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1.
Ir J Med Sci ; 188(3): 815-819, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30661174

RESUMO

BACKGROUND: Food-dependent exercise-induced anaphylaxis (FDEIA) is a life-threatening disorder in which the signs and symptoms of anaphylaxis occur if physical exertion occurs within a few hours of exposure to a food. AIMS: The aim of this study was to characterise patients diagnosed with FDEIA and related disorders. METHODS: A retrospective review of electronic clinical data from 2001 to 2016 was carried out. Fifty-seven cases were identified and analysed to establish clinical features, triggering factors and sensitisation patterns. RESULTS: The number of patients per annum diagnosed with FDEIA or related reactions increased from 1 in 2001 to 18 patients in 2016. Sixty-nine percent reported systemic symptoms consistent with anaphylaxis, and 31% had skin manifestations only. In 33% of cases, the level of triggering exercise was mild. Forty-four percent of patients were sensitised to the omega-5-gliadin fraction of wheat. CONCLUSIONS: FDEIA is an increasingly recognised serious allergic disease. The clinical diagnosis is supported by targeted sensitisation testing and molecular-based allergy diagnostics. These tools allow implementation of effective dietary and lifestyle modifications that mitigate against future serious reactions. Given the limited access to physicians with specialist allergy training in Ireland, increased awareness of this condition amongst sports medicine specialists and general physicians is required.


Assuntos
Anafilaxia/diagnóstico , Exercício/fisiologia , Hipersensibilidade Alimentar/diagnóstico , Adolescente , Adulto , Anafilaxia/patologia , Feminino , Hipersensibilidade Alimentar/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Fatores de Tempo , Adulto Jovem
2.
Artigo em Inglês | MEDLINE | ID: mdl-30170123

RESUMO

BACKGROUND: Caspase activation and recruitment domain 11 (CARD11) encodes a scaffold protein in lymphocytes that links antigen receptor engagement with downstream signaling to nuclear factor κB, c-Jun N-terminal kinase, and mechanistic target of rapamycin complex 1. Germline CARD11 mutations cause several distinct primary immune disorders in human subjects, including severe combined immune deficiency (biallelic null mutations), B-cell expansion with nuclear factor κB and T-cell anergy (heterozygous, gain-of-function mutations), and severe atopic disease (loss-of-function, heterozygous, dominant interfering mutations), which has focused attention on CARD11 mutations discovered by using whole-exome sequencing. OBJECTIVES: We sought to determine the molecular actions of an extended allelic series of CARD11 and to characterize the expanding range of clinical phenotypes associated with heterozygous CARD11 loss-of-function alleles. METHODS: Cell transfections and primary T-cell assays were used to evaluate signaling and function of CARD11 variants. RESULTS: Here we report on an expanded cohort of patients harboring novel heterozygous CARD11 mutations that extend beyond atopy to include other immunologic phenotypes not previously associated with CARD11 mutations. In addition to (and sometimes excluding) severe atopy, heterozygous missense and indel mutations in CARD11 presented with immunologic phenotypes similar to those observed in signal transducer and activator of transcription 3 loss of function, dedicator of cytokinesis 8 deficiency, common variable immunodeficiency, neutropenia, and immune dysregulation, polyendocrinopathy, enteropathy, X-linked-like syndrome. Pathogenic variants exhibited dominant negative activity and were largely confined to the CARD or coiled-coil domains of the CARD11 protein. CONCLUSION: These results illuminate a broader phenotypic spectrum associated with CARD11 mutations in human subjects and underscore the need for functional studies to demonstrate that rare gene variants encountered in expected and unexpected phenotypes must nonetheless be validated for pathogenic activity.

3.
Immunol Cell Biol ; 96(10): 1060-1071, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-29790605

RESUMO

Premature T-cell immunosenescence with CD57+ CD8+ T-cell accumulation has been linked to immunodeficiency and autoimmunity in primary immunodeficiencies including activated PI3 kinase delta syndrome (APDS). To address whether CD57 marks the typical senescent T-cell population seen in adult individuals or identifies a distinct population in APDS, we compared CD57+ CD8+ T cells from mostly pediatric APDS patients to those of healthy adults with similarly prominent senescent T cells. CD57+ CD8+ T cells from APDS patients were less differentiated with more CD27+ CD28+ effector memory T cells showing increased PD1 and Eomesodermin expression. In addition, transition of naïve to CD57+ CD8+ T cells was not associated with the characteristic telomere shortening. Nevertheless, they showed the increased interferon-gamma secretion, enhanced degranulation and reduced in vitro proliferation typical of senescent CD57+ CD8+ T cells. Thus, hyperactive PI3 kinase signaling favors premature accumulation of a CD57+ CD8+ T-cell population, which shows most functional features of typical senescent T cells, but is different in terms of differentiation and relative telomere shortening. Initial observations indicate that this specific differentiation state may offer the opportunity to revert premature T-cell immunosenescence and its potential contribution to inflammation and immunodeficiency in APDS.

5.
J Allergy Clin Immunol ; 139(2): 597-606.e4, 2017 02.
Artigo em Inglês | MEDLINE | ID: mdl-27555459

RESUMO

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


Assuntos
Classe I de Fosfatidilinositol 3-Quinases/genética , Síndromes de Imunodeficiência/genética , Transtornos Linfoproliferativos/genética , Mutação/genética , Infecções Respiratórias/genética , Adolescente , Adulto , Animais , Antibioticoprofilaxia , Criança , Pré-Escolar , Classe I de Fosfatidilinositol 3-Quinases/antagonistas & inibidores , Estudos de Coortes , Inibidores Enzimáticos/uso terapêutico , Feminino , Transplante de Células-Tronco Hematopoéticas , Infecções por Herpesviridae/genética , Infecções por Herpesviridae/mortalidade , Infecções por Herpesviridae/terapia , Humanos , Imunoglobulinas Intravenosas/uso terapêutico , Síndromes de Imunodeficiência/mortalidade , Síndromes de Imunodeficiência/terapia , Lactente , Cooperação Internacional , Transtornos Linfoproliferativos/mortalidade , Transtornos Linfoproliferativos/terapia , Masculino , Camundongos , Pessoa de Meia-Idade , Recidiva , Infecções Respiratórias/mortalidade , Infecções Respiratórias/terapia , Inquéritos e Questionários , Análise de Sobrevida , Adulto Jovem
6.
Clin Immunol ; 176: 23-30, 2017 03.
Artigo em Inglês | MEDLINE | ID: mdl-28011187

RESUMO

Common variable immunodeficiency (CVID) is a primary immunoglobulin deficiency characterized by recurrent infections and complications, including autoimmunity, enteropathy, polyclonal lymphocytic infiltration or lymphoid malignancy. Innate T cells can support B cell maturation and antibody production. We investigated the numbers, phenotypes and functions of circulating B cell, γδ T cell, invariant natural killer T (iNKT) cell and mucosal-associated invariant T (MAIT) cell subsets in 23 CVID patients and 27 healthy controls. Switched-memory B cells and plasmablasts were depleted in CVID patients (p<0.0001). γδ T cells were found at normal numbers, but iNKT and MAIT cells were depleted (p<0.0001 and p<0.002). MAIT cells were especially low in patients with complicated CVID (p<0.05). MAIT cells from patients appeared more activated and more frequently produced interleukin-17A, interleukin-22 and tumor necrosis factor-α than MAIT cells from healthy subjects in vitro. Thus, MAIT cell depletion and activation may contribute to immunodeficiency and complications associated with CVID.


Assuntos
Imunodeficiência de Variável Comum/imunologia , Células T Invariáveis Associadas à Mucosa/imunologia , Subpopulações de Linfócitos T/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Formação de Anticorpos/imunologia , Linfócitos B/imunologia , Feminino , Humanos , Interleucina-17/imunologia , Interleucinas/imunologia , Ativação Linfocitária/imunologia , Contagem de Linfócitos/métodos , Masculino , Pessoa de Meia-Idade , Células T Matadoras Naturais/imunologia , Fator de Necrose Tumoral alfa/imunologia , Adulto Jovem
7.
Artigo em Inglês | MEDLINE | ID: mdl-27544398

RESUMO

Circumorificial plasmacytosis is a rare plasma cell proliferative disorder of the orificial mucous membranes. The etiology is unknown, and there are no reported effective treatments to date. We report three cases of idiopathic circumorificial plasmacytosis with varying clinical presentations and responses to treatment, including a first reported case of resolution with adalimumab therapy.


Assuntos
Adalimumab/uso terapêutico , Anti-Inflamatórios/uso terapêutico , Mucosa Bucal/patologia , Mucosite/diagnóstico , Mucosite/tratamento farmacológico , Plasmócitos/patologia , Idoso , Biópsia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade
8.
BMJ Case Rep ; 20162016 Jul 19.
Artigo em Inglês | MEDLINE | ID: mdl-27436032

RESUMO

Granulomatosis with polyangiitis is an uncommon condition characterised by vasculitis and associated granuloma formation with a highly specific autoantibody, namely proteinase 3-anti-neutrophil cytoplasmic antibody (ANCA). The respiratory tract and kidneys are the organ systems most often involved. Symptoms can be non-specific, and isolated hearing loss can predate other symptoms by months, leading to lengthy delays in diagnosis and treatment. Left untreated, hearing loss can be irreversible, and therefore early diagnosis is crucial. We present a case study of severe hearing impairment in an attempt to raise awareness of ear involvement as an early feature of this unusual condition.


Assuntos
Granulomatose com Poliangiite/complicações , Granulomatose com Poliangiite/diagnóstico , Perda Auditiva/complicações , Perda Auditiva/diagnóstico , Odontalgia/complicações , Odontalgia/diagnóstico , Adulto , Azatioprina/uso terapêutico , Ciclofosfamida/uso terapêutico , Diagnóstico Diferencial , Difosfonatos/uso terapêutico , Feminino , Granulomatose com Poliangiite/tratamento farmacológico , Humanos , Prednisolona/uso terapêutico , Inibidores da Bomba de Prótons/uso terapêutico , Odontalgia/tratamento farmacológico , Combinação Trimetoprima e Sulfametoxazol/uso terapêutico
9.
Clin J Am Soc Nephrol ; 11(8): 1392-9, 2016 08 08.
Artigo em Inglês | MEDLINE | ID: mdl-27401523

RESUMO

BACKGROUND AND OBJECTIVES: An environmental trigger has been proposed as an inciting factor in the development of anti-GBM disease. This multicenter, observational study sought to define the national incidence of anti-GBM disease during an 11-year period (2003-2014) in Ireland, investigate clustering of cases in time and space, and assess the effect of spatial variability in incidence on outcome. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We ascertained cases by screening immunology laboratories for instances of positivity for anti-GBM antibody and the national renal histopathology registry for biopsy-proven cases. The population at risk was defined from national census data. We used a variable-window scan statistic to detect temporal clustering. A Bayesian spatial model was used to calculate standardized incidence ratios (SIRs) for each of the 26 counties. RESULTS: Seventy-nine cases were included. National incidence was 1.64 (95% confidence interval [95% CI], 0.82 to 3.35) per million population per year. A temporal cluster (n=10) was identified during a 3-month period; six cases were resident in four rural counties in the southeast. Spatial analysis revealed wide regional variation in SIRs and a cluster (n=7) in the northwest (SIR, 1.71; 95% CI, 1.02 to 3.06). There were 29 deaths and 57 cases of ESRD during a mean follow-up of 2.9 years. Greater distance from diagnosis site to treating center, stratified by median distance traveled, did not significantly affect patient (hazard ratio, 1.80; 95% CI, 0.87 to 3.77) or renal (hazard ratio, 0.76; 95% CI, 0.40 to 1.13) survival. CONCLUSIONS: To our knowledge, this is the first study to report national incidence rates of anti-GBM disease and formally investigate patterns of incidence. Clustering of cases in time and space supports the hypothesis of an environmental trigger for disease onset. The substantial variability in regional incidence highlights the need for comprehensive country-wide studies to improve our understanding of the etiology of anti-GBM disease.


Assuntos
Doença Antimembrana Basal Glomerular/epidemiologia , Falência Renal Crônica/epidemiologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Doença Antimembrana Basal Glomerular/etiologia , Doença Antimembrana Basal Glomerular/mortalidade , Análise por Conglomerados , Exposição Ambiental/efeitos adversos , Feminino , Humanos , Incidência , Irlanda/epidemiologia , Falência Renal Crônica/etiologia , Masculino , Pessoa de Meia-Idade , Análise Espaço-Temporal , Taxa de Sobrevida
10.
Expert Rev Clin Immunol ; 12(7): 705-11, 2016 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-27156362

RESUMO

The number of patients with secondary immune deficiencies (SID) is on the rise, mostly since the arrival on the market of novel targeted therapies that have increased the survival rates of patients with hematological malignancies. The recent changes in the SID landscape have brought with them new and diverse medical needs that treatments for SID management should strive to meet. In this special report, we study the opportunities provided by facilitated subcutaneous immunoglobulin administration (fSCIg) to treat patients for whom the conventional routes (intravenous and subcutaneous) are sub-optimal. Experts in the treatment of SID describe real-life cases from their daily practice, in which fSCIg has led to reducing the burden of treatment and increasing the treatment satisfaction.


Assuntos
Neoplasias Hematológicas/terapia , Imunoglobulinas Intravenosas/uso terapêutico , Síndromes de Imunodeficiência/terapia , Infecção/terapia , Exposição Ambiental/efeitos adversos , Feminino , Neoplasias Hematológicas/complicações , Neoplasias Hematológicas/imunologia , Humanos , Síndromes de Imunodeficiência/etiologia , Síndromes de Imunodeficiência/imunologia , Infecção/complicações , Infecção/imunologia , Infusões Subcutâneas , Masculino , Medicina de Precisão
15.
Eur J Gastroenterol Hepatol ; 26(4): 478-84, 2014 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-24535594

RESUMO

Eosinophilic disease of the gastrointestinal tract is rare and is characterized by the presence of gastrointestinal symptoms in association with eosinophilic infiltration of any part of the gastrointestinal tract. Clinical presentation of eosinophilic gastroenteritis (EGE) varies not only by the part of the gastrointestinal tract involved but also with the depth of eosinophilic infiltration of the gut wall. We describe the case of a 41-year-old woman with a history of atopy who presented with severe abdominal pain and diarrhoea. Investigations showed large-volume eosinophil-rich ascites and a markedly elevated peripheral blood eosinophil count and immunoglobulin E level. Bone marrow aspirate, trephine biopsy and T-cell studies showed no evidence of underlying haematological malignancy. Vasculitic disease and parasitic infection were systematically excluded. Colonic and upper gastrointestinal biopsies confirmed a diagnosis of EGE with eosinophilic ascites. The patient was treated with systemic corticosteroids and dietary allergen elimination with dramatic therapeutic response. The diagnostic and therapeutic challenges associated with EGE in its various forms are discussed.


Assuntos
Ascite/etiologia , Enterite/etiologia , Eosinofilia/etiologia , Gastrite/etiologia , Dor Abdominal/etiologia , Corticosteroides/uso terapêutico , Adulto , Ascite/sangue , Ascite/diagnóstico , Ascite/terapia , Biomarcadores/sangue , Biópsia , Diarreia/etiologia , Endoscopia Gastrointestinal , Enterite/sangue , Enterite/diagnóstico , Enterite/terapia , Eosinofilia/sangue , Eosinofilia/diagnóstico , Eosinofilia/terapia , Feminino , Gastrite/sangue , Gastrite/diagnóstico , Gastrite/terapia , Humanos , Imunoglobulina E/sangue , Fatores de Risco , Tomografia Computadorizada por Raios X , Resultado do Tratamento
17.
Eur J Gastroenterol Hepatol ; 18(11): 1173-5, 2006 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-17033437

RESUMO

Serological screening tests for coeliac disease have significantly advanced the diagnosis of this condition. The very high specificity (almost 100%) of anti-endomysial antibody detection has been repeatedly confirmed, whereas a lower specificity (90-95%) is found with anti-tissue transglutaminase antibody assays. In the study by Malekzadeh and colleagues, a group of study participants were identified with raised anti-tissue transglutaminase antibodies, but the endomysial antibody test was negative in 86%. Although many of these participants were found to have raised intra-epithelial lymphocytes in their small intestinal mucosa, there is currently insufficient evidence to confidently diagnose gluten-sensitive disease in these patients. Hence, their report that a minimum prevalence of 1:104 of gluten sensitivity is found in the general population of Iran is likely to be an over-estimate and requires confirmation.


Assuntos
Autoanticorpos/sangue , Doença Celíaca/diagnóstico , Proteínas de Ligação ao GTP/imunologia , Programas de Rastreamento/métodos , Transglutaminases/imunologia , Adulto , Anticorpos/sangue , Ensaio de Imunoadsorção Enzimática , Técnica Indireta de Fluorescência para Anticorpo , Humanos , Imunoglobulina A/imunologia , Sensibilidade e Especificidade , Testes Sorológicos , Triticum/imunologia
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