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1.
J Inherit Metab Dis ; 2020 Feb 16.
Artigo em Inglês | MEDLINE | ID: mdl-32064623

RESUMO

Congenital disorders of glycosylation (CDGs) are clinically heterogeneous disorders defined by a decreased ability to modify biomolecules with oligosaccharides. Critical disruptions in protein recognition, interaction, binding, and anchoring lead to broad physiological effects. Patients present with endocrinopathy, immunodeficiency, hepatopathy, coagulopathy, and neurodevelopmental impairment. Patients may experience mortality/morbidity associated with shock physiology that is frequently culture negative and poorly responsive to standard care. Oedema, pleural and pericardial effusions, ascites, proteinuria, and protein-losing enteropathy are observed with an exaggerated inflammatory response. The negative serum protein steady state results from several mechanisms including reduced hepatic synthesis and secretion, increased consumption, and extravasation. Disruption of the glycocalyx, a layer of glycosylated proteins that lines the endothelium preventing thrombosis and extravasation, is a suspected cause of endothelial dysfunction in CDG patients. We performed a retrospective review of CDG patients admitted to our institution with acute illness over the past 2 years. Longitudinal clinical and laboratory data collected during the sick and well states were assessed for biomarkers of inflammation and efficacy of interventions. Six patients representing 4 CDG subtypes and 14 hospitalisations were identified. Acute D-dimer elevation, proteinuria, decreased serum total protein levels, coagulation proteins, and albumin were observed with acute illness. Infusion of fresh frozen plasma, and in some cases protein C concentrate, was associated with clinical and biomarker improvement. This was notable with intra-patient comparison of treated vs untreated courses. Use of endothelial barrier support therapy may reduce endothelial permeability by restoring both regulatory serum protein homeostasis and supporting the glycocalyx and is likely a critical component of care for this population.

2.
3.
J Allergy Clin Immunol Pract ; 7(2): 451-461.e7, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30267889

RESUMO

BACKGROUND: We successfully used omalizumab to facilitate peanut oral immunotherapy (OIT) in children with reactivity to ≤50mg peanut protein and with high peanut IgE (median, 229 kU/L). OBJECTIVE: We report on long-term OIT outcomes in these patients, including dosing changes, adverse events, peanut immunoglobulin changes, and quality of life (QoL). METHODS: Patients were followed for up to 72 months (67 months of maintenance). Outcomes were collected on peanut dose amount, form, and frequency, as well as adverse events, (QoL), and laboratory studies. RESULTS: Of 13 patients initially enrolled, 7 patients (54%) continued on peanut OIT through month 72; 6 (46%) discontinued therapy because of adverse reactions. Maintenance peanut protein dose varied between 500 and 3500mg. Most patients consumed different peanut-containing products. All patients experienced at least 1 adverse event, and 1 patient developed eosinophilic esophagitis. Peanut-IgE, Arah1-IgE and Arah2-IgE, peanut-SPT, peanut-IgE:IgE ratio, and Arah2-IgE:Arah2-IgG4 ratio decreased on OIT. Peanut-IgG4, Arah1-IgG4, and Arah2-IgG4 initially increased on OIT and then decreased, though not falling to baseline levels. In patients who stopped OIT, there was a trend for reversal of these biomarker changes. Higher peanut-IgE and Arah2-IgE at study month 12 were associated with discontinuation. Patient and parent QoL improved from baseline, even in patients who discontinued OIT. CONCLUSIONS: Although adjunctive omalizumab allowed for faster and successful desensitization in patients with high peanut-IgE, almost half of patients discontinued OIT within 72 months because of reactions. Patients who stopped therapy had higher month 12 peanut-IgE and Arah2-IgE. It is possible that these patients might benefit from longer omalizumab administration.

4.
J Allergy Clin Immunol Pract ; 7(3): 1024-1031.e3, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30385406

RESUMO

BACKGROUND: Acquired cold-induced urticaria (ACU) has not been well evaluated in pediatrics. OBJECTIVE: To further evaluate the presentation of ACU in children and associated risk of anaphylaxis. METHODS: A retrospective chart review was performed in children 18 years or younger diagnosed with ACU at Boston Children's Hospital (US, Northeast) from 1996 to 2017. RESULTS: A total of 415 patients with ACU were identified, aged 4 months to 18.3 years at the time of diagnosis, with similar male:female distribution. Most patients had a history of atopic disease (78.3%), and 25.8% had other urticaria. Around two-third of patients experienced only localized cold-induced symptoms (grade 1), whereas 14.0% had diffuse cutaneous symptoms (grade 2) as the most severe reaction, and 18.6% experienced anaphylaxis (grade 3). Swimming triggered 77.6% of grade 3 reactions, whereas the rest were secondary to ingestion of cold food or beverages, or cold air or cold water exposure. Seven percent of subjects had more than 1 episode of anaphylaxis. Cold stimulation test (CST) was performed in 61.7% of patients, and the result was positive in 69.9% of those tested. Positive CST result was significantly associated with increased risk of anaphylaxis. There was a 11.7% rate of anaphylaxis among patients with negative CST result. Disease resolution at any point in the study period was documented in 8.9% of patients and was associated with a negative history of anaphylaxis. CONCLUSIONS: In the largest study to date on ACU, grade 3 reactions occurred in about a fifth of patients. Positive CST result was associated with a higher risk for anaphylaxis from ACU. Epinephrine prescription and patient/family counseling about risk factors for grade 3 reactions are recommended.

5.
Ann Allergy Asthma Immunol ; 121(6): 722-728.e1, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30102964

RESUMO

BACKGROUND: The rate of systemic reactions (SRs) to venom immunotherapy (VIT) in children has not been well evaluated. OBJECTIVE: To evaluate the rate of SRs to VIT in pediatric patients age 5 to 18 years who were treated with a standard protocol. METHODS: A retrospective chart review was conducted to identify patients who received VIT at Boston Children's Hospital from 1996 through 2018. Information on venom testing, severity of reaction to insect field sting, and SRs to VIT were retrieved. RESULTS: A total of 78 patients were included. Most had moderate to severe reactions to insect sting before VIT. The rate of SRs was 0.2% of injection visits, occurring in 9% of patients. The SRs from VIT were mild (mostly grade 1 and some grade 2), and no grades 3, 4, or 5 reactions were seen. Male sex was a significant risk factor for moderate to severe reactions to insect sting. Positive testing to vespinae was seen in 98.7% of patients, and none had exclusive sensitivity to honeybee. The severity of the initial, pre-VIT insect sting reactions in our patients did not correlate with the occurrence of SRs from VIT. Twenty-seven percent of the patients were subsequently stung while on VIT. Only 1 patient (5%) had a mild SR, while all others had only local or no reaction at all. CONCLUSION: In the largest US study evaluating the safety of VIT in children, SRs to VIT were mild, and none required epinephrine. Male sex was significantly associated with higher risk of moderate to severe reactions to insect sting. Larger multicenter studies are needed to further evaluate the rate of SRs to VIT in pediatric patients.


Assuntos
Venenos de Abelha/uso terapêutico , Dessensibilização Imunológica/métodos , Hipersensibilidade Imediata/prevenção & controle , Imunoterapia/métodos , Mordeduras e Picadas de Insetos/imunologia , Adolescente , Animais , Abelhas , Criança , Pré-Escolar , Epinefrina/uso terapêutico , Feminino , Humanos , Mordeduras e Picadas de Insetos/patologia , Masculino , Estudos Retrospectivos , Centros de Atenção Terciária/estatística & dados numéricos
6.
Blood ; 131(21): 2335-2344, 2018 05 24.
Artigo em Inglês | MEDLINE | ID: mdl-29653965

RESUMO

Integrity of the T-cell receptor/CD3 complex is crucial for positive and negative selection of T cells in the thymus and for effector and regulatory functions of peripheral T lymphocytes. In humans, CD3D, CD3E, and CD3Z gene defects are a cause of severe immune deficiency and present early in life with increased susceptibility to infections. By contrast, CD3G mutations lead to milder phenotypes, mainly characterized by autoimmunity. However, the role of CD3γ in establishing and maintaining immune tolerance has not been elucidated. In this manuscript, we aimed to investigate abnormalities of T-cell repertoire and function in patients with genetic defects in CD3G associated with autoimmunity. High throughput sequencing was used to study composition and diversity of the T-cell receptor ß (TRB) repertoire in regulatory T cells (Tregs), conventional CD4+ (Tconv), and CD8+ T cells from 6 patients with CD3G mutations and healthy controls. Treg function was assessed by studying its ability to suppress proliferation of Tconv cells. Treg cells of patients with CD3G defects had reduced diversity, increased clonality, and reduced suppressive function. The TRB repertoire of Tconv cells from patients with CD3G deficiency was enriched for hydrophobic amino acids at positions 6 and 7 of the CDR3, a biomarker of self-reactivity. These data demonstrate that the T-cell repertoire of patients with CD3G mutations is characterized by a molecular signature that may contribute to the increased rate of autoimmunity associated with this condition.


Assuntos
Complexo CD3/genética , Imunomodulação , Mutação , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/metabolismo , Biomarcadores , Complexo CD3/metabolismo , Expressão Gênica , Humanos , Imunofenotipagem , Ativação Linfocitária/imunologia , Complexos Multiproteicos/metabolismo , Ligação Proteica , Receptores de Antígenos de Linfócitos T/metabolismo
9.
Psychol Serv ; 13(3): 292-299, 2016 08.
Artigo em Inglês | MEDLINE | ID: mdl-27195530

RESUMO

Interest in animal assisted interventions (AAI) has grown over the years, but acceptance of AAI by the clinical and research community has been hampered by safety, hygiene, and logistical concerns. Advances in the field of social robotics have provided a promising route to deliver AAI while avoiding these aforementioned obstacles. Although there has been promising initial research on social robotics in older adults, to date there has been no such research conducted with a veteran population. The present pilot study followed 23 veteran residents of a Veterans Affairs (VA) geropsychiatric long-term care facility over the span of approximately a year and a half. It was found that use of Paro, a social robot, resulted in increased observed positive affective and behavioral indicators, with concomitant decreases observed in negative affective and behavioral indicators. The authors concluded that Paro is likely an effective nonpharmacological approach for managing dementia-related mood and behavior problems with veterans in VA long term care facilities. They additionally observed that Paro is best presented to residents who are relatively calm and approachable, as opposed to actively exhibiting behavior or mood problems. Future research directions are discussed in light of both the positive results noted and the inherent limitations of our pilot study. (PsycINFO Database Record


Assuntos
Doença de Alzheimer/psicologia , Doença de Alzheimer/terapia , Assistência de Longa Duração/métodos , Transtornos Mentais/psicologia , Transtornos Mentais/terapia , Reforço Social , Robótica/métodos , Terapia Assistida por Computador/métodos , Veteranos/psicologia , Afeto , Idoso , Seguimentos , Humanos , Masculino , Aceitação pelo Paciente de Cuidados de Saúde/psicologia , Projetos Piloto , Comportamento Social
10.
Curr Allergy Asthma Rep ; 16(4): 25, 2016 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-26922433

RESUMO

Food allergy is a potentially life-threatening disease which affects up to 8% of children and 2-3% of adults. Increasing food allergy prevalence poses a major public health concern. Induction of desensitization to food allergens through oral immunotherapy (OIT) is an expanding area of study encompassing peanut, egg, milk, and other food allergens. OIT consists of administering incremental doses of food allergen to food-allergic patients, to induce a state of desensitization. Safety, tolerability, and efficacy all remain ongoing concerns. Clinical trials for oral immunotherapy have encompassed many variations, including differences in dosage sizes and frequency, duration of build-up, type of allergen used, patient characteristics, and adjuvant therapies. Consequently, studies have also shown variation in rates of adverse effects, and successful desensitization. Here, we provide an overview of the key studies and discuss the implications of this heterogeneity. While desensitization is successful in the majority of patients, only a minority appear to develop sustained unresponsiveness even after years of therapy. Much larger and longitudinal studies using more homogenous protocols are needed in order to evaluate the clinical applicability of OIT, its long-term effectiveness, and effect on quality of life. The role of adjunctive therapies, including omalizumab and probiotics, requires further evaluation.


Assuntos
Alérgenos/administração & dosagem , Dessensibilização Imunológica/métodos , Hipersensibilidade Alimentar/terapia , Administração Oral , Ensaios Clínicos como Assunto , Dessensibilização Imunológica/tendências , Humanos , Omalizumab
11.
J Allergy Clin Immunol ; 137(3): 879-88.e2, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-26476480

RESUMO

BACKGROUND: Coronin-1A (CORO1A) is a regulator of actin dynamics important for T-cell homeostasis. CORO1A deficiency causes T(-)B(+) natural killer-positive severe combined immunodeficiency or T-cell lymphopenia with severe viral infections. However, because all known human mutations in CORO1A abrogate protein expression, the role of the protein's functional domains in host immunity is unknown. OBJECTIVE: We sought to identify the cause of the primary immunodeficiency in 2 young adult siblings with a history of disseminated varicella, cutaneous warts, and CD4(+) T-cell lymphopenia. METHODS: We performed immunologic, genetic, and biochemical studies in the patients, family members, and healthy control subjects. RESULTS: Both patients had CD4(+) T-cell lymphopenia and decreased lymphocyte proliferation to mitogens. IgG, IgM, IgA, and specific antibody responses were normal. Whole-genome sequencing identified a homozygous frameshift mutation in CORO1A disrupting the last 2 C-terminal domains by replacing 61 amino acids with a novel 91-amino-acid sequence. The CORO1A(S401fs) mutant was expressed in the patients' lymphocytes at a level comparable with that of wild-type CORO1A in normal lymphocytes but did not oligomerize and had impaired cytoskeletal association. CORO1A(S401fs) was associated with increased filamentous actin accumulation in T cells, severely defective thymic output, and impaired T-cell survival but normal calcium flux and cytotoxicity, demonstrating the importance of CORO1A oligomerization and subcellular localization in T-cell homeostasis. CONCLUSIONS: We describe a truncating mutation in CORO1A that permits protein expression and survival into young adulthood. Our studies demonstrate the importance of intact CORO1A C-terminal domains in thymic egress and T-cell survival, as well as in defense against viral pathogens.


Assuntos
Citoesqueleto/metabolismo , Homozigoto , Proteínas dos Microfilamentos/genética , Mutação , Multimerização Proteica , Viroses/etiologia , Viroses/metabolismo , Actinas/química , Actinas/metabolismo , Adolescente , Animais , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/metabolismo , Degranulação Celular/genética , Degranulação Celular/imunologia , Sobrevivência Celular/genética , Análise Mutacional de DNA , Feminino , Mutação da Fase de Leitura , Humanos , Imunoglobulinas/sangue , Imunoglobulinas/imunologia , Contagem de Linfócitos , Linfopenia , Masculino , Camundongos , Proteínas dos Microfilamentos/química , Proteínas dos Microfilamentos/metabolismo , Linhagem , Fenótipo , Multimerização Proteica/genética , Transporte Proteico , Irmãos , Transdução de Sinais , Dermatopatias/patologia , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo , Viroses/diagnóstico , Verrugas/patologia
12.
J Clin Invest ; 125(11): 4135-48, 2015 Nov 02.
Artigo em Inglês | MEDLINE | ID: mdl-26457731

RESUMO

Patients with mutations of the recombination-activating genes (RAG) present with diverse clinical phenotypes, including severe combined immune deficiency (SCID), autoimmunity, and inflammation. However, the incidence and extent of immune dysregulation in RAG-dependent immunodeficiency have not been studied in detail. Here, we have demonstrated that patients with hypomorphic RAG mutations, especially those with delayed-onset combined immune deficiency and granulomatous/autoimmune manifestations (CID-G/AI), produce a broad spectrum of autoantibodies. Neutralizing anti-IFN-α or anti-IFN-ω antibodies were present at detectable levels in patients with CID-G/AI who had a history of severe viral infections. As this autoantibody profile is not observed in a wide range of other primary immunodeficiencies, we hypothesized that recurrent or chronic viral infections may precipitate or aggravate immune dysregulation in RAG-deficient hosts. We repeatedly challenged Rag1S723C/S723C mice, which serve as a model of leaky SCID, with agonists of the virus-recognizing receptors TLR3/MDA5, TLR7/-8, and TLR9 and found that this treatment elicits autoantibody production. Altogether, our data demonstrate that immune dysregulation is an integral aspect of RAG-associated immunodeficiency and indicate that environmental triggers may modulate the phenotypic expression of autoimmune manifestations.


Assuntos
Autoanticorpos/imunologia , Autoantígenos/imunologia , Doenças Autoimunes/imunologia , Citocinas/imunologia , Proteínas de Ligação a DNA/deficiência , Doença Granulomatosa Crônica/imunologia , Proteínas de Homeodomínio/imunologia , Proteínas Nucleares/deficiência , Imunodeficiência Combinada Severa/imunologia , Adolescente , Adulto , Animais , Anticorpos Neutralizantes/sangue , Anticorpos Neutralizantes/imunologia , Especificidade de Anticorpos , Autoanticorpos/sangue , Doenças Autoimunes/genética , Criança , Pré-Escolar , RNA Helicases DEAD-box/imunologia , Proteínas de Ligação a DNA/genética , Modelos Animais de Doenças , Feminino , Doença Granulomatosa Crônica/genética , Doença Granulomatosa Crônica/terapia , Proteínas de Homeodomínio/genética , Humanos , Lactente , Helicase IFIH1 Induzida por Interferon , Masculino , Camundongos , Camundongos Endogâmicos , Proteínas Nucleares/genética , Imunodeficiência Combinada Severa/genética , Imunodeficiência Combinada Severa/terapia , Receptores Toll-Like/agonistas , Receptores Toll-Like/imunologia , Viroses/imunologia , Adulto Jovem
14.
J Exp Med ; 211(5): 929-42, 2014 May 05.
Artigo em Inglês | MEDLINE | ID: mdl-24752297

RESUMO

Lrrc8a is a ubiquitously expressed gene that encodes a leucine-rich repeat (LRR)-containing protein detected at higher levels on the surface of thymocytes than on other immune cells. We generated Lrrc8a(-/-) mice to investigate the role of LRRC8A in lymphocyte development and function. Lrrc8a(-/-) mice had increased prenatal and postnatal mortality, growth retardation, and multiple tissue abnormalities. Lrrc8a(-/-) mice displayed a modest block in B cell development but intact intrinsic B cell function. In contrast, both Lrrc8a(-/-) mice and Lrrc8a(-/-)→Rag2(-/-) bone marrow chimeras exhibited a severe cell-intrinsic block in early thymic development, with decreased proliferation and increased apoptosis of thymocytes, and impaired peripheral T cell function. Thymic epithelial cells expressed an LRRC8A ligand that was critical for double-negative to double-positive thymocyte differentiation and survival in vitro. LRRC8A constitutively associated with the GRB2-GAB2 complex and lymphocyte-specific protein tyrosine kinase (LCK) in thymocytes. LRRC8A ligation activated AKT via the LCK-ZAP-70-GAB2-PI3K pathway, and AKT phosphorylation was markedly reduced in the thymus of Lrrc8a(-/-) mice. These findings reveal an essential role for LRRC8A in T cell development, survival, and function.


Assuntos
Diferenciação Celular/imunologia , Proteínas de Membrana/imunologia , Linfócitos T/fisiologia , Timócitos/imunologia , Análise de Variância , Animais , Anticorpos Monoclonais , Proteínas de Ligação a DNA/genética , Citometria de Fluxo , Immunoblotting , Imuno-Histoquímica , Proteínas de Membrana/genética , Camundongos , Camundongos Knockout , Microscopia de Fluorescência , Fosforilação , Proteínas Proto-Oncogênicas c-akt/metabolismo , Reação em Cadeia da Polimerase em Tempo Real , Timócitos/metabolismo
16.
J Immunol ; 175(10): 6481-8, 2005 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-16272302

RESUMO

Vaccinia virus (VV), currently used in humans as a live vaccine for smallpox, can interfere with host immunity via several discrete mechanisms. In this study, the effect of VV on MHC class II-mediated Ag presentation was investigated. Following VV infection, the ability of professional and nonprofessional APC to present Ag and peptides to CD4+ T cells was impaired. Viral inhibition of class II Ag presentation could be detected within 1 h, with diminished T cell responses dependent upon the duration of APC infection and virus titer. Exposure of APC to replication-deficient virus also diminished class II Ag presentation. Virus infection of APC perturbed Ag presentation by newly synthesized and recycling class II molecules, with disruptions in both exogenous and cytoplasmic Ag presentation. Virus-driven expression of an endogenous Ag, failed to restore T cell responsiveness specific for this Ag in the context of MHC class II molecules. Yet, both class II protein steady-state and cell surface expression were not altered by VV. Biochemical and functional analysis revealed that VV infection directly interfered with ligand binding to class II molecules. Together, these observations suggest that disruption of MHC class II-mediated Ag presentation may be one of multiple strategies VV has evolved to escape host immune surveillance.


Assuntos
Apresentação do Antígeno , Antígenos de Histocompatibilidade Classe II/metabolismo , Vírus Vaccinia/imunologia , Animais , Células Apresentadoras de Antígenos/imunologia , Células Apresentadoras de Antígenos/virologia , Linfócitos B/imunologia , Linfócitos B/virologia , Sequência de Bases , Linfócitos T CD4-Positivos/imunologia , Linhagem Celular , DNA Complementar/genética , Glutamato Descarboxilase/genética , Glutamato Descarboxilase/imunologia , Humanos , Proteínas Recombinantes/genética , Proteínas Recombinantes/imunologia , Transdução de Sinais/imunologia , Vírus Vaccinia/genética
17.
J Immunol ; 174(3): 1222-9, 2005 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-15661876

RESUMO

Dendritic cells (DC) are professional APCs that play a critical role in regulating immunity. In DC, maturation-induced changes in MHC class II expression and Ag presentation require transcriptional regulation by CIITA. To study the role of CIITA in DC, we evaluated key cell functions in DC from CIITA-deficient (CIITA(-/-)) mice. The ability to take up Ag, measured by fluid phase endocytosis, was comparable between CIITA(-/-) and control DC. Although CIITA(-/-) DC lack MHC class II, they maintained normal expression of costimulatory molecules CD80, CD86, and CD40. In contrast, CIITA(-/-) DC activated with LPS or CpG expressed increased IL-10 levels, but normal levels of TNF-alpha and IL-12 relative to control. Enhanced IL-10 was due to greater IL-10 mRNA in CIITA(-/-) DC. Abeta(-/-) DC, which lack MHC class II but express CIITA normally, had exhibited no difference in IL-10 compared with control. When CIITA was cotransfected with an IL-10 promoter-reporter into a mouse monocyte cell line, RAW 264.7, IL-10 promoter activity was decreased. In addition, reintroducing CIITA into CIITA(-/-) DC reduced production of IL-10. In all, these data suggest that CIITA negatively regulates expression of IL-10, and that CIITA may direct DC function in ways that extend beyond control of MHC class II.


Assuntos
Células Dendríticas/imunologia , Células Dendríticas/metabolismo , Fluoresceína-5-Isotiocianato/análogos & derivados , Antígenos de Histocompatibilidade Classe II/fisiologia , Interleucina-10/biossíntese , Proteínas Nucleares/deficiência , Proteínas Nucleares/genética , Transativadores/deficiência , Transativadores/genética , Regulação para Cima/genética , Regulação para Cima/imunologia , Animais , Subpopulações de Linfócitos B/imunologia , Subpopulações de Linfócitos B/metabolismo , Biomarcadores/metabolismo , Células da Medula Óssea/imunologia , Células da Medula Óssea/metabolismo , Membrana Celular/genética , Membrana Celular/imunologia , Membrana Celular/metabolismo , Células Cultivadas , Ilhas de CpG/imunologia , Citocinas/biossíntese , Dextranos/imunologia , Dextranos/metabolismo , Regulação para Baixo/genética , Regulação para Baixo/imunologia , Fluoresceína-5-Isotiocianato/metabolismo , Antígenos de Histocompatibilidade Classe II/genética , Interleucina-10/antagonistas & inibidores , Interleucina-10/genética , Lipopolissacarídeos/farmacologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Regiões Promotoras Genéticas/imunologia , Retroviridae/genética , Retroviridae/imunologia , Baço/citologia , Baço/imunologia , Baço/metabolismo , Transdução Genética/métodos
18.
J Immunol ; 172(9): 5528-34, 2004 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-15100295

RESUMO

The aspartic proteinase cathepsin E (CatE) has been implicated in Ag processing. In this study we report that CatE expression is negatively regulated by the MHC class II transactivator (CIITA). CIITA-deficient murine and human B cells expressed greater CatE than wild-type B cells, whereas overexpression of CIITA in a human gastric carcinoma cell line, AGS, resulted in decreased CatE mRNA and protein. AGS cells expressing CIITA also exhibited decreased processing of OVA Ag. Inhibition of CatE expression is specific to the type III CIITA isoform and maps to the acidic and proline/serine/threonine-rich (PST) protein domains of CIITA. We found that CatE expression is inducible by PU.1 and p300, and that this induction can be reversed by CIITA. These findings demonstrate a novel phenomenon: regulation of CatE Ag processing by CIITA in an isoform-dependent manner.


Assuntos
Catepsina E/biossíntese , Proteínas Nucleares/fisiologia , Transativadores/fisiologia , Animais , Apresentação do Antígeno/genética , Apresentação do Antígeno/imunologia , Catepsina E/antagonistas & inibidores , Catepsina E/genética , Linhagem Celular , Linhagem Celular Transformada , Linhagem Celular Tumoral , Regulação para Baixo/genética , Proteína p300 Associada a E1A , Precursores Enzimáticos/antagonistas & inibidores , Precursores Enzimáticos/genética , Repressão Enzimática , Genes Supressores de Tumor , Humanos , Isoenzimas/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteínas Nucleares/antagonistas & inibidores , Proteínas Nucleares/deficiência , Proteínas Nucleares/genética , Proteínas Nucleares/farmacologia , Ovalbumina/imunologia , Ovalbumina/metabolismo , Fragmentos de Peptídeos/fisiologia , Proteínas Proto-Oncogênicas/antagonistas & inibidores , Proteínas Proto-Oncogênicas/farmacologia , RNA Mensageiro/biossíntese , Transativadores/antagonistas & inibidores , Transativadores/deficiência , Transativadores/genética , Transativadores/farmacologia , Transfecção , Regulação para Cima/genética
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