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1.
Clin Immunol ; : 108311, 2019 Nov 21.
Artigo em Inglês | MEDLINE | ID: mdl-31760094

RESUMO

Activated PI3Kδ syndrome (APDS) Type I results from gain-of-function mutations in PIK3CD, which encodes the p110δ subunit of PI3Kδ. Abnormal actin dynamics have been hypothesized to contribute to the lymphopenia associated with this disease but have not been studied in patients with APDS. We report a patient with APDS who had widespread necrotic skin lesions that were responsive specifically to immunosuppressive therapy. EBV-transformed lymphoblastoid cells (EBV-LCLs) from patients with APDS exhibit increased polymerized actin and increased apoptosis, suggesting a contribution of impaired actin dynamics to this disease.

2.
Clin Immunol ; 207: 40-42, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31301515

RESUMO

Mutations in MYD88 cause susceptibility to invasive bacterial infections through impaired signaling downstream of toll-like receptors (TLRs) and IL-1 receptors. We studied a patient presenting with neutropenia, delayed umbilical cord separation, BCG adenitis, andP. aeruginosapneumonia. Next-generation DNA sequencing identified a novel homozygous truncation mutation in MYD88 that abolishes MyD88 expression. The patient's dermal fibroblasts had severely impaired IL-6 production after stimulation with ligands for the MyD88-dependent receptors TLR2, TLR4 and IL-1R, while responses to ligands for the MyD88-independent receptors TLR3 and TNF-α were preserved. Notably, secretion of TNF-α, which is essential for BCG control, was also impaired after LPS stimulation. In this first report of BCG infection in MyD88 deficiency, data suggest that MyD88-dependent TNF-α production contributes to control of mycobacterial disease.

5.
Immunity ; 50(5): 1262-1275.e4, 2019 05 21.
Artigo em Inglês | MEDLINE | ID: mdl-31027995

RESUMO

Mast cell (MC) mediator release after crosslinking of surface-bound IgE antibody by ingested antigen underlies food allergy. However, IgE antibodies are not uniformly associated with food allergy, and intestinal MC load is an important determinant. Atopic dermatitis (AD), characterized by pruritis and cutaneous sensitization to allergens, including foods, is strongly associated with food allergy. Tape stripping mouse skin, a surrogate for scratching, caused expansion and activation of small intestinal MCs, increased intestinal permeability, and promoted food anaphylaxis in sensitized mice. Tape stripping caused keratinocytes to systemically release interleukin-33 (IL-33), which synergized with intestinal tuft-cell-derived IL-25 to drive the expansion and activation of intestinal type-2 innate lymphoid cells (ILC2s). These provided IL-4, which targeted MCs to expand in the intestine. Duodenal MCs were expanded in AD. In addition to promoting cutaneous sensitization to foods, scratching may promote food anaphylaxis in AD by expanding and activating intestinal MCs.


Assuntos
Dermatite Atópica/imunologia , Hipersensibilidade Alimentar/imunologia , Mucosa Intestinal/imunologia , Linfócitos/imunologia , Mastócitos/imunologia , Adolescente , Anafilaxia/imunologia , Animais , Proliferação de Células , Criança , Pré-Escolar , Feminino , Humanos , Imunoglobulina E/imunologia , Interleucina-13/metabolismo , Interleucina-33/metabolismo , Interleucina-4/metabolismo , Interleucinas/metabolismo , Mucosa Intestinal/citologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Transdução de Sinais/imunologia , Pele/imunologia , Pele/lesões
7.
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.

10.
J Allergy Clin Immunol ; 144(2): 574-583.e5, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30872117

RESUMO

BACKGROUND: The tumor TNF receptor family member 4-1BB (CD137) is encoded by TNFRSF9 and expressed on activated T cells. 4-1BB provides a costimulatory signal that enhances CD8+ T-cell survival, cytotoxicity, and mitochondrial activity, thereby promoting immunity against viruses and tumors. The ligand for 4-1BB is expressed on antigen-presenting cells and EBV-transformed B cells. OBJECTIVE: We investigated the genetic basis of recurrent sinopulmonary infections, persistent EBV viremia, and EBV-induced lymphoproliferation in 2 unrelated patients. METHODS: Whole-exome sequencing, immunoblotting, immunophenotyping, and in vitro assays of lymphocyte and mitochondrial function were performed. RESULTS: The 2 patients shared a homozygous G109S missense mutation in 4-1BB that abolished protein expression and ligand binding. The patients' CD8+ T cells had reduced proliferation, impaired expression of IFN-γ and perforin, and diminished cytotoxicity against allogeneic and HLA-matched EBV-B cells. Mitochondrial biogenesis, membrane potential, and function were significantly reduced in the patients' activated T cells. An inhibitory antibody against 4-1BB recapitulated the patients' defective CD8+ T-cell activation and cytotoxicity against EBV-infected B cells in vitro. CONCLUSION: This novel immunodeficiency demonstrates the critical role of 4-1BB costimulation in host immunity against EBV infection.

12.
J Allergy Clin Immunol ; 143(3): 894-913, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30639346

RESUMO

Atopic dermatitis (AD) affects up to 20% of children worldwide and is an increasing public health problem, particularly in developed countries. Although AD in infants and young children can resolve, there is a well-recognized increased risk of sequential progression from AD to other atopic diseases, including food allergy (FA), allergic rhinitis, allergic asthma, and allergic rhinoconjunctivitis, a process referred to as the atopic march. The mechanisms underlying the development of AD and subsequent progression to other atopic comorbidities, particularly FA, are incompletely understood and the subject of intense investigation. Other major research objectives are the development of effective strategies to prevent AD and FA, as well as therapeutic interventions to inhibit the atopic march. In 2017, the Division of Allergy, Immunology, and Transplantation of the National Institute of Allergy and Infectious Diseases sponsored a workshop to discuss current understanding and important advances in these research areas and to identify gaps in knowledge and future research directions. International and national experts in the field were joined by representatives from several National Institutes of Health institutes. Summaries of workshop presentations, key conclusions, and recommendations are presented herein.

13.
Immunol Rev ; 287(1): 121-134, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30565251

RESUMO

The identification of patients with monogenic gene defects have illuminated the function of different proteins in the immune system, including proteins that regulate the actin cytoskeleton. Many of these actin regulatory proteins are exclusively expressed in leukocytes and regulate the formation and branching of actin filaments. Their absence or abnormal function leads to defects in immune cell shape, cellular projections, migration, and signaling. Through the study of patients' mutations and generation of mouse models that recapitulate the patients' phenotypes, our laboratory and others have gained a better understanding of the role these proteins play in cell biology and the underlying pathogenesis of immunodeficiencies and immune dysregulatory syndromes.


Assuntos
Citoesqueleto de Actina/metabolismo , Síndromes de Imunodeficiência/genética , Proteínas dos Microfilamentos/genética , Mutação/genética , Citoesqueleto de Actina/genética , Animais , Movimento Celular/genética , Extensões da Superfície Celular/genética , Modelos Animais de Doenças , Humanos , Síndromes de Imunodeficiência/imunologia , Camundongos , Fenótipo , Transdução de Sinais/genética
14.
Artigo em Inglês | MEDLINE | ID: mdl-30391550

RESUMO

BACKGROUND: Biallelic variations in the DOCK8 gene cause a combined immunodeficiency with eczema, recurrent bacterial and viral infections, and malignancy. Natural disease outcome is dismal, but allogeneic hematopoietic stem cell transplantation (HSCT) can cure the disease. OBJECTIVE: To determine outcome of HSCT for DOCK8 deficiency and define possible outcome variables. METHODS: We performed a retrospective study of the results of HSCT in a large international cohort of DOCK8 deficient patients. RESULTS: We identified 81 patients from 22 centers transplanted at a median age of 9.7 years (range: 0.7-27.2) between 1995 and 2015. After median follow-up of 26 months (3-135), 68 of 81 patients are alive (84%). Severe acute (III-IV) or chronic graft versus host disease (GVHD) occurred in 11% and 10% respectively. Causes of death wereinfections (n=5), GVHD (5), multi-organ failure (2) and pre-existent lymphoma (1). Survival after matched related (n=40) or unrelated (35) HSCT was 89% and 81%, respectively. Reduced toxicity conditioning based on either treosulfan or reduced-dose busulfan resulted in superior survival compared to fully myeloablative busulfan-based regimens (97% vs. 78%; p=0.049). 96% of patients aged <8 years at HSCT survived, compared to 78% of those ≥8 years (p=0.06). Of 73 patients with chimerism data available, 65 (89%) had >90% donor T-cell chimerism at last follow-up. Not all disease manifestations responded equally well to HSCT: eczema, infections and Mollusca resolved better than food allergies or failure to thrive. CONCLUSION: HSCT is curative in most DOCK8 deficient patients, confirming this approach as the treatment of choice. HSCT using a reduced toxicity regimen may offer the best chance for survival.

17.
Artigo em Inglês | MEDLINE | ID: mdl-30240702

RESUMO

BACKGROUND: Atopic dermatitis (AD) is associated with epidermal barrier defects, dysbiosis, and skin injury caused by scratching. In particular, the barrier-defective epidermis in patients with AD with loss-of-function filaggrin mutations has increased IL-1α and IL-1ß levels, but the mechanisms by which IL-1α, IL-1ß, or both are induced and whether they contribute to the aberrant skin inflammation in patients with AD is unknown. OBJECTIVE: We sought to determine the mechanisms through which skin injury, dysbiosis, and increased epidermal IL-1α and IL-1ß levels contribute to development of skin inflammation in a mouse model of injury-induced skin inflammation in filaggrin-deficient mice without the matted mutation (ft/ft mice). METHODS: Skin injury of wild-type, ft/ft, and myeloid differentiation primary response gene-88-deficient ft/ft mice was performed, and ensuing skin inflammation was evaluated by using digital photography, histologic analysis, and flow cytometry. IL-1α and IL-1ß protein expression was measured by means of ELISA and visualized by using immunofluorescence and immunoelectron microscopy. Composition of the skin microbiome was determined by using 16S rDNA sequencing. RESULTS: Skin injury of ft/ft mice induced chronic skin inflammation involving dysbiosis-driven intracellular IL-1α release from keratinocytes. IL-1α was necessary and sufficient for skin inflammation in vivo and secreted from keratinocytes by various stimuli in vitro. Topical antibiotics or cohousing of ft/ft mice with unaffected wild-type mice to alter or intermix skin microbiota, respectively, resolved the skin inflammation and restored keratinocyte intracellular IL-1α localization. CONCLUSIONS: Taken together, skin injury, dysbiosis, and filaggrin deficiency triggered keratinocyte intracellular IL-1α release that was sufficient to drive chronic skin inflammation, which has implications for AD pathogenesis and potential therapeutic targets.

18.
Clin Immunol ; 197: 40-44, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30145329

RESUMO

B cell activation by Toll-like receptor 9 (TLR9) ligands is dependent on STAT3 and is important for optimal antibody responses to microbial antigens. B cells from patients with common variable immune deficiency (CVID) have impaired proliferation and differentiation in response to the TLR9 ligand CpG, despite normal levels of TLR9 expression. We demonstrate that CpG-driven STAT3 phosphorylation, but not activation of NFκB and p38, is selectively impaired in B cells from CVID patients. These results suggest that defective STAT3 activation contributes to the defective TLR9 and antibody response of B cells in CVID.

19.
Clin Immunol ; 195: 88-92, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30099194

RESUMO

Mutations in filaggrin are associated with atopic dermatitis. Filaggrin-deficient flaky tail (Flgft/ft) mice develop spontaneous inflammatory skin lesion that wax and wane. We show that loss of MyD88 promotes the persistence of skin lesions in Flgft/ft mice and exaggerates their expression of the Th17-associated cytokines Il7a and Il22. The development and persistence of skin lesions in Flgft/ft mice was independent of the microbiota. MyD88-mediated signals are shown to be important for the accumulation of T regulatory cells (Tregs) in lesional skin of Flgft/ft mice. Adoptive transfer of WT Tregs dampened the severity of skin lesions in MyD88-/-/Flgft/ft mice. These results suggest that MyD88 signaling in Treg cells by endogenous ligands attenuates skin inflammation in filaggrin deficiency.

20.
JCI Insight ; 3(16)2018 Aug 23.
Artigo em Inglês | MEDLINE | ID: mdl-30135305

RESUMO

Ion channel-controlled cell volume regulation is of fundamental significance to the physiological function of sperm. In addition to volume regulation, LRRC8A-dependent volume-regulated anion channel (VRAC) activity is involved in cell cycle progression, insulin signaling, and cisplatin resistance. Nevertheless, the contribution of LRRC8A and its dependent VRAC activity in the germ cell lineage remain unknown. By utilizing a spontaneous Lrrc8a mouse mutation (c.1325delTG, p.F443*) and genetically engineered mouse models, we demonstrate that LRRC8A-dependent VRAC activity is essential for male germ cell development and fertility. Lrrc8a-null male germ cells undergo progressive degeneration independent of the apoptotic pathway during postnatal testicular development. Lrrc8a-deficient mouse sperm exhibit multiple morphological abnormalities of the flagella (MMAF), a feature commonly observed in the sperm of infertile human patients. Importantly, we identified a human patient with a rare LRRC8A hypomorphic mutation (c.1634G>A, p.Arg545His) possibly linked to Sertoli cell-only syndrome (SCOS), a male sterility disorder characterized by the loss of germ cells. Thus, LRRC8A is a critical factor required for germ cell development and volume regulation in the mouse, and it might serve as a novel diagnostic and therapeutic target for SCOS patients.

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