the group of children with IgG deficiency implicated in long-lasting monitoring of vitamin D level require adding to the practice guidelines for Central Europe 2013. 2. Intervention treatment with suitable doses of vitamin D to clarified metabolism of vitamin D has to be plan for children with IgG deficiency and significant lower vitamin D concentration.


Assuntos
Imunoglobulinas/deficiência , Infecções Respiratórias/complicações , Deficiência de Vitamina D/complicações , Adolescente , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , Recidiva , Infecções Respiratórias/sangue , Estações do Ano , Vitamina D/sangue , Deficiência de Vitamina D/sangue
4.
Am J Clin Exp Immunol ; 6(5): 76-83, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-29181272

RESUMO

Immunoglobulin replacement therapy (IRT) is standard treatment for patients with primary immunodeficiency (PID). Because most of the patients with PID will require long life-time immunoglobulin replacement therapy, the quality of the prescribed products is of utmost importance. The IRT is generally administered either intravenously (abbreviated IVIG), or subcutaneously (abbreviated SCIG). Both routes have been demonstrated to be effective. The preferred route may vary at different times during a given patient's life. Options are therefore not fixed and the choice of route for immunoglobulin therapy will depend on several factors, including patient characteristics, clinical indication, venous access, side effects, rural or remote location, treatment compliance and patient preference. Many years ago, immunoglobulin therapy was associated with side effects which may compromise patient's compliance and quality of life of the patients. Most of the side effects were related to impurities. Recently, major advances in the manufacturing process have been made and new processes, such as the Quality by design (QbD) approach were added into the manufacturing steps to ensure patients tolerability and safety. Due to the improved purity of the immunoglobulin products obtained by these processes, the incidence of side effects is lower, while the ways of administration of Ig therapy and the choice of the regimen has widened to suit patient's preference and needs.

5.
Front Immunol ; 8: 685, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28952612

RESUMO

Immunodeficiency-associated vaccine-derived polioviruses (iVDPVs) have been isolated from primary immunodeficiency (PID) patients exposed to oral poliovirus vaccine (OPV). Patients may excrete poliovirus strains for months or years; the excreted viruses are frequently highly divergent from the parental OPV and have been shown to be as neurovirulent as wild virus. Thus, these patients represent a potential reservoir for transmission of neurovirulent polioviruses in the post-eradication era. In support of WHO recommendations to better estimate the prevalence of poliovirus excreters among PIDs and characterize genetic evolution of these strains, 635 patients including 570 with primary antibody deficiencies and 65 combined immunodeficiencies were studied from 13 OPV-using countries. Two stool samples were collected over 4 days, tested for enterovirus, and the poliovirus positive samples were sequenced. Thirteen patients (2%) excreted polioviruses, most for less than 2 months following identification of infection. Five (0.8%) were classified as iVDPVs (only in combined immunodeficiencies and mostly poliovirus serotype 2). Non-polio enteroviruses were detected in 30 patients (4.7%). Patients with combined immunodeficiencies had increased risk of delayed poliovirus clearance compared to primary antibody deficiencies. Usually, iVDPV was detected in subjects with combined immunodeficiencies in a short period of time after OPV exposure, most for less than 6 months. Surveillance for poliovirus excretion among PID patients should be reinforced until polio eradication is certified and the use of OPV is stopped. Survival rates among PID patients are improving in lower and middle income countries, and iVDPV excreters are identified more frequently. Antivirals or enhanced immunotherapies presently in development represent the only potential means to manage the treatment of prolonged excreters and the risk they present to the polio endgame.

6.
J Clin Immunol ; 37(6): 539-547, 2017 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-28711959

RESUMO

This multicentre, open-label, prospective, single-arm study was designed to evaluate the efficacy, pharmacokinetics, and safety of IqYmune®, a highly purified 10% polyvalent immunoglobulin preparation for intravenous administration in patients with primary immunodeficiency. IqYmune® was administered to 62 patients (aged 2-61 years) with X-linked agammaglobulinemia or common variable immune deficiency at a dose from 0.22 to 0.97 g/kg every 3 to 4 weeks for 12 months with an infusion rate up to 8 mL/kg/h. A pharmacokinetic study was performed at steady state between the 8th and the 9th infusion. A single case of serious bacterial infection was observed, leading to an annualized rate of serious bacterial infections/patient (primary endpoint) of 0.017 (98% CI: 0.000, 0.115). Overall, 228 infections were reported, most frequently bronchitis, chronic sinusitis, nasopharyngitis and upper respiratory tract infection. The mean annualized rate of infections was 3.79/patient. A lower risk of infections was associated with an IgG trough level > 8 g/L (p = 0.01). The mean annualized durations of absence from work or school and of hospitalization due to infections were 1.01 and 0.89 days/patient, respectively. The mean serum IgG trough level before the 6th infusion was 7.73 g/L after a mean dose of IqYmune® of 0.57 g/kg. The pharmacokinetic profile of IqYmune® was consistent with that of other intravenous immunoglobulins. Overall, 15.5% of infusions were associated with an adverse event occurring within 72 h post infusion. Headache was the most common adverse event. In conclusion, IqYmune® was shown to be effective and well tolerated in patients with primary immunodeficiency.


Assuntos
Agamaglobulinemia/terapia , Imunodeficiência de Variável Comum/terapia , Doenças Genéticas Ligadas ao Cromossomo X/terapia , Imunoglobulinas Intravenosas/uso terapêutico , Imunoterapia/métodos , Adolescente , Adulto , Agamaglobulinemia/imunologia , Criança , Pré-Escolar , Ensaios Clínicos como Assunto , Imunodeficiência de Variável Comum/imunologia , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/diagnóstico , Europa (Continente) , Feminino , Doenças Genéticas Ligadas ao Cromossomo X/imunologia , Cefaleia/diagnóstico , Cefaleia/etiologia , Humanos , Imunoglobulinas Intravenosas/efeitos adversos , Imunoglobulinas Intravenosas/farmacocinética , Imunoterapia/efeitos adversos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Adulto Jovem
7.
Arch Med Sci ; 13(2): 412-417, 2017 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-28261296

RESUMO

INTRODUCTION: Respiratory tract infections constitute the most frequent manifestation of X-linked agammaglobulinemia (XLA). There are not many papers elucidating gastrointestinal (GI) disorders, including inflammatory bowel disease (IBD), in such patients. The aim of the study was to evaluate the occurrence of gastrointestinal disorders and IBD compared to respiratory tract infections in XLA individuals. MATERIAL AND METHODS: Of 1563 patients with primary immunodeficiencies diagnosed in the Department of Immunology, the Children's Memorial Health Institute (CMHI), 66 boys had a provisional diagnosis of agammaglobulinemia. Forty-four subjects fulfilled definitive ESID (European Society for Immunodeficiencies) diagnostic criteria of XLA. A retrospective analysis of medical history of XLA patients was undertaken. RESULTS: Recurrent respiratory tract infections, particularly bronchitis (73%) and pneumonia (59%), were the most common symptoms of XLA. The GI disorders constituted the next main manifestation (63.6%), followed by upper respiratory tract infections. Twenty-six of 28 XLA patients with GI disorders complained of diarrhea, which was resolved generally after immunoglobulin therapy introduction. Single but prolonged episodes of Campylobacter jejuni diarrhea were reported in two individuals. Inflammatory bowel disease of mild to moderate activity was diagnosed in 1 patient, and local enteritis of mild activity in another one. CONCLUSIONS: Gastrointestinal disorders were one of the main manifestations of XLA, reported almost as often as lower respiratory tract infections. The most common GI symptom was diarrhea, which usually resolved after immunoglobulin therapy was started. Infections caused by Giardia lamblia were reported occasionally. Inflammatory bowel disease was diagnosed quite exceptionally, which presumably may be connected with normal T cell immunity.

8.
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
9.
Oxid Med Cell Longev ; 2017: 6745840, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-29456787

RESUMO

This study compared the antioxidant status and major lipophilic antioxidants in patients with ataxia-telangiectasia (AT) and Nijmegen breakage syndrome (NBS). Total antioxidant status (TAS), total oxidant status (TOS), oxidative stress index (OSI), and concentrations of coenzyme Q10 (CoQ10) and vitamins A and E were estimated in the plasma of 22 patients with AT, 12 children with NBS, and the healthy controls. In AT patients, TAS (median 261.7 µmol/L) was statistically lower but TOS (496.8 µmol/L) was significantly elevated in comparison with the healthy group (312.7 µmol/L and 311.2 µmol/L, resp.). Tocopherol (0.8 µg/mL) and CoQ10 (0.1 µg/mL) were reduced in AT patients versus control (1.4 µg/mL and 0.3 µg/mL, resp.). NBS patients also displayed statistically lower TAS levels (290.3 µmol/L), while TOS (404.8 µmol/L) was comparable to the controls. We found that in NBS patients retinol concentration (0.1 µg/mL) was highly elevated and CoQ10 (0.1 µg/mL) was significantly lower in comparison with those in the healthy group. Our study confirms disturbances in redox homeostasis in AT and NBS patients and indicates a need for diagnosing oxidative stress in those cases as a potential disease biomarker. Decreased CoQ10 concentration found in NBS and AT indicates a need for possible supplementation.


Assuntos
Ataxia Telangiectasia/metabolismo , Síndrome de Quebra de Nijmegen/metabolismo , Oxirredução , Adolescente , Ataxia Telangiectasia/genética , Proteínas Mutadas de Ataxia Telangiectasia/genética , Proteínas de Ciclo Celular/genética , Criança , Feminino , Homeostase , Humanos , Masculino , Síndrome de Quebra de Nijmegen/genética , Proteínas Nucleares/genética , Estresse Oxidativo , Ubiquinona/análogos & derivados , Ubiquinona/sangue , Vitamina A/sangue , Vitamina E/sangue
10.
Eur J Pediatr ; 175(8): 1099-105, 2016 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-27357411

RESUMO

UNLABELLED: The study presents an overview on current situation of primary immunodeficiency (PID) patients in Poland and the 2014 annual report of the Polish Working Group for Immunodeficiency (PWGID). The group was set up in 2005 to improve diagnosis, treatment, and care of patients with immunodeficiencies and currently includes 15 pediatric and 13 adult centers. According to PWGID report 4099, PID patients are recognized in Poland, with the prevalence 10.6/100,000. The majority of them (54.2 %) have predominantly antibody deficiency (PAD). In 2014 alone, a total number of 731 newly diagnosed individuals are reported. As predicted, the vast majority (70 %) of them have PAD. Approximately one third of PAD patients require immunoglobulin replacement therapy. Within the entire cohort, an intravenous route of immunoglobulin therapy dominates (67.3 %). However, within the age groups, distribution of immunoglobulin therapy varies and seems to be age related. Among children, 36 % receive subcutaneous immunoglobulin, while with adults 26 %. CONCLUSION: Analysis of numbers of either newly recognized or treated patients indicates its dynamic increase in recent years. This is the result of comprehensive activities by PWGID supported by governmental institutions, outstanding foundations, and patient's organization. WHAT IS KNOWN: • Immunoglobulins' treatment has substantially changed the life of individuals with PAD. Patients with common variable immunodeficiency (CVID) or X-linked agammaglobulinemia (XLA) can live and lead a near normal life. Early diagnosis of the disease followed by earlier implementation of appropriate treatment, including gammaglobulin replacement therapy, improves the quality of life. • Targeted efforts of health care professionals and government are required to optimize diagnostic and therapeutic approach for PAD. What is New: • Comprehensive activities of PWGID lead to better recognition of PID individuals and should improve reporting Polish PIDs to the ESID database. • Following the joint efforts of immunologists, patient's, and governmental organizations in the end of 2014, the Therapeutic Program for Treatment Adults with PID was introduced, leading to universal access to currently available treatment options and to improve the quality of life.


Assuntos
Imunização Passiva/estatística & dados numéricos , Síndromes de Imunodeficiência/epidemiologia , Adolescente , Adulto , Distribuição por Idade , Criança , Pré-Escolar , Acesso aos Serviços de Saúde/estatística & dados numéricos , Humanos , Imunoglobulinas/uso terapêutico , Síndromes de Imunodeficiência/tratamento farmacológico , Testes Imunológicos/estatística & dados numéricos , Incidência , Lactente , Cooperação Internacional , Polônia/epidemiologia , Prevalência , Adulto Jovem
11.
J Clin Immunol ; 35(6): 538-49, 2015 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-26271390

RESUMO

PURPOSE: Nijmegen Breakage Syndrome (NBS) is a rare inherited condition, characterized by microcephaly, chromosomal instability, immunodeficiency, and predisposition to malignancy. This retrospective study, characterizing the clinical and immunological status of patients with NBS at time of diagnosis, was designed to assess whether any parameters were useful in disease prognosis, and could help determine patients qualified for hematopoietic stem cell transplantation. METHODS: The clinical and immunological characteristics of 149 NBS patients registered in the online database of the European Society for Immune Deficiencies were analyzed. RESULTS: Of the 149 NBS patients, 91 (61%), of median age 14.3 years, remained alive at the time of analysis. These patients were clinically heterogeneous, with variable immune defects, ranging from negligible to severe dysfunction. Humoral deficiencies predisposed NBS patients to recurrent/chronic respiratory tract infections and worsened long-term clinical prognosis. Eighty malignancies, most of lymphoid origin (especially non-Hodgkin's lymphomas), were diagnosed in 42% of patients, with malignancy being the leading cause of death in this cohort. Survival probabilities at 5, 10, 20 and 30 years of age were 95, 85, 50 and 35%, respectively, and were significantly lower in patients with than without malignancies. CONCLUSIONS: The extremely high incidence of malignancies, mostly non-Hodgkin's lymphomas, was the main risk factor affecting survival probability in NBS patients. Because treatment of NBS is very difficult and frequently unsuccessful, the search for an alternative medical intervention such as hematopoietic stem cell transplantation is of great clinical importance.


Assuntos
Transplante de Células-Tronco Hematopoéticas , Síndrome de Quebra de Nijmegen/diagnóstico , Fatores de Tempo , Adolescente , Adulto , Criança , Pré-Escolar , Instabilidade Cromossômica , Feminino , Humanos , Síndromes de Imunodeficiência , Lactente , Linfoma não Hodgkin , Masculino , Microcefalia , Síndrome de Quebra de Nijmegen/genética , Síndrome de Quebra de Nijmegen/terapia , Prognóstico , Estudos Retrospectivos , Adulto Jovem
12.
Cent Eur J Immunol ; 40(1): 109-14, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26155192

RESUMO

INTRODUCTION: Münchausen syndrome by proxy (MSBP) describes a pattern in which a caregiver induces a disease in a child. The symptoms may manifest in the oral cavity. MATERIAL AND METHODS: PubMed was researched for articles between 1990-2014, presenting manifestations of MSPB, following PRISMA 2009 guidelines, and an in-house case of MSBP with oral manifestations was presented. REVIEW: Among 66 articles presenting MSBP symptoms, four included descriptions of oral lesions in five children. They included: tooth loss, ulcerations and ulcers on oral mucosa, scars due to old, healed lesions, bleeding, black tongue, polysialia, and discolouration and swelling in the lips. Münchausen syndrome by proxy with participation of the mother was diagnosed in four cases. CASE: A 13-year-old girl was hospitalised because of a non-healing ulcer of the septum, loose and lost mandibular teeth, skin lesions, and suspected immunodeficiency. She had been hospitalised numerous times at other facilities. Consultations and diagnostic tests did not confirm an organic disease. The patient and her mother agreed to undergo all examinations, and some symptoms 'went away' during the examinations. The behaviour of the patient and her mother during hospital stays, ambulatory care, and the psychiatric observations all pointed towards MPSB. They refused further treatment at the present facility. CONCLUSIONS: A dentist should take into account the potential 'fabrication' of symptoms in a child by the latter or by a caregiver. Consultations with a paediatrician or psychiatrist enable a diagnosis and treatment.

13.
PLoS One ; 9(12): e114901, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25502423

RESUMO

Primary Immunodeficiencies (PID) are genetically inherited disorders characterized by defects of the immune system, leading to increased susceptibility to infection. Due to the variety of clinical symptoms and the complexity of current diagnostic procedures, accurate diagnosis of PID is often difficult in daily clinical practice. Thanks to the advent of "next generation" sequencing technologies and target enrichment methods, the development of multiplex diagnostic assays is now possible. In this study, we applied a selector-based target enrichment assay to detect disease-causing mutations in 179 known PID genes. The usefulness of this assay for molecular diagnosis of PID was investigated by sequencing DNA from 33 patients, 18 of which had at least one known causal mutation at the onset of the experiment. We were able to identify the disease causing mutations in 60% of the investigated patients, indicating that the majority of PID cases could be resolved using a targeted sequencing approach. Causal mutations identified in the unknown patient samples were located in STAT3, IGLL1, RNF168 and PGM3. Based on our results, we propose a stepwise approach for PID diagnostics, involving targeted resequencing, followed by whole transcriptome and/or whole genome sequencing if causative variants are not found in the targeted exons.


Assuntos
Sequenciamento de Nucleotídeos em Larga Escala/métodos , Síndromes de Imunodeficiência/genética , Mutação/genética , Transcriptoma/genética , Genoma Humano , Projeto HapMap , Humanos , Síndromes de Imunodeficiência/diagnóstico , Síndromes de Imunodeficiência/patologia , Fosfoglucomutase/genética , Fator de Transcrição STAT3/genética , Ubiquitina-Proteína Ligases/genética
14.
Pol Merkur Lekarski ; 36(212): 79-87, 2014 Feb.
Artigo em Polonês | MEDLINE | ID: mdl-24720101

RESUMO

Invasive pneumococcal disease (IPD) is a main cause of mortality associated with pneumococcal infections. Although, IPD is regarding mainly small children and persons in the age > 65 years, the investigations showed that because of IPD exactly sick persons are burdened with the greatest mortality in the older age, rather than of children. The most frequent form of IPD is community acquired pneumonia (CAP) with the bacteremia. The presence of even a single additional risk factor is increasing the probability of the unfavorable descent of pneumococcal infection. The risk factors for IPD and/or pneumonia with bacteremia apart from the age are among others asthma (> 2 x), chronic obstructive pulmonary disease (COPD), sarcoidosis (4 x), idiopathic pulmonary fibrosis (5 x), bronchiectases (2 x), allergic alveolitis (1.9 x) and pneumoconiosis (2 x), type 1 diabetes (4.4 x), type 2 diabetes (1.2 x), autoimmune diseases (e.g. rheumatoid arthritis (4.2 to 14.9 x), kidney failure with the necessity to dialysis (12 x), immunosuppression, cardiovascular disease, alcoholism and cancers. Examinations show that the best method of IPD and CAP preventing are pneumococcal vaccinations. On the market for ages 23-valent polysaccharide vaccine (PPV23) is available covering close the 90% of IPD triggering stereotypes. Her role in preventing CAP is uncertain and the immunological answer after vaccination at older persons and after revaccination is weak. Widely discussed disadvantageous effects of growing old of the immunological system show on the benefit from applying the immunization inducing the immunological memory, i.e. of conjugated vaccines which are activating the T-dependent reply and are ensuring the readiness for the effective secondary response. Examinations so far conducted with conjugated 7-valent and 13-valent (PCV13) vaccines at persons in the age > 50 years are confirming these expectations. Also sick persons can take benefits from PCV13 applying back from so-called IPD risk groups in the age > 19 years. At these work research findings were described above PPV23 and PCV13 at adults and world recommendations of applying both vaccines in risk groups from 19 years up to the advanced years. Also Polish recommendations of optimum applying of these vaccines were presented. They are recommending applying PCV13 at first in them, while PPV23, if to her readings exist should be given to > or = 8 of weeks from PCV13. In persons > or = 19 years which earlier received 1 or should receive more PPV23 doses first PCV13 dose should be given after the year or later than the last PPV23 dose, and then again PPV23 > or = 8 of weeks from PCV13 and the second PPV23 dose not earlier than 5 years from last PPV23. If the PPV23 application seems to be justified, it is irrespective of the more previous state vaccination against pneumococci, PCV13 should be given to as first.


Assuntos
Bacteriemia/prevenção & controle , Infecções Pneumocócicas/prevenção & controle , Vacinas Pneumocócicas/imunologia , Vacinas Pneumocócicas/uso terapêutico , Pneumonia/prevenção & controle , Adulto , Envelhecimento/imunologia , Bacteriemia/epidemiologia , Infecções Comunitárias Adquiridas/epidemiologia , Infecções Comunitárias Adquiridas/prevenção & controle , Feminino , Humanos , Memória Imunológica , Pneumopatias/epidemiologia , Masculino , Pessoa de Meia-Idade , Infecções Pneumocócicas/epidemiologia , Pneumonia/epidemiologia , Polônia/epidemiologia , Guias de Prática Clínica como Assunto , Fatores de Risco , Adulto Jovem
15.
J Autoimmun ; 50: 42-50, 2014 May.
Artigo em Inglês | MEDLINE | ID: mdl-24369837

RESUMO

Wiskott-Aldrich Syndrome protein (WASp) regulates the cytoskeleton in hematopoietic cells and mutations in its gene cause the Wiskott-Aldrich Syndrome (WAS), a primary immunodeficiency with microthrombocytopenia, eczema and a higher susceptibility to develop tumors. Autoimmune manifestations, frequently observed in WAS patients, are associated with an increased risk of mortality and still represent an unsolved aspect of the disease. B cells play a crucial role both in immune competence and self-tolerance and defects in their development and function result in immunodeficiency and/or autoimmunity. We performed a phenotypical and molecular analysis of central and peripheral B-cell compartments in WAS pediatric patients. We found a decreased proportion of immature B cells in the bone marrow correlating with an increased presence of transitional B cells in the periphery. These results could be explained by the defective migratory response of WAS B cells to SDF-1α, essential for the retention of immature B cells in the BM. In the periphery, we observed an unusual expansion of CD21(low) B-cell population and increased plasma BAFF levels that may contribute to the high susceptibility to develop autoimmune manifestations in WAS patients. WAS memory B cells were characterized by a reduced in vivo proliferation, decreased somatic hypermutation and preferential usage of IGHV4-34, an immunoglobulin gene commonly found in autoreactive B cells. In conclusion, our findings demonstrate that WASp-deficiency perturbs B-cell homeostasis thus adding a new layer of immune dysregulation concurring to the increased susceptibility to develop autoimmunity in WAS patients.


Assuntos
Autoimunidade , Linfócitos B/imunologia , Suscetibilidade a Doenças/imunologia , Proteína da Síndrome de Wiskott-Aldrich/deficiência , Síndrome de Wiskott-Aldrich/imunologia , Fator Ativador de Células B/sangue , Fator Ativador de Células B/genética , Fator Ativador de Células B/imunologia , Linfócitos B/patologia , Medula Óssea/imunologia , Medula Óssea/patologia , Diferenciação Celular , Movimento Celular , Quimiocina CXCL12/genética , Quimiocina CXCL12/imunologia , Expressão Gênica , Homeostase/imunologia , Humanos , Cadeias Pesadas de Imunoglobulinas/genética , Cadeias Pesadas de Imunoglobulinas/imunologia , Memória Imunológica , Receptores de Complemento 3d/genética , Receptores de Complemento 3d/imunologia , Síndrome de Wiskott-Aldrich/genética , Síndrome de Wiskott-Aldrich/patologia , Proteína da Síndrome de Wiskott-Aldrich/genética , Proteína da Síndrome de Wiskott-Aldrich/imunologia
16.
J Clin Immunol ; 33(4): 731-41, 2013 May.
Artigo em Inglês | MEDLINE | ID: mdl-23389235

RESUMO

Common variable immune deficiency (CVID) is a heterogeneous disease associated with ineffective production of antibodies. It is usually diagnosed in adulthood, but a variable proportion of children develop CVID. Early identification of patients with potentially worse prognosis may help to avoid serious complications. The goal of this study was to associate the clinical phenotype of patients with early onset CVID with peripheral B-cell maturation profile. Four color flow cytometry was used to define distribution of peripheral B-cell subsets in 49 children with early-onset CVID. All clinical data were extracted from medical records. A proportion of patients demonstrated diminishing with time total B-lymphocytes pool, beyond physiological age-related changes. Irrespective from duration of the follow-up period the B-cell maturation profile in individual patients remained unchanged. We identified six different aberrant peripheral B cell maturation profiles associated with different clinical characteristics. Patients with an early B-cell maturation block earlier required replacement therapy and were at significantly greater risk of enteropathy, granuloma formation, cytopenia, and lymphoproliferation. B-cell maturation inhibited at the natural effector stage was associated with higher risk of autoimmune manifestations other than autoimmune cytopenia. Prevalence of male patients was observed among patients with B-cell maturation inhibited at naïve B-cell stage. In conclusion, the diagnostic process in patients with suspected early-onset CVID shall include routine analysis of peripheral B-cell maturation to provide surrogate markers identifying patients at greater risk of developing certain complications.


Assuntos
Subpopulações de Linfócitos B/imunologia , Linfócitos B/imunologia , Imunodeficiência de Variável Comum/diagnóstico , Imunodeficiência de Variável Comum/epidemiologia , Adolescente , Idade de Início , Circulação Sanguínea , Diferenciação Celular , Separação Celular , Criança , Pré-Escolar , Imunodeficiência de Variável Comum/imunologia , Testes Diagnósticos de Rotina , Progressão da Doença , Feminino , Citometria de Fluxo , Seguimentos , Humanos , Masculino , Prognóstico , Risco , Fatores Sexuais
17.
Cytometry A ; 81(10): 835-42, 2012 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-22851427

RESUMO

Patients with an immunodeficiency in the course of Nijmegen breakage syndrome (NBS) that is caused by mutations in the NBN/NBS1 gene are prone to recurrent infections and malignancies, due to a defective DNA double-strand breaks repair mechanism. Four-color flow cytometry was used to analyze changes in B lymphocyte subsets reflecting the most important stages of peripheral B cell maturation. It was demonstrated that the humoral immune defect observed in NBS patients was caused by reduced numbers of B lymphocytes, but also by their aberrant maturation. Reduced relative and absolute counts of naïve and memory B cells were accompanied by a significant accumulation of the natural effector B lymphocytes. The elevated proportion of IgM-only memory and reduced proportion of IgM-negative cells within the memory B cell pool suggests that there is class-switch recombination defect in this population of cells in NBS patients, resulting in inadequate production of immunoglobulins. Because of the reduced T-cell counts, the T-cell dependent antigen response is severely impaired resulting in a lower frequency of memory B-cells. The T-cell independent B-cell differentiation pathway seems less affected. The reduced IgG and IgA levels in patients with NBS are caused both by ineffective class switch, at least due to poor T cell help, and low number of memory B cells. This study illustrates that the NBN gene product nibrin plays an important role at different levels in the B-cell system.


Assuntos
Subpopulações de Linfócitos B/imunologia , Linfócitos B/imunologia , Proteínas de Ciclo Celular/imunologia , Imunidade Humoral , Síndrome de Quebra de Nijmegen/imunologia , Proteínas Nucleares/imunologia , Adolescente , Subpopulações de Linfócitos B/patologia , Linfócitos B/patologia , Proteínas de Ciclo Celular/genética , Diferenciação Celular/genética , Diferenciação Celular/imunologia , Criança , Pré-Escolar , Citometria de Fluxo , Expressão Gênica/imunologia , Humanos , Imunoglobulina A/sangue , Switching de Imunoglobulina , Imunoglobulina G/sangue , Imunoglobulina M/sangue , Memória Imunológica , Imunofenotipagem , Lactente , Contagem de Linfócitos , Síndrome de Quebra de Nijmegen/genética , Síndrome de Quebra de Nijmegen/patologia , Proteínas Nucleares/genética , Linfócitos T/imunologia , Linfócitos T/patologia
18.
Hum Immunol ; 73(11): 1091-7, 2012 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-22902394

RESUMO

The aim of the current study was to examine whether a congenital lack of the spleen changes distribution, state of activation and function of peripheral lymphocyte T subsets. Seven children with congenital asplenia (CA) aged 1.5-17 years and seven age-matched controls were tested. By triple-color flow cytometry we examined: (1) the expression of CD3(+), CD4(+), CD8(+), CD19(+), and CD56(+) on lymphocytes; (2) the distribution of CD45RA(+) and CD45RO(+) in CD4(+) and CD8(+); (3) the expression of CD27(+) in the CD4(+) and CD8(+) T-cell-bearing CD45RA(+), CD45RO(+), or CD45RB(+). Lymphocyte proliferative responses and cytokines production (IFN-gamma, IL-6, TNF-alfa, and IL-10) in anti-CD3-induced peripheral blood mononuclear cells were tested. The results indicate (1) a normal distribution of the basic lymphocyte subsets, (2) low CD3(+)/CD8(+) percentage but expressing CD8(+high) and non-significantly elevated CD4(+)/CD8(+) ratio, (3) CD45RA(+high) and CD27(+high) in the CD4(+) and CD8(+) T cell, and (4) CD45RB(+high) in the CD4(+) and CD45RO(+high) in the CD8(+). The distribution of CD27(+) in the CD45RA(+) and CD45RO(+) CD4(+) T cells remained unchanged. However, the percentage of CD8(+)/CD45RO(+)/CD27(+) T cells tended to be elevated. Altogether, these data indicate that CA is connected with (1) the presence CD4(+) T cells expressing the "naive" phenotype (CD45RA(+high) RB(+high) and CD27(+high)), (2) high numbers of activated CD8(+) T cells shifted toward the memory phenotype (CD45RO(+high)) but still showing high CD27(+) expression, which may indicate failure in T CD8(+) cytotoxic effectors differentiation, and (3) a tendency to the rather pro-inflammatory status of cells, low IL-10 expression, and suboptimal lymphocytes responses to mitogenic stimulation.


Assuntos
Síndromes de Imunodeficiência/imunologia , Subpopulações de Linfócitos T/imunologia , Adolescente , Antígenos CD/metabolismo , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/metabolismo , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Criança , Pré-Escolar , Citocinas/biossíntese , Feminino , Humanos , Imunofenotipagem , Lactente , Antígenos Comuns de Leucócito/metabolismo , Ativação Linfocitária/imunologia , Masculino , Fenótipo , Baço/anormalidades , Baço/imunologia , Subpopulações de Linfócitos T/metabolismo , Membro 7 da Superfamília de Receptores de Fatores de Necrose Tumoral/metabolismo
19.
Immunol Invest ; 41(1): 61-74, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-21877936

RESUMO

The spleen plays an important role in the granulocyte homeostasis due to such mechanisms as pooling, elimination of senescent cells and regulatory effects on granulocyte renewal in the bone marrow. The expression profile of granulocyte receptors was tested in children with congenital asplenia, and splenectomized for spherocytosis. Receptors tested included those appearing with maturation (CD16, CD11b, CD11c, TREM-1), disappearing (CD54, CD49d, CD64) and maintained during maturation (CD11a, CD45). In general, we found that the circulating granulocyte pool in the asplenic patients had phenotypical features of highly matured but not apoptotic neutrophils with a significantly elevated expression of CD16 (CD16(high)), tendency to a lower expression of CD45 (CD45(low)) and an unchanged expression of CD64 (and other markers indicating systemic inflammatory reactions). The high fluorescence intensity of CD11b,c, and TREM-1 in the congenital asplenia may indicate a potentially elevated pro-inflammatory status of granulocytes, possibly due to the low activity of vagus nerve and spleen-dependent cholinergic anti-inflammatory pathway.


Assuntos
Anemia Hemolítica Autoimune/imunologia , Síndrome de Heterotaxia/imunologia , Neutrófilos/metabolismo , Baço/imunologia , Esplenectomia , Adolescente , Antígenos CD/metabolismo , Diferenciação Celular , Sobrevivência Celular , Criança , Pré-Escolar , Feminino , Regulação da Expressão Gênica/imunologia , Síndrome de Heterotaxia/cirurgia , Humanos , Imunofenotipagem , Lactente , Mediadores da Inflamação/metabolismo , Masculino , Neutrófilos/imunologia , Neutrófilos/patologia , Baço/anormalidades
20.
Lancet Infect Dis ; 11(7): 557-70, 2011 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-21600850

RESUMO

Although the introduction of universal pertussis immunisation in infants has greatly reduced the number of reported cases in infants and young children, disease incidence has been increasing in adolescents and adults in recent years. This changing epidemiological pattern is probably largely attributable to waning immunity after natural infection or vaccination. Furthermore, improved diagnostic testing, active surveillance, changes in disease susceptibility, vaccine characteristics, and increased awareness of the disease might also be contributing factors. Susceptibility to pertussis in adolescents and adults results not only in direct morbidity in these age groups, but also poses a transmission risk to susceptible non-immune infants who are often too young to be vaccinated. Because vaccination schedules vary across Europe, we review the pertussis situation in this region and propose considerations for use of pertussis booster vaccinations at different ages to reduce individual morbidity and transmission from present rates and increase herd protection.


Assuntos
Bordetella pertussis/imunologia , Imunização Secundária/métodos , Vacina contra Coqueluche/administração & dosagem , Coqueluche/imunologia , Coqueluche/prevenção & controle , Adolescente , Adulto , Europa (Continente)/epidemiologia , Humanos , Coqueluche/epidemiologia , Adulto Jovem
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