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1.
J Exp Med ; 217(2)2020 Feb 03.
Artigo em Inglês | MEDLINE | ID: mdl-31841125

RESUMO

Antibody-mediated autoimmune diseases are a major health burden. However, our understanding of how self-reactive B cells escape self-tolerance checkpoints to secrete pathogenic autoantibodies remains incomplete. Here, we demonstrate that patients with monogenic immune dysregulation caused by gain-of-function mutations in PIK3CD, encoding the p110δ catalytic subunit of phosphoinositide 3-kinase (PI3K), have highly penetrant secretion of autoreactive IgM antibodies. In mice with the corresponding heterozygous Pik3cd activating mutation, self-reactive B cells exhibit a cell-autonomous subversion of their response to self-antigen: instead of becoming tolerized and repressed from secreting autoantibody, Pik3cd gain-of-function B cells are activated by self-antigen to form plasmablasts that secrete high titers of germline-encoded IgM autoantibody and hypermutating germinal center B cells. However, within the germinal center, peripheral tolerance was still enforced, and there was selection against B cells with high affinity for self-antigen. These data show that the strength of PI3K signaling is a key regulator of pregerminal center B cell self-tolerance and thus represents a druggable pathway to treat antibody-mediated autoimmunity.

2.
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.

3.
J Clin Immunol ; 2019 Dec 21.
Artigo em Inglês | MEDLINE | ID: mdl-31865525

RESUMO

Variants in MAGT1 have been identified as the cause of an immune deficiency termed X-linked immunodeficiency with magnesium defect, Epstein-Barr virus (EBV) infection and neoplasia (XMEN) disease. Here, we describe 2 cases of XMEN disease due to novel mutations in MAGT1, one of whom presented with classical features of XMEN disease and another who presented with a novel phenotype including probable CNS vasculitis, HHV-8 negative multicentric Castelman disease and severe molluscum contagiosum, thus highlighting the clinical diversity that may be seen in this condition. Peripheral blood immunophenotyping of these 2 patients, together with an additional 4 XMEN patients, revealed reduced NKG2D expression, impaired CD28 expression on CD8+ T cells, CD4+ T cell lymphopenia, an inverted CD4:CD8 ratio and decreased memory B cells. In addition, we showed for the first time alterations to the CD8+ T cell memory compartment, reduced CD56hi NK cells, MAIT and iNKT cells, as well as compromised differentiation of naïve CD4+ T cells into IL-21-producing Tfh-type cells in vitro. Both patients were treated with supplemental magnesium with limited benefit. However, one patient has undergone allogeneic haematopoietic stem cell transplant, with full donor chimerism and immune reconstitution. These results expand our understanding of the clinical and immunological phenotype in XMEN disease, adding to the current literature, which we further discuss here.

4.
Nat Immunol ; 20(10): 1299-1310, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31534238

RESUMO

Resisting and tolerating microbes are alternative strategies to survive infection, but little is known about the evolutionary mechanisms controlling this balance. Here genomic analyses of anatomically modern humans, extinct Denisovan hominins and mice revealed a TNFAIP3 allelic series with alterations in the encoded immune response inhibitor A20. Each TNFAIP3 allele encoded substitutions at non-catalytic residues of the ubiquitin protease OTU domain that diminished IκB kinase-dependent phosphorylation and activation of A20. Two TNFAIP3 alleles encoding A20 proteins with partial phosphorylation deficits seemed to be beneficial by increasing immunity without causing spontaneous inflammatory disease: A20 T108A;I207L, originating in Denisovans and introgressed in modern humans throughout Oceania, and A20 I325N, from an N-ethyl-N-nitrosourea (ENU)-mutagenized mouse strain. By contrast, a rare human TNFAIP3 allele encoding an A20 protein with 95% loss of phosphorylation, C243Y, caused spontaneous inflammatory disease in humans and mice. Analysis of the partial-phosphorylation A20 I325N allele in mice revealed diminished tolerance of bacterial lipopolysaccharide and poxvirus inoculation as tradeoffs for enhanced immunity.

5.
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.

6.
J Allergy Clin Immunol ; 144(1): 236-253, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30738173

RESUMO

BACKGROUND: Gain-of-function (GOF) mutations in PIK3CD cause a primary immunodeficiency characterized by recurrent respiratory tract infections, susceptibility to herpesvirus infections, and impaired antibody responses. Previous work revealed defects in CD8+ T and B cells that contribute to this clinical phenotype, but less is understood about the role of CD4+ T cells in disease pathogenesis. OBJECTIVE: We sought to dissect the effects of increased phosphoinositide 3-kinase (PI3K) signaling on CD4+ T-cell function. METHODS: We performed detailed ex vivo, in vivo, and in vitro phenotypic and functional analyses of patients' CD4+ T cells and a novel murine disease model caused by overactive PI3K signaling. RESULTS: PI3K overactivation caused substantial increases in numbers of memory and follicular helper T (TFH) cells and dramatic changes in cytokine production in both patients and mice. Furthermore, PIK3CD GOF human TFH cells had dysregulated phenotype and function characterized by increased programmed cell death protein 1, CXCR3, and IFN-γ expression, the phenotype of a TFH cell subset with impaired B-helper function. This was confirmed in vivo in which Pik3cd GOF CD4+ T cells also acquired an aberrant TFH phenotype and provided poor help to support germinal center reactions and humoral immune responses by antigen-specific wild-type B cells. The increase in numbers of both memory and TFH cells was largely CD4+ T-cell extrinsic, whereas changes in cytokine production and TFH cell function were cell intrinsic. CONCLUSION: Our studies reveal that CD4+ T cells with overactive PI3K have aberrant activation and differentiation, thereby providing mechanistic insight into dysfunctional antibody responses in patients with PIK3CD GOF mutations.

7.
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
9.
Med J Aust ; 198(11): 600-2, 2013 Jun 17.
Artigo em Inglês | MEDLINE | ID: mdl-23919705

RESUMO

A review of case notes from our Sydney-based paediatric allergy services, between 1 January 2003 and 31 December 2011, identified 74 children who had been prescribed diets that eliminated foods containing natural salicylates before attending our clinics. The most common indications for starting the diets were eczema (34/74) and behavioural disturbances (17/74) including attention deficit hyperactivity disorder (ADHD). We could find no peer-reviewed evidence to support the efficacy of salicylate elimination diets in managing these diseases. We do not prescribe these diets, and in a survey of European and North American food allergy experts, only 1/23 respondents used a similar diet for eczema, with none of the respondents using salicylate elimination to treat ADHD. A high proportion (31/66) of children suffered adverse outcomes, including nutritional deficiencies and food aversion, with four children developing eating disorders. We could find no published evidence to support the safety of these diets in children. While this uncontrolled study does not prove a causal relationship between salicylate elimination diets and harm, the frequency of adverse events appears high, and in the absence of evidence of safety or efficacy, we cannot recommend the use of these diets in children.


Assuntos
Dieta/métodos , Salicilatos/efeitos adversos , Transtorno do Deficit de Atenção com Hiperatividade/dietoterapia , Criança , Transtornos do Comportamento Infantil/dietoterapia , Dieta/efeitos adversos , Eczema/dietoterapia , Humanos , Resultado do Tratamento
11.
Int J Pediatr Otorhinolaryngol ; 77(4): 480-2, 2013 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-23294930

RESUMO

OBJECTIVE: Pediatric airway foreign body aspiration is a life-threatening clinical entity. The standard of care for managing this situation is endoscopic retrieval using rigid bronchoscopy. However in resource-limited settings rigid bronchoscopy may not be available. This retrospective case series describes the successful application of one treatment modality for pediatric airway foreign body. METHODS: A retrospective review was performed for seven pediatric patients who were treated at Soddo Christian Hospital with a diagnosis of airway foreign body aspiration. All patients were treated in the operating room using general anesthesia, a combination of inhaled halothane and intravenous ketamine. Paralytics were not used in any patient and spontaneous breathing was maintained. Flexible fiberoptic bronchoscopy was initially performed on each patient to confirm the presence of a foreign body and identify the anatomic position with the airway. Using a standard technique, a tracheotomy was performed. If the foreign body was still noted to be distal to the tracheotomy, postural percussion was performed to dislodge the foreign body into the trachea. Once the foreign body was identified at the tracheotomy, it was removed. RESULTS: All seven patients presented in respiratory distress and were emergently managed in the operating room. The average age was 2.8 years (6 months-8 years of age). The foreign bodies were successfully removed in all patients. There were no mortalities and all patients were successfully discharged from the hospital. CONCLUSIONS: Pediatric airway foreign body aspiration is a life-threatening clinical entity in any setting, but it presents unique challenges in resource-limited settings where rigid bronchoscopy is not available. This report presents one such treatment modality and utilizes a combination of flexible fiberoptic bronchoscopy and tracheotomy to treat such patients.


Assuntos
Brônquios/cirurgia , Broncoscopia/métodos , Corpos Estranhos/cirurgia , Aspiração Respiratória/cirurgia , Traqueia/cirurgia , Traqueotomia/métodos , Criança , Pré-Escolar , Feminino , Corpos Estranhos/diagnóstico , Corpos Estranhos/terapia , Humanos , Lactente , Masculino , Aspiração Respiratória/terapia , Estudos Retrospectivos , Resultado do Tratamento
12.
Pediatr Infect Dis J ; 32(4): 415-6, 2013 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-23271442

RESUMO

We describe a case of Q fever associated with the transient presence of antiphospholipid antibodies in a 9-year-old boy presenting with acalculous cholecystitis and splenic infarction. Antiphospholipid antibodies are commonly associated with acute Q fever in adults but have previously been thought to be of little clinical significance. Recent data suggest that antiphospholipid antibodies may be responsible for certain clinical manifestations of acute Q fever.


Assuntos
Anticorpos Antifosfolipídeos/sangue , Colecistite/complicações , Colecistite/diagnóstico , Febre Q/complicações , Febre Q/diagnóstico , Infarto do Baço/complicações , Infarto do Baço/diagnóstico , Criança , Colecistite/patologia , Humanos , Masculino , Febre Q/patologia , Infarto do Baço/patologia , Migrantes
13.
Pediatrics ; 129(5): e1353-9, 2012 May.
Artigo em Inglês | MEDLINE | ID: mdl-22508923

RESUMO

Sweet syndrome is an inflammatory disease characterized by fever and painful erythematous plaques with a dermal neutrophilic infiltrate. It is most common in adults, where it is often parainflammatory or paraneoplastic, but is rare in children. We describe 3 cases of neonatal Sweet syndrome, including 1 patient who had myelodysplastic syndrome and immunodeficiency, the first report of a premalignancy underlying infantile Sweet syndrome. We reviewed the literature on patients presenting with neutrophilic dermatosis in the first 6 months of life. Of 20 cases, 6 had a probable viral etiology, 4 primary immunodeficiencies, 3 neonatal lupus syndrome, 1 gastrointestinal involvement, 1 HIV, and 5 probable genetic cases. Three of these had chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature syndrome, caused by mutations in the PSMB8 gene. Most children who presented within the first 6 weeks of life had either a serious underlying condition, such as primary immunodeficiency, or a genetic Sweet syndrome, with 2 fatalities among this latter group. The outcome of postinfective cases was good. Extracutaneous involvement was unusual, whereas postinflammatory scarring and cutis laxa occurred in a minority of patients. In conclusion, Sweet syndrome in the neonatal period often heralds a serious underlying disorder and requires thorough investigation.


Assuntos
Síndromes de Imunodeficiência/congênito , Síndromes de Imunodeficiência/diagnóstico , Lesões Pré-Cancerosas/congênito , Lesões Pré-Cancerosas/diagnóstico , Síndrome de Sweet/congênito , Síndrome de Sweet/diagnóstico , Anemia Refratária/congênito , Anemia Refratária/diagnóstico , Criança , Pré-Escolar , Diagnóstico Diferencial , Feminino , Seguimentos , Doença Granulomatosa Crônica/congênito , Doença Granulomatosa Crônica/diagnóstico , Humanos , Lactente , Recém-Nascido , Masculino
14.
J Paediatr Child Health ; 48(3): 202-9, 2012 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-21564385

RESUMO

While the impact of infectious diseases in developed countries has been diminished by improved nutrition, hygiene, vaccination coverage and health care, infections remain common, and even the healthiest children may suffer frequent infections, occasionally necessitating admission to hospital. When investigating a child with recurrent infections, it is therefore important to know the frequency, severity, infectious syndrome and infecting organisms which a normal child might experience, and to understand the impact of the child's underlying health on their susceptibility to infection. This paper examines infectious susceptibility in the healthy and immunocompromised child and explores the respective presentations of some primary immunodeficiencies.


Assuntos
Hospedeiro Imunocomprometido , Síndromes de Imunodeficiência/diagnóstico , /etiologia , Adolescente , Austrália/epidemiologia , Criança , Pré-Escolar , Doenças Transmissíveis/epidemiologia , Suscetibilidade a Doenças , Humanos , Síndromes de Imunodeficiência/complicações , Lactente , Recidiva
17.
Proc (Bayl Univ Med Cent) ; 21(2): 120-6, 2008 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-18382749

RESUMO

Hypothermia is a significant contributor to mortality in severely injured patients. Rewarming is an enormous challenge, especially in those who require operative or angiographic intervention. In this patient population, external warming methods are only capable of reducing further heat loss, whereas active rewarming adds heat to the body's core but is invasive. This article analyzes our initial experience with a minimally invasive, continuous, automated, and easily portable intravascular rewarming technique using the Alsius Corporation's CoolGard system. The records of 11 hypothermic critically injured patients presenting to our level 1 trauma center over a 6-month period were reviewed. The patients' mean age was 39 +/- 22 years, 7 (64%) were male, and 7 (64%) had blunt mechanisms of injury. The mean injury severity score was 40 +/- 16, and the mean initial systolic blood pressure was 91 +/- 60 mm Hg. The mean core temperature at the initiation of rewarming was 33.6 +/- 1.0 degrees C, and the mean rewarming rate was 1.5 +/- 1.0 degrees C/h. Six patients died (55%), two of acute exsanguination and four of unsurvivable traumatic brain injuries. One patient developed a deep vein thrombosis at the femoral catheter site and experienced a nonfatal pulmonary embolus. Our experience demonstrates that active intravascular balloon-catheter rewarming represents a practical, automated technique for the immediate and continuous treatment of hypothermia in all phases of the acute care of trauma patients.

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