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1.
Front Immunol ; 10: 2659, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31798588

RESUMO

Background: Goodpasture's disease (GP) is mediated by autoantibodies that bind the glomerular and alveolar basement membrane, causing rapidly progressive glomerulonephritis with or without pulmonary hemorrhage. The autoantibodies bind neoepitopes formed upon disruption of the quaternary structure of α345NC1 hexamer, a critical structural domain of α345 collagen IV scaffolds. Hexamer disruption leads to a conformational changes that transitions α3 and α5NC1 subunits into immunogens, however, the trigger remains unknown. This contrasts with another anti-GBM disease, Alports' post-transplant nephritis (APTN), where the pathogenic alloantibody binds directly to native NC1 hexamer. The current report includes the first study of antigenic specificity and allo-incompatability in anti-GBM disease occurring after allogeneic haematopoietic stem cell transplant (HSCT). Results: The anti-GBM antibodies were found to be directed predominantly against the EA epitope of the α3 NC1 monomer of collagen IV and developed rapidly in patient serum reaching peak level within 5 weeks. Autoantibody binding to native α345NC1 hexamer was minimal; however, binding was greatly increased upon dissociation of the native hexamer. There were no polymorphic genetic differences between donor and recipient collagen IV genes which would be predicted to cause a significant NC1 conformational change or to provide a target for antibody binding. Both patient and donor possessed the Goodpasture's susceptibility HLA-allele DRB1 * 1501. Conclusions: The current report includes the first in-depth study of allo-incompatability and antigenic specificity in anti-GBM disease occurring after allogeneic haematopoietic stem cell transplant (HSCT). No polymorphic genetic differences were identified between donor and recipient collagen IV genes which would be predicted to provide a target for antibody binding. Furthermore, autoantibody binding to native α345NC1 hexamer was minimal, increasing greatly upon dissociation of the native hexamer, resembling wild-type GP diseases and marking this as the first example of a post-HSCT conformeropathy.

2.
Intern Med J ; 49(12): 1480-1487, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31808255

RESUMO

Peanut allergy is increasingly prevalent and for most patients is a life-long condition, with the potential to cause life-threatening reactions. Accurate diagnosis and appropriate management are essential to minimise risks due to accidental peanut exposure. Current management strategies focus on strict allergen avoidance and access to emergency medicines to treat potential reactions; however, active approaches are an area of intense research. Promising new methods of food allergen immunotherapy are set to change the approach to managing peanut allergic patients in the near future.

3.
JCI Insight ; 52019 Apr 25.
Artigo em Inglês | MEDLINE | ID: mdl-31021819

RESUMO

Bi-allelic inactivating mutations in DOCK8 cause a combined immunodeficiency characterised by severe pathogen infections, eczema, allergies, malignancy and impaired humoral responses. These clinical features result from functional defects in most lymphocyte lineages. Thus, DOCK8 plays a key role in immune cell function. Hematopoietic stem cell transplantation (HSCT) is curative for DOCK8 deficiency. While previous reports have described clinical outcomes for DOCK8 deficiency following HSCT, the effect on lymphocyte reconstitution and function has not been investigated. Our study determined whether defects in lymphocyte differentiation and function in DOCK8-deficient patients were restored following HSCT. DOCK8-deficient T and B lymphocytes exhibited aberrant activation and effector function in vivo and in vitro. Frequencies of αß T and MAIT cells were reduced while γδT cells were increased in DOCK8-deficient patients. HSCT improved, abnormal lymphocyte function in DOCK8-deficient patients. Elevated total and allergen-specific IgE in DOCK8-deficient patients decreased over time following HSCT. Our results document the extensive catalogue of cellular defects in DOCK8-deficient patients, and the efficacy of HSCT to correct these defects, concurrent with improvements in clinical phenotypes. Overall, our findings provide mechanisms at a functional cellular level for improvements in clinical features of DOCK8 deficiency post-HSCT, identify biomarkers that correlate with improved clinical outcomes, and inform the general dynamics of immune reconstitution in patients with monogenic immune disorders following HSCT.

5.
J Paediatr Child Health ; 53(10): 988-994, 2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-28752571

RESUMO

AIM: Haematopoietic stem cell transplantation (HSCT) is a central therapy in the treatment of primary immunodeficiency diseases (PIDs). Over the past 5 years, outcomes have been greatly improved due to earlier diagnosis, improved donor availability, advancements in graft manipulation and the use of less toxic preparative regimens. We present a 5-year audit of HSCT for PID at a single Australian tertiary hospital. METHODS: Retrospective case note review identified diagnosis, pre-transplant medical morbidity, transplant protocol, engraftment, adverse events, post-transplant immune reconstitution and general health. RESULTS: A total of 22 patients with PID underwent 24 HSCTs at our institution between 2012 and 2016. The most common indications were severe combined immunodeficiency, chronic granulomatous disease and familial haemophagocytic lymphohistiocytosis, with a genetic diagnosis in all but two patients. Reduced intensity or reduced toxicity conditioning was used in 91% of cases, and 75% of the donors were unrelated. Transplant-related mortality at day +100 was 9.5%, and cumulative overall survival was 86%. There were three mortalities, all secondary to viral infection, one of which occurred in the context of graft failure. Two patients remained on immune support, with the remainder achieving adequate immune reconstitution. CONCLUSIONS: The outcomes for HSCT for PIDs performed at Sydney Children's Hospital were in line with the world's best practice. HSCT should be considered a potential therapeutic option for all Australian PID patients with a valid disease indication.


Assuntos
Transplante de Células-Tronco Hematopoéticas , Síndromes de Imunodeficiência/terapia , Centros de Atenção Terciária , Adolescente , Austrália , Criança , Pré-Escolar , Feminino , Doença Enxerto-Hospedeiro , Humanos , Lactente , Masculino , Auditoria Médica , Estudos Retrospectivos
6.
J Paediatr Child Health ; 53(8): 766-770, 2017 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-28513891

RESUMO

AIM: To examine the long-term follow-up and health outcomes of patients who have undergone haematopoietic stem cell transplant (HSCT) for severe combined immunodeficiency (SCID). METHODS: Through a structured questionnaire, we examined follow-up arrangements and long-term health outcomes in 22 children who have had a successful HSCT for SCID during the period of 1984-2012 at the Sydney Children's Hospital, Sydney, Australia. RESULTS: Most children considered themselves healthy and 'cured' from SCID. Whilst many children enjoy relatively good bio-social health outcomes, specific negative health outcomes and absenteeism from school were perceived negatively. Two-thirds of children see their general practitioner or specialist regularly; however, there did not appear to be consistency with the nature of this follow-up. CONCLUSION: The findings from our study highlight the complex bio-psychosocial health needs of post-HSCT SCID children and encourage SCID centres to consider a multidisciplinary approach to their follow-up. Further studies into the determinants of patients' perceptions of their health are needed.


Assuntos
Transplante de Células-Tronco Hematopoéticas , Avaliação de Resultados da Assistência ao Paciente , Imunodeficiência Combinada Severa/cirurgia , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , New South Wales , Imunodeficiência Combinada Severa/diagnóstico , Inquéritos e Questionários
7.
J Allergy Clin Immunol ; 140(5): 1323-1330, 2017 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-28427879

RESUMO

BACKGROUND: Food protein-induced enterocolitis syndrome (FPIES) is a non-IgE-mediated gastrointestinal allergic disorder. Large population-based FPIES studies are lacking. OBJECTIVE: We sought to determine the incidence and clinical characteristics of FPIES in Australian infants. METHODS: An Australia-wide survey (2012-2014) was undertaken through the Australian Paediatric Surveillance Unit, with monthly notification of new cases of acute FPIES in infants aged less than 24 months by 1400 participating pediatricians. RESULTS: Two hundred thirty infants with FPIES were identified. The incidence of FPIES in Australian infants (<24 months) was 15.4/100,000/y. Median age of first episode, diagnosis, and notification were 5, 7, and 10 months, respectively. There was no sex predilection. Seven percent of infants had siblings with a history of FPIES, and 5% reacted during exclusive breast-feeding. Sixty-eight had a single food trigger (20% had 2 and 12% had ≥3 food triggers). The most common FPIES triggers were rice (45%), cow's milk (33%), and egg (12%). Fifty-one percent of infants reacted on their first known exposure. Infants with FPIES to multiple versus single food groups were younger at the initial episode (4.6 vs 5.8 months [mean], P = .001) and more frequently had FPIES to fruits, vegetables, or both (66% vs 21%, P < .0001). Infants exclusively breast-fed for more than 4 months had a trend toward lower rates of FPIES to multiple food groups (23% vs 36%, P = .06). Sixty-four percent of infants with FPIES to multiple foods, which included cow's milk, had coassociated FPIES to solid foods. Forty-two percent of infants with FPIES to fish reacted to other food groups. CONCLUSIONS: FPIES is not rare, with an estimated incidence of 15.4/100,000/y. Rice is the most common food trigger in Australia. Factors associated with FPIES to multiple foods included early-onset disease and FPIES to fruits, vegetables, or both.


Assuntos
Enterocolite/epidemiologia , Hipersensibilidade Alimentar/epidemiologia , Grupos Populacionais , Idade de Início , Alérgenos/efeitos adversos , Alérgenos/imunologia , Animais , Austrália/epidemiologia , Bovinos , Enterocolite/imunologia , Feminino , Hipersensibilidade Alimentar/imunologia , Humanos , Incidência , Lactente , Recém-Nascido , Masculino , Oryza/efeitos adversos , Fatores de Risco , Síndrome
8.
Aust Fam Physician ; (10): 699, 2016 Oct 10.
Artigo em Inglês | MEDLINE | ID: mdl-27806458
10.
J Clin Immunol ; 35(7): 604-9, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-26433589

RESUMO

UNLABELLED: Vasculitis occurs rarely in association with X-linked lymphoproliferative disease (XLP). There are four published cases of non-EBV XLP-associated cerebral vasculitis reported, none of whom have survived without major cognitive impairment. CASE: A 9-year old boy initially presented aged 5 years with a restrictive joint disease. He subsequently developed dysgammaglobulinemia, episodic severe pneumonitis, aplastic anaemia, gastritis and cerebral vasculitis. A diagnosis of XLP was made, based on flow cytometric analysis and the identification of a novel mutation in SH2D1A, c.96G>C. No peripheral blood lymphocyte clonal proliferation was identified and he was EBV negative, although human herpes virus-7 (HHV7) was detected repeatedly in his cerebrospinal fluid. He underwent a reduced intensity unrelated umbilical cord blood transplant, but failed to engraft. A second 5/6 matched cord gave 100 % donor engraftment. Complications included BK virus-associated haemorrhagic cystitis, a possible NK-cell mediated immune reconstitution syndrome and post-transplant anti-glomerular basement membrane disease, the latter treated with cyclophosphamide and rituximab. At +450 days post-transplant he is in remission from his vasculitis and anti-glomerular basement membrane disease, and HHV-7 has remained undetectable. CONCLUSION: This is the second published description of joint disease in XLP, and only the fourth case of non-EBV associated cerebral vasculitis in XLP, as well as being the first to be successfully treated for this manifestation. This case raises specific questions about vasculitis in XLP, in particular the potential relevance of HHV-7 to the pathogenesis.


Assuntos
Transplante de Células-Tronco de Sangue do Cordão Umbilical , Herpesvirus Humano 7/imunologia , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Artropatias/terapia , Células Matadoras Naturais/fisiologia , Transtornos Linfoproliferativos/terapia , Complicações Pós-Operatórias/tratamento farmacológico , Infecções por Roseolovirus/terapia , Vasculite do Sistema Nervoso Central/terapia , Austrália , Criança , Ciclofosfamida/administração & dosagem , Antígenos HLA/imunologia , Herpesvirus Humano 7/isolamento & purificação , Humanos , Imunidade/genética , Peptídeos e Proteínas de Sinalização Intracelular/genética , Artropatias/diagnóstico , Artropatias/etiologia , Células Matadoras Naturais/transplante , Células Matadoras Naturais/virologia , Transtornos Linfoproliferativos/complicações , Transtornos Linfoproliferativos/diagnóstico , Masculino , Mutação de Sentido Incorreto/genética , Linhagem , Indução de Remissão , Rituximab/administração & dosagem , Infecções por Roseolovirus/complicações , Infecções por Roseolovirus/diagnóstico , Proteína Associada à Molécula de Sinalização da Ativação Linfocitária , Vasculite do Sistema Nervoso Central/diagnóstico , Vasculite do Sistema Nervoso Central/etiologia
11.
Pediatrics ; 135(3): e730-5, 2015 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-25713284

RESUMO

Adult subjects with systemic capillary leak syndrome (SCLS) present with acute and recurrent episodes of vascular leak manifesting as severe hypotension, hypoalbuminemia, hemoconcentration, and generalized edema. We studied clinical disease characteristics, serum cytokine profiles, and treatment modalities in a cohort of children with documented SCLS. Six children with SCLS were recruited from the United States, Australia, Canada, and Italy. Serum cytokines from SCLS subjects and a group of 10 healthy children were analyzed. Children with SCLS (aged 5-11 years old) presented with at least 1 acute, severe episode of hypotension, hypoalbuminemia, and hemoconcentration in the absence of underlying causes for these abnormalities. In contrast to what is observed in adult SCLS, identifiable infectious triggers precipitated most episodes in these children, and none of them had a monoclonal gammopathy. We found elevated levels of chemokine (C-C motif) ligand 2 (CCL2), interleukin-8, and tumor necrosis factor α in baseline SCLS sera compared with the control group. All patients are alive and well on prophylactic therapy, with 4 patients receiving intravenous or subcutaneous immunoglobulins at regular intervals. The clinical manifestations of pediatric and adult SCLS are similar, with the notable exceptions of frequent association with infections and the lack of monoclonal gammopathy. Prophylactic medication, including high dose immunoglobulins or theophylline plus verapamil, appears to be safe and efficacious therapy for SCLS in children.


Assuntos
Síndrome de Vazamento Capilar/complicações , Edema/etiologia , Síndrome de Vazamento Capilar/sangue , Síndrome de Vazamento Capilar/tratamento farmacológico , Criança , Pré-Escolar , Edema/sangue , Edema/tratamento farmacológico , Humanos , Lactente , Interleucina-8/sangue , Masculino , Teofilina/uso terapêutico , Vasodilatadores/uso terapêutico
12.
Expert Rev Vaccines ; 13(9): 1081-106, 2014 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-25093268

RESUMO

The recent epidemics of pertussis (whooping cough) in parts of the USA and Australia have led to the largest numbers of annual cases reported in over half a century. These epidemics demonstrated a new pattern, with particularly high rates of disease among pre-adolescents and early adolescents. These high rates of pertussis coincided with the first cohorts vaccinated with purely acellular pertussis vaccine, which replaced whole-cell pertussis (wP) vaccine in the later 1990s in the USA and Australia. Studies undertaken during these epidemics provide new evidence of more rapid waning of acellular pertussis-containing vaccines and longer-term protection from effective wP-containing vaccines. There is evidence that receiving wP as at least the first dose of pertussis-containing vaccine provides greater and more long-lived protection, irrespective of the nature of subsequent doses. This evidence will be reviewed together with the immunobiology associated with both vaccines, and the implications for pertussis control discussed.


Assuntos
Vacina contra Coqueluche/administração & dosagem , Vacina contra Coqueluche/imunologia , Coqueluche/epidemiologia , Coqueluche/imunologia , Adolescente , Fatores Etários , Austrália/epidemiologia , Epidemias , Humanos , Estados Unidos/epidemiologia , Vacinas Acelulares/administração & dosagem , Vacinas Acelulares/imunologia , Coqueluche/prevenção & controle
13.
Curr Opin Allergy Clin Immunol ; 14(3): 208-16, 2014 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-24686277

RESUMO

PURPOSE OF REVIEW: To summarize the epidemiology of food protein-induced enterocolitis syndrome (FPIES). RECENT FINDINGS: FPIES is regarded as a rare non-IgE-mediated gastrointestinal allergic disorder. Older nonpopulation-based studies reported an average of 1-15 cases presenting to allergy clinics a year, but recent studies have reported figures as high as 90 cases a year. The yearly incidence of FPIES in one Australian study was one in 10,000 infants less than 2 years of age. Chronic FPIES typically presents in neonates, whereas acute FPIES is primarily a disorder of young infants. FPIES has a slight male predominance; eczema and a family history of atopy are commonly present at diagnosis; almost one in 10 infants have coexistent IgE food allergies and siblings are rarely affected. There is regional variation in common triggering foods, rates of combined cow milk and soy FPIES and multiple food group FPIES. Understanding of the epidemiology of FPIES is limited by the lack of a universally accepted definition and the publication of few prospective population-based case series. SUMMARY: FPIES is not as rare as once thought, but how common it is, what factors predispose to its development, and why there is regional variation needs to be addressed by future well designed population-based studies?


Assuntos
Enterocolite/epidemiologia , Hipersensibilidade Alimentar/epidemiologia , Proteínas do Leite/efeitos adversos , Proteínas de Vegetais Comestíveis/efeitos adversos , Proteínas de Soja/efeitos adversos , Austrália/epidemiologia , Pré-Escolar , Enterocolite/etiologia , Feminino , Hipersensibilidade Alimentar/etiologia , Humanos , Lactente , Masculino , Fatores Sexuais , Síndrome
14.
Pediatrics ; 123(3): e459-64, 2009 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-19188266

RESUMO

OBJECTIVE: The goal was to examine the demographic characteristics, causative foods, clinical features, treatments, and outcomes for children presenting with acute food protein-induced enterocolitis syndrome. METHODS: This was a retrospective study of children with food protein-induced enterocolitis syndrome who presented to the Children's Hospital at Westmead (Sydney, Australia) over 16 years. RESULTS: Thirty-five children experienced 66 episodes of food protein-induced enterocolitis syndrome. The mean age at initial presentation was 5.5 months. Children frequently experienced multiple episodes before a correct diagnosis was made. Twenty-nine children reacted to 1 food, and 6 reacted to 2 foods. Causative foods for the 35 children were rice (n = 14), soy (n = 12), cow's milk (n = 7), vegetables and fruits (n = 3), meats (n = 2), oats (n = 2), and fish (n = 1). In the 66 episodes, vomiting was the most common clinical feature (100%), followed by lethargy (85%), pallor (67%), and diarrhea (24%). A temperature of <36 degrees C at presentation was recorded for 24% of episodes. A platelet count of >500 x 10(9) cells per L was recorded for 63% of episodes with blood count results. Only 2 of the 19 children who presented to an emergency department with their initial reactions were discharged with correct diagnoses. Additional investigations of food protein-induced enterocolitis syndrome episodes presenting to the hospital were common, with 34% of patients undergoing abdominal imaging, 28% undergoing a septic evaluation, and 22% having a surgical consultation. Prognosis was good, with high rates of resolution for the 2 most common food triggers (ie, rice and soy) by 3 years of age. CONCLUSIONS: Misdiagnosis and delays in diagnosis for children with food protein-induced enterocolitis syndrome were common, leading many children to undergo unnecessary, often painful investigations. Decreased body temperature and thrombocytosis emerge as additional features of the syndrome.


Assuntos
Proteínas na Dieta/efeitos adversos , Enterocolite/diagnóstico , Hipersensibilidade Alimentar/diagnóstico , Adolescente , Criança , Pré-Escolar , Diagnóstico Diferencial , Enterocolite/dietoterapia , Insuficiência de Crescimento/etiologia , Feminino , Hipersensibilidade Alimentar/dietoterapia , Humanos , Imunoglobulina E/sangue , Testes Intradérmicos , Masculino , Carne/efeitos adversos , Proteínas do Leite/efeitos adversos , Oryza/efeitos adversos , Recidiva , Estudos Retrospectivos , Fatores de Risco , Proteínas de Soja/efeitos adversos
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