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1.
Front Immunol ; 10: 998, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31156616

RESUMO

CTLA-4 is essential for immune tolerance. Heterozygous CTLA4 mutations cause immune dysregulation evident in defective regulatory T cells with low levels of CTLA-4 expression. Biallelic mutations in LRBA also result in immune dysregulation with low levels of CTLA-4 and clinical presentation indistinguishable from CTLA-4 haploinsufficiency. CTLA-4 has become an immunotherapy target whereby its blockade with a monoclonal antibody has resulted in improved survival in advanced melanoma patients, amongst other malignancies. However, this therapeutic manipulation can result in autoimmune/inflammatory complications reminiscent of those seen in genetic defects affecting the CTLA-4 pathway. Despite efforts made to understand and establish disease genotype/phenotype correlations in CTLA-4-haploinsufficiency and LRBA-deficiency, such relationships remain elusive. There is currently no specific immunological marker to assess the degree of CTLA-4 pathway disruption or its relationship with clinical manifestations. Here we compare three different patient groups with disturbances in the CTLA-4 pathway-CTLA-4-haploinsufficiency, LRBA-deficiency, and ipilimumab-treated melanoma patients. Assessment of CTLA4 mRNA expression in these patient groups demonstrated an inverse correlation between the CTLA4 message and degree of CTLA-4 pathway disruption. CTLA4 mRNA levels from melanoma patients under therapeutic CTLA-4 blockade (ipilimumab) were increased compared to patients with either CTLA4 or LRBA mutations that were clinically stable with abatacept treatment. In summary, we show that increased CTLA4 mRNA levels correlate with the degree of CTLA-4 pathway disruption, suggesting that CTLA4 mRNA levels may be a quantifiable surrogate for altered CTLA-4 expression.

2.
J Exp Med ; 216(6): 1255-1267, 2019 Jun 03.
Artigo em Inglês | MEDLINE | ID: mdl-31040184

RESUMO

The pleiotropic actions of interleukin-2 (IL-2) are essential for regulation of immune responses and maintenance of immune tolerance. The IL-2 receptor (IL-2R) is composed of IL-2Rα, IL-2Rß, and IL-2Rγ subunits, with defects in IL-2Rα and IL-2Rγ and their downstream signaling effectors resulting in known primary immunodeficiency disorders. Here, we report the first human defect in IL-2Rß, occurring in two infant siblings with a homozygous IL2RB mutation in the WSXWS motif, manifesting as multisystem autoimmunity and susceptibility to CMV infection. The hypomorphic mutation results in diminished IL-2Rß surface expression and dysregulated IL-2/15 signaling, with an anticipated reduction in regulatory T cells. However, in contrast to the IL-2Rß-/- animal model, which lacks NK cells, these siblings demonstrate an expansion of NK cells, particularly the CD56bright subset, and a lack of terminally differentiated NK cells. Thus, the early-onset autoimmunity and immunodeficiency are linked to functional deficits arising from altered IL-2Rß expression and signaling in T and NK cells.

4.
J Allergy Clin Immunol Pract ; 7(6): 1970-1985.e4, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30877075

RESUMO

BACKGROUND: Although autoimmunity and hyperinflammation secondary to recombination activating gene (RAG) deficiency have been associated with delayed diagnosis and even death, our current understanding is limited primarily to small case series. OBJECTIVE: Understand the frequency, severity, and treatment responsiveness of autoimmunity and hyperinflammation in RAG deficiency. METHODS: In reviewing the literature and our own database, we identified 85 patients with RAG deficiency, reported between 2001 and 2016, and compiled the largest case series to date of 63 patients with prominent autoimmune and/or hyperinflammatory pathology. RESULTS: Diagnosis of RAG deficiency was delayed a median of 5 years from the first clinical signs of immune dysregulation. Most patients (55.6%) presented with more than 1 autoimmune or hyperinflammatory complication, with the most common etiologies being cytopenias (84.1%), granulomas (23.8%), and inflammatory skin disorders (19.0%). Infections, including live viral vaccinations, closely preceded the onset of autoimmunity in 28.6% of cases. Autoimmune cytopenias had early onset (median, 1.9, 2.1, and 2.6 years for autoimmune hemolytic anemia, immune thrombocytopenia, and autoimmune neutropenia, respectively) and were refractory to intravenous immunoglobulin, steroids, and rituximab in most cases (64.7%, 73.7%, and 71.4% for autoimmune hemolytic anemia, immune thrombocytopenia, and autoimmune neutropenia, respectively). Evans syndrome specifically was associated with lack of response to first-line therapy. Treatment-refractory autoimmunity/hyperinflammation prompted hematopoietic stem cell transplantation in 20 patients. CONCLUSIONS: Autoimmunity/hyperinflammation can be a presenting sign of RAG deficiency and should prompt further evaluation. Multilineage cytopenias are often refractory to immunosuppressive treatment and may require hematopoietic cell transplantation for definitive management.

5.
Curr Opin Allergy Clin Immunol ; 18(2): 139-147, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29406360

RESUMO

PURPOSE OF REVIEW: Children living in US inner cities experience disparate burdens of asthma, especially in severity, impairment, exacerbations, and morbidity. Investigations seeking to better understand the factors and mechanisms underlying asthma prevalence, severity, and exacerbation in children living in these communities can lead to interventions that can narrow asthma disparities and potentially benefit all children with asthma. This update will focus on recent (i.e. late 2016-2017) advances in the understanding of asthma in US inner city children. RECENT FINDINGS: Studies published in the past year expand understanding of asthma prevalence, severity, exacerbation, and the outcomes of guidelines-based management of these at-risk children, including: asthma phenotypes in US inner city children that are severe and difficult-to-control; key environmental determinants and mechanisms underlying asthma severity and exacerbations (e.g. allergy-mediated exacerbation susceptibility to rhinovirus); the importance of schools as a place for provocative exposures (e.g. mouse allergen, nitrogen dioxide) as well as a place where asthma care and outcomes can be improved; and the development and validation of clinically useful indices for gauging asthma severity and predicting exacerbations. SUMMARY: These recent studies provide a trove of actionable findings that can improve asthma care and outcomes for these at-risk children.


Assuntos
Asma/epidemiologia , Exposição Ambiental/efeitos adversos , Estresse Psicológico/imunologia , População Urbana/estatística & dados numéricos , Alérgenos/efeitos adversos , Alérgenos/imunologia , Asma/diagnóstico , Asma/etiologia , Criança , Cidades/epidemiologia , Progressão da Doença , Epigênese Genética/imunologia , Humanos , Fenótipo , Prevalência , Rhinovirus/imunologia , Instituições Acadêmicas , Índice de Gravidade de Doença , Estresse Psicológico/psicologia , Estados Unidos/epidemiologia
6.
J Allergy Clin Immunol ; 140(3): 671-680, 2017 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-28709967

RESUMO

In this year's Advances in Asthma review, we discuss viral infections in asthmatic patients and potential therapeutic agents, the microbiome, novel genetic associations with asthma, air quality and climate effects on asthma, exposures during development and long-term sequelae of childhood asthma, patient-centered outcomes research, and precision medicine. In addition, we discuss application of biomarkers to precision medicine and new information on asthma medications. New evidence indicates that rhinovirus-triggered asthma exacerbations become more severe as the degree of sensitization to dust mite and mouse increase. The 2 biggest drivers of asthma severity are an allergy pathway starting with allergic sensitization and an environmental tobacco smoke pathway. In addition, allergic sensitization and blood eosinophils can be used to select medications for management of early asthma in young children. These current findings, among others covered in this review, represent significant steps toward addressing rapidly advancing areas of knowledge that have implications for asthma management.


Assuntos
Asma/tratamento farmacológico , Poluição do Ar , Animais , Asma/epidemiologia , Asma/genética , Asma/microbiologia , Biomarcadores , Clima , Comorbidade , Humanos , Pulmão/microbiologia , Avaliação de Resultados da Assistência ao Paciente , Medicina de Precisão , Fatores de Risco , Viroses/epidemiologia
7.
J Allergy Clin Immunol ; 138(2): 397-404, 2016 08.
Artigo em Inglês | MEDLINE | ID: mdl-27497278

RESUMO

In 2015, progress in understanding asthma ranged from insights to asthma inception, exacerbations, and severity to advancements that will improve disease management throughout the lifespan. 2015's insights to asthma inception included how the intestinal microbiome affects asthma expression with the identification of specific gastrointestinal bacterial taxa in early infancy associated with less asthma risk, possibly by promoting regulatory immune development at a critical early age. The relevance of epigenetic mechanisms in regulating asthma-related gene expression was strengthened. Predicting and preventing exacerbations throughout life might help to reduce progressive lung function decrease and disease severity in adulthood. Although allergy has long been linked to asthma exacerbations, a mechanism through which IgE impairs rhinovirus immunity and underlies asthma exacerbations was demonstrated and improved by anti-IgE therapy (omalizumab). Other key molecular pathways underlying asthma exacerbations, such as cadherin-related family member 3 (CDHR3) and orosomucoid like 3 (ORMDL3), were elucidated. New anti-IL-5 therapeutics, mepolizumab and reslizumab, were US Food and Drug Administration approved for the treatment of patients with severe eosinophilic asthma. In a clinical trial the novel therapeutic inhaled GATA3 mRNA-specific DNAzyme attenuated early- and late-phase allergic responses to inhaled allergen. These current findings are significant steps toward addressing unmet needs in asthma prevention, severity modification, disparities, and lifespan outcomes.


Assuntos
Asma/etiologia , Asma/metabolismo , Alérgenos/imunologia , Asma/diagnóstico , Asma/terapia , Terapia Combinada , Gerenciamento Clínico , Progressão da Doença , Exposição Ambiental , Epigênese Genética , Humanos , Imunização , Microbiota/imunologia , Pesquisa , Índice de Gravidade de Doença
8.
Curr Opin Allergy Clin Immunol ; 16(2): 148-56, 2016 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-26859370

RESUMO

PURPOSE OF REVIEW: Asthma is prevalent in inner-city populations, exhibiting significant morbidity and mortality. This review focuses on the consequential findings of recent literature, providing insight into onset of asthma, complicating factors, prediction of exacerbations, and novel treatment strategies. RECENT FINDINGS: Analyses of environmental influence on inner-city children demonstrated novel interactions, implicating potentially protective benefits from early life exposures to pests and pets and isolating detrimental effects of air pollution on asthma morbidity. Through detailed characterization of inner-city asthmatics, predictors of seasonal exacerbations surfaced. Focused, season-specific treatment of inner-city asthmatics with omalizumab identified those most likely to benefit from season-tailored therapy. Comparative studies of urban and rural populations revealed that race and household income, rather than location of residence, impose the greatest risk for increased asthma prevalence and morbidity. SUMMARY: Challenging previously conceived exposure-disease relationships, recent literature has elucidated new avenues in the complex interplay between immunologically active exposures and their effects on inner-city asthma. These findings, and improved understanding of other relevant exposures, could steer the direction of primary (and secondary) disease prevention research. Moreover, careful identification of asthma characteristics has effectively established predictors of exacerbations, highlighting individuals for which additional therapies are warranted and for whom such treatments are most likely to be effective.


Assuntos
Asma/epidemiologia , Pobreza , População Urbana , Animais , Asma/tratamento farmacológico , Grupos de Populações Continentais , Gerenciamento Clínico , Humanos , Omalizumab/uso terapêutico , Prevalência , Fatores de Risco
9.
J Clin Immunol ; 35(8): 754-60, 2015 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-26515615

RESUMO

PURPOSE: Hypomorphic mutations in RAG1 and RAG2 are associated with significant clinical heterogeneity and symptoms of immunodeficiency or autoimmunity may be late in appearance. As a result, immunosuppressive medications may be introduced that can have life-threatening consequences. We describe a previously healthy 13-month-old girl presenting with rash and autoimmune hemolytic anemia, while highlighting the importance of vigilance and consideration of an underlying severe immunodeficiency disease prior to instituting immunosuppressive therapy. METHODS: Given clinical deterioration of the patient and a temporal association with recently administered vaccinations, virus genotyping was carried out via 4 real-time Forster Resonance Energy Transfer PCR protocols targeting vaccine-associated single nucleotide polymorphisms. Genomic DNA was extracted from whole blood and analyzed via the next-generation sequencing method of sequencing-by-synthesis. Immune function studies included immunophenotyping of peripheral blood lymphocytes, mitogen-induced proliferation and TLR ligand-induced production of TNFα. Analysis of recombination activity of wild-type and mutant RAG2 constructs was performed. RESULTS: Virus genotyping revealed vaccine-strain VZV, mumps, and rubella. Next-generation sequencing identified heterozygosity for RAG2 R73H and P180H mutations. Profound lymphopenia was associated with intense corticosteroid therapy, with some recovery after steroid reduction. Residual, albeit low, RAG2 protein activity was demonstrated. CONCLUSIONS: Because of the association of RAG deficiency with late-onset presentation and autoimmunity, live virus vaccination and immunosuppressive therapies are often initiated and can result in negative consequences. Here, hypomorphic RAG2 mutations were linked to disseminated vaccine-strain virus infections following institution of corticosteroid therapy for autoimmune hemolytic anemia.


Assuntos
Anemia Hemolítica Autoimune/diagnóstico , Herpes Zoster/diagnóstico , Herpesvirus Humano 3/fisiologia , Síndromes de Imunodeficiência/diagnóstico , Vacinas Virais/imunologia , Adolescente , Corticosteroides/administração & dosagem , Corticosteroides/efeitos adversos , Anemia Hemolítica Autoimune/complicações , Anemia Hemolítica Autoimune/tratamento farmacológico , Células Cultivadas , Proteínas de Ligação a DNA/genética , Feminino , Herpes Zoster/complicações , Herpes Zoster/tratamento farmacológico , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Síndromes de Imunodeficiência/complicações , Síndromes de Imunodeficiência/tratamento farmacológico , Imunossupressão , Ativação Linfocitária/efeitos dos fármacos , Proteínas Nucleares/genética , Linhagem
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