Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 45
Filtrar
1.
J Biol Chem ; 300(5): 107249, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38556084

RESUMO

Tripartite-motif protein-56 (TRIM56) positively regulates the induction of type I interferon response via the TLR3 pathway by enhancing IRF3 activation and depends on its C-terminal residues 621-750 for interacting with the adaptor TRIF. However, the precise underlying mechanism and detailed TRIM56 determinants remain unclear. Herein, we show ectopic expression of murine TRIM56 also enhances TLR3-dependent interferon-ß promoter activation, suggesting functional conservation. We found that endogenous TRIM56 and TRIF formed a complex early (0.5-2 h) after poly-I:C stimulation and that TRIM56 overexpression also promoted activation of NF-κB by poly-I:C but not that by TNF-α or IL-1ß, consistent with a specific effect on TRIF prior to the bifurcation of NF-κB and IRF3. Using transient transfection and Tet-regulated cell lines expressing various TRIM56 mutants, we demonstrated the Coiled-coil domain and a segment spanning residues ∼434-610, but not the B-box or residues 355-433, were required for TRIM56 augmentation of TLR3 signaling. Moreover, alanine substitution at each putative phosphorylation site, Ser471, Ser475, and Ser710, abrogated TRIM56 function. Concordantly, mutants bearing Ser471Ala, Ser475Ala, or Ser710Ala, or lacking the Coiled-coil domain, all lost the capacity to enhance poly-I:C-induced establishment of an antiviral state. Furthermore, the Ser710Ala mutation disrupted the TRIM56-TRIF association. Using phospho-specific antibodies, we detected biphasic phosphorylation of TRIM56 at Ser471 and Ser475 following TLR3 stimulation, with the early phase occurring at ∼0.5 to 1 h, prior to IRF3 phosphorylation. Together, these data reveal novel molecular details critical for the TRIM56 augmentation of TLR3-dependent antiviral response and highlight important roles for TRIM56 scaffolding and phosphorylation.


Assuntos
Proteínas Adaptadoras de Transporte Vesicular , Imunidade Inata , Receptor 3 Toll-Like , Proteínas com Motivo Tripartido , Animais , Humanos , Camundongos , Proteínas Adaptadoras de Transporte Vesicular/metabolismo , Proteínas Adaptadoras de Transporte Vesicular/genética , Proteínas Adaptadoras de Transporte Vesicular/imunologia , Células HEK293 , Fator Regulador 3 de Interferon/metabolismo , Fator Regulador 3 de Interferon/genética , NF-kappa B/metabolismo , Fosforilação , Poli I-C/farmacologia , Domínios Proteicos , Transdução de Sinais , Receptor 3 Toll-Like/metabolismo , Receptor 3 Toll-Like/genética , Proteínas com Motivo Tripartido/metabolismo , Proteínas com Motivo Tripartido/genética , Ubiquitina-Proteína Ligases/metabolismo , Ubiquitina-Proteína Ligases/genética
2.
Cytokine Growth Factor Rev ; 73: 40-51, 2023 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-37419766

RESUMO

B cells play an important role in adaptive immunity and participate in the process of humoral immunity mainly by secreting antibodies. The entire development and differentiation process of B cells occurs in multiple microenvironments and is regulated by a variety of environmental factors and immune signals. Differentiation biases or disfunction of B cells participate in the process of many autoimmune diseases. Emerging studies report the impact of altered metabolism in B cell biology, including lipid metabolism. Here, we discuss how extracellular lipid environment and metabolites, membrane lipid-related components, and lipid synthesis and catabolism programs coordinate B cell biology and describe the crosstalk of lipid metabolic programs with signal transduction pathways and transcription factors. We conclude with a summary of therapeutic targets for B cell lipid metabolism and signaling in autoimmune diseases and discuss important future directions.

3.
Viruses ; 15(2)2023 02 09.
Artigo em Inglês | MEDLINE | ID: mdl-36851695

RESUMO

Females often exhibit superior immune responses compared to males toward vaccines and pathogens such as influenza viruses and SARS-CoV-2. To help explain these differences, we first studied serum immunoglobulin isotype patterns in C57BL/6 male and female mice. We focused on IgG2b, an isotype that lends to virus control and that has been previously shown to be elevated in murine females compared to males. Improvements in IgG2b serum levels, and/or IgG2b ratios with other non-IgM isotypes, were observed when: (i) wildtype (WT) female mice were compared to estrogen receptor knockout mice (IgG2b, IgG2b/IgG3, IgG2b/IgG1, and IgG2b/IgA were all higher in WT mice), (ii) unmanipulated female mice were compared to ovariectomized mice (IgG2b/IgA was higher in unmanipulated animals), (iii) female mice were supplemented with estrogen in the context of an inflammatory insult (IgG2b and IgG2b/IgG3 were improved by estrogen supplementation), and (iv) male mice were supplemented with testosterone, a hormone that can convert to estrogen in vivo (IgG2b, IgG2b/IgG3, IgG2b/IgG1, and IgG2b/IgA were all improved by supplementation). We next examined data from three sets of previously described male and female human blood samples. In each case, there were higher IgG2 levels, and/or ratios of IgG2 with non-IgM isotypes, in human females compared to males. The effects of sex and sex hormones in the mouse and human studies were subtle, but frequent, suggesting that sex hormones represent only a fraction of the factors that influence isotype patterns. Examination of the gene loci suggested that upregulation of murine IgG2b or human IgG2 could be mediated by estrogen receptor binding to estrogen response elements and cytosine-adenine (CA) repeats upstream of respective Cγ genes. Given that murine IgG2b and human IgG2 lend to virus control, the isotype biases in females may be sufficient to improve outcomes following vaccination or infection. Future attention to sex hormone levels, and consequent immunoglobulin isotype patterns, in clinical trials are encouraged to support the optimization of vaccine and drug products for male and female hosts.


Assuntos
COVID-19 , Testosterona , Humanos , Feminino , Masculino , Animais , Camundongos , Camundongos Endogâmicos C57BL , Receptores de Estrogênio , Caracteres Sexuais , SARS-CoV-2 , Imunoglobulina G , Estrogênios , Camundongos Knockout , Imunoglobulina A
4.
Elife ; 112022 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-35775614

RESUMO

Bariatric surgery is a sustainable weight loss approach, including vertical sleeve gastrectomy (VSG). Obesity exacerbates tumor growth, while diet-induced weight loss impairs progression. It remains unknown how bariatric surgery-induced weight loss impacts cancer progression or alters response to therapy. Using a pre-clinical model of obesity followed by VSG or diet-induced weight loss, breast cancer progression and immune checkpoint blockade therapy were investigated. Weight loss by VSG or weight-matched dietary intervention before tumor engraftment protected against obesity-exacerbated tumor progression. However, VSG was not as effective as diet in reducing tumor burden despite achieving similar weight and adiposity loss. Leptin did not associate with changes in tumor burden; however, circulating IL-6 was elevated in VSG mice. Uniquely, VSG tumors displayed elevated inflammation and immune checkpoint ligand PD-L1+ myeloid and non-immune cells. VSG tumors also had reduced T lymphocytes and markers of cytolysis, suggesting an ineffective anti-tumor microenvironment which prompted investigation of immune checkpoint blockade. While obese mice were resistant to immune checkpoint blockade, anti-PD-L1 potently impaired tumor progression after VSG through improved anti-tumor immunity. Thus, in formerly obese mice, surgical weight loss followed by immunotherapy reduced breast cancer burden. Finally, we compared transcriptomic changes in adipose tissue after bariatric surgery from patients and mouse models. A conserved bariatric surgery-associated weight loss signature (BSAS) was identified which significantly associated with decreased tumor volume. Findings demonstrate conserved impacts of obesity and bariatric surgery-induced weight loss pathways associated with breast cancer progression.


As the number of people classified as obese rises globally, so do obesity-related health risks. Studies show that people diagnosed with obesity have inflammation that contributes to tumor growth and their immune system is worse at detecting cancer cells. But weight loss is not currently used as a strategy for preventing or treating cancer. Surgical procedures for weight loss, also known as 'bariatric surgeries', are becoming increasingly popular. Recent studies have shown that individuals who lose weight after these treatments have a reduced risk of developing tumors. But how bariatric surgery directly impacts cancer progression has not been well studied: does it slow tumor growth or boost the anti-tumor immune response? To answer these questions, Sipe et al. compared breast tumor growth in groups of laboratory mice that were obese due to being fed a high fat diet. The first group of mice lost weight after undergoing a bariatric surgery in which part of their stomach was removed. The second lost the same amount of weight but after receiving a restricted diet, and the third underwent a fake surgery and did not lose any weight. The experiments found that surgical weight loss cuts breast cancer tumor growth in half compared with obese mice. But mice who lost the same amount of weight through dietary restrictions had even less tumor growth than surgically treated mice. The surgically treated mice who lost weight had more inflammation than mice in the two other groups, and had increased amounts of proteins and cells that block the immune response to tumors. Giving the surgically treated mice a drug that enhances the immune system's ability to detect and destroy cancer cells reduced inflammation and helped shrink the mice's tumors. Finally, Sipe et al. identified 54 genes which were turned on or off after bariatric surgery in both mice and humans, 11 of which were linked with tumor size. These findings provide crucial new information about how bariatric surgery can impact cancer progression. Future studies could potentially use the conserved genes identified by Sipe et al. to develop new ways to stimulate the anti-cancer benefits of weight loss without surgery.


Assuntos
Cirurgia Bariátrica , Neoplasias , Animais , Cirurgia Bariátrica/efeitos adversos , Gastrectomia/efeitos adversos , Inibidores de Checkpoint Imunológico , Camundongos , Camundongos Obesos , Neoplasias/cirurgia , Obesidade/metabolismo , Redução de Peso
5.
Cell Rep ; 38(10): 110482, 2022 03 08.
Artigo em Inglês | MEDLINE | ID: mdl-35263574

RESUMO

Infection and vaccination repeatedly expose individuals to antigens that are conserved between influenza virus subtypes. Nevertheless, antibodies recognizing variable influenza epitopes greatly outnumber antibodies reactive against conserved epitopes. Elucidating factors contributing to the paucity of broadly reactive influenza antibodies remains a major obstacle for developing a universal influenza vaccine. Here, we report that inducing broadly reactive influenza antibodies increases autoreactive antibodies in humans and mice and exacerbates disease in four distinct models of autoimmune disease. Importantly, transferring broadly reactive influenza antibodies augments disease in the presence of inflammation or autoimmune susceptibility. Further, broadly reactive influenza antibodies spontaneously arise in mice with defects in B cell tolerance. Together, these data suggest that self-tolerance mechanisms limit the prevalence of broadly reactive influenza antibodies, which can exacerbate disease in the context of additional risk factors.


Assuntos
Vacinas contra Influenza , Influenza Humana , Infecções por Orthomyxoviridae , Animais , Anticorpos Neutralizantes , Anticorpos Antivirais , Autoimunidade , Epitopos , Glicoproteínas de Hemaglutininação de Vírus da Influenza , Humanos , Camundongos
6.
Cancer Lett ; 531: 98-108, 2022 04 10.
Artigo em Inglês | MEDLINE | ID: mdl-35074498

RESUMO

Myeloid-derived suppressor cells (MDSCs) are an immature innate cell population that expands in pathological conditions such as cancer and suppresses T cells via production of immunosuppressive factors. Conversely, efficient cytotoxic T cell priming is dependent on the ability of antigen-presenting cells (APCs) to cross-present tumor antigens to CD8+ T cells, a process that requires a specific subtype of dendritic cells (DCs) called conventional DC1 (cDC1) which are often dysfunctional in cancer. One way to activate cDC1 is ligation of CD40 which is abundantly expressed by myeloid cells and its agonism leads to myeloid cell activation. Thus, targeting MDSCs while simultaneously expanding cross-presenting DCs represents a promising strategy that, when combined with agonistic CD40, may result in long-lasting protective immunity. In this study, we investigated the effect of PKC agonists PEP005 and prostratin on MDSC expansion, differentiation, and recruitment to the tumor microenvironment. Our findings demonstrate that PKC agonists decreased MDSC expansion from hematopoietic progenitors and induced M-MDSC differentiation to an APC-like phenotype that expresses cDC1-related markers via activation of the p38 mitogen-activated protein kinase (MAPK) pathway. Simultaneously, PKC agonists favored cDC1 expansion at the expense of cDC2 and plasmacytoid DCs (pDC). Functionally, PKC agonists blunted MDSC suppressive activity and enhanced MDSC cross-priming capacity both in vitro and in vivo. Finally, combination of PKC agonism with agonistic CD40 mAb resulted in a marked reduction in tumor growth with a significant increase in intratumoral activated CD8+ T cells and tissue-resident memory CD8+ T cells in a syngeneic breast cancer mouse model. In sum, this work proposes a novel promising strategy to simultaneously target MDSCs and promote APC function that may have highly impactful clinical relevance in cancer patients.


Assuntos
Neoplasias da Mama , Apresentação Cruzada , Animais , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/metabolismo , Antígenos CD40/metabolismo , Linfócitos T CD8-Positivos , Células Dendríticas , Feminino , Humanos , Imunidade Inata , Camundongos , Microambiente Tumoral
7.
Expert Opin Biol Ther ; 22(4): 499-507, 2022 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-35089116

RESUMO

INTRODUCTION: Medicine stands at the threshold of a new era heralded by the vast potential of cell engineering. Like advances made possible by genetic engineering, current prospects for purposeful control of cell functions through cell engineering may bring breakthroughs in the treatment of previously intractable diseases. AREAS COVERED: Engineering of cytotoxic T cells for expression of chimeric antigen receptors (CARs) instructs them to attack and destroy malignant cells and thus provides an exciting new approach in oncology. A decade of practical experience and first-in-human trials encourage the search for new and broader uses of CAR technology, including in autoimmune diseases. EXPERT OPINION: Systemic lupus erythematosus is an example of a broader category of autoimmune diseases, for which cell engineering will provide a powerful new therapeutic approach. This article describes different types of CAR T cell strategies that will provide new treatment options for patients with autoimmune diseases and replace conventional therapies.


Assuntos
Doenças Autoimunes , Lúpus Eritematoso Sistêmico , Neoplasias , Receptores de Antígenos Quiméricos , Doenças Autoimunes/terapia , Humanos , Imunoterapia , Imunoterapia Adotiva , Lúpus Eritematoso Sistêmico/terapia , Neoplasias/metabolismo , Receptores de Antígenos de Linfócitos T/genética , Receptores de Antígenos de Linfócitos T/metabolismo , Receptores de Antígenos Quiméricos/metabolismo , Linfócitos T
8.
Tohoku J Exp Med ; 255(2): 143-146, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34670919

RESUMO

Antibody deficiency is a type of primary immunodeficiency that often manifests as primary hypogammaglobulinemia, with or without repeated infections. Although primary immunodeficiency appears to be contrary to autoimmunity, they usually occur simultaneously, and the specific pathogenesis remains unknown. We herein describe an adult patient with autoimmune manifestations and recurrent infections. The case was characterized by a sustained decrease in serum immunoglobulin A, accompanied by decreased T lymphocytes, B lymphocytes, monocytes, and platelets in the peripheral blood and the presence of antinuclear and anti-SSA antibodies. Whole-exome sequencing for the patient revealed two spontaneous mutations in GATA2 (c.1084C>T) and STAT5B (c.1924A>C). This case report provides evidence that mutations in the GATA2 and STAT5B genes may be pathogenic in primary immunodeficiency and provides genetic evidence for the possible pathogenesis of primary immunodeficiency with autoimmune symptoms. However, further studies are needed to confirm the causal relationship.


Assuntos
Agamaglobulinemia , Autoimunidade , Agamaglobulinemia/genética , Autoimunidade/genética , Linfócitos B , Fator de Transcrição GATA2/genética , Humanos , Mutação/genética , Fator de Transcrição STAT5/genética , Sequenciamento do Exoma
9.
Cell Rep ; 35(12): 109285, 2021 06 22.
Artigo em Inglês | MEDLINE | ID: mdl-34161764

RESUMO

Immune checkpoint blockade (ICB) has improved outcomes in some cancers. A major limitation of ICB is that most patients fail to respond, which is partly attributable to immunosuppression. Obesity appears to improve immune checkpoint therapies in some cancers, but impacts on breast cancer (BC) remain unknown. In lean and obese mice, tumor progression and immune reprogramming were quantified in BC tumors treated with anti-programmed death-1 (PD-1) or control. Obesity augments tumor incidence and progression. Anti-PD-1 induces regression in lean mice and potently abrogates progression in obese mice. BC primes systemic immunity to be highly responsive to obesity, leading to greater immunosuppression, which may explain greater anti-PD-1 efficacy. Anti-PD-1 significantly reinvigorates antitumor immunity despite persistent obesity. Laminin subunit beta-2 (Lamb2), downregulated by anti-PD-1, significantly predicts patient survival. Lastly, a microbial signature associated with anti-PD-1 efficacy is identified. Thus, anti-PD-1 is highly efficacious in obese mice by reinvigorating durable antitumor immunity. VIDEO ABSTRACT.


Assuntos
Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/imunologia , Inibidores de Checkpoint Imunológico/uso terapêutico , Obesidade/complicações , Microambiente Tumoral/imunologia , Animais , Neoplasias da Mama/complicações , Neoplasias da Mama/genética , Progressão da Doença , Feminino , Microbioma Gastrointestinal , Humanos , Inibidores de Checkpoint Imunológico/farmacologia , Terapia de Imunossupressão , Imunoterapia , Linfócitos do Interstício Tumoral/imunologia , Macrófagos/metabolismo , Camundongos Endogâmicos C57BL , Células Supressoras Mieloides/metabolismo , Receptor de Morte Celular Programada 1/metabolismo , Receptores de Estrogênio/metabolismo , Baço/patologia , Carga Tumoral , Microambiente Tumoral/efeitos dos fármacos
10.
J Autoimmun ; 116: 102564, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33203617

RESUMO

Gut dysbiosis precedes clinic symptoms in rheumatoid arthritis (RA) and has been implicated in the initiation and persistence of RA. The early treatment of RA is critical to better clinical outcome especially for joint destruction. Although dietary interventions have been reported to be beneficial for RA patients, it is unclear to whether diet-induced gut microbiome changes can be a preventive strategy to RA development. Here, we investigated the effect of a high fiber diet (HFD) rich with resistant starch (RS) on collagen-induced arthritis (CIA) and gut microbial composition in mice. RS-HFD significantly reduced arthritis severity and bone erosion in CIA mice. The therapeutic effects of RS-HFD were correlated with splenic regulatory T cell (Treg) expansion and serum interleukin-10 (IL-10) increase. The increased abundance of Lactobacillus and Lachnoclostridium genera concomitant with CIA were eliminated in CIA mice fed the RS-HFD diet. Notably, RS-HFD also led to a predominance of Bacteroidetes, and increased abundances of Lachnospiraceae_NK4A136_group and Bacteroidales_S24-7_group genera in CIA mice. Accompanied with the gut microbiome changes, serum levels of the short-chain fatty acid (SCFA) acetate, propionate and isobutyrate detected by GC-TOFMS were also increased in CIA mice fed RS-HFD. While, addition of ß-acids from hops extract to the drinking water of mice fed RS-HFD significantly decreased serum propionate and completely eliminated RS-HFD-induced disease improvement, Treg cell increase and IL-10 production in CIA mice. Moreover, exogenous propionate added to drinking water replicated the protective role of RS-HFD in CIA including reduced bone damage. The direct effect of propionate on T cells in vitro was further explored as at least one mechanistic explanation for the dietary effects of microbial metabolites on immune regulation in experimental RA. Taken together, RS-HFD significantly reduced CIA and bone damage and altered gut microbial composition with concomitant increase in circulating propionate, indicating that RS-rich diet might be a promising therapy especially in the early stage of RA.


Assuntos
Artrite Experimental/prevenção & controle , Dieta Hiperlipídica , Modelos Animais de Doenças , Microbioma Gastrointestinal/efeitos dos fármacos , Propionatos/metabolismo , Amido Resistente/administração & dosagem , Animais , Artrite Experimental/sangue , Artrite Experimental/metabolismo , Bactérias/classificação , Bactérias/genética , Proliferação de Células/efeitos dos fármacos , Citocinas/sangue , Ácidos Graxos Voláteis/sangue , Microbioma Gastrointestinal/genética , Humanos , Interleucina-10/sangue , Intestinos/efeitos dos fármacos , Intestinos/imunologia , Intestinos/microbiologia , Masculino , Camundongos Endogâmicos DBA , RNA Ribossômico 16S/genética , Análise de Sequência de DNA , Linfócitos T Reguladores/citologia , Linfócitos T Reguladores/efeitos dos fármacos
11.
BMC Pulm Med ; 20(1): 218, 2020 Aug 14.
Artigo em Inglês | MEDLINE | ID: mdl-32795329

RESUMO

BACKGROUND: This study was undertaken in an attempt to characterize the frequency and clinical features of lung nodules in IgG4 related disease (IgG4-RD) patients as an insight for help with the diagnosis of lung nodules. METHODS: A retrospective study was carried out in West China Hospital, Sichuan University from January 2012 to December 2018, 89 patients with definite IgG4-RD were enrolled. RESULTS: Fifty of 89 patients with definite IgG4-RD had radiologically confirmed lung nodules, 6 of whom were diagnosed with definite IgG4 related lung disease. Lung nodules detected in more than 40 patients were small and solid, always with regular margins. Multiple (41/50) and bilateral (34/50) distributions was also a major characteristic of these lung nodules. Lobulation and speculation were simultaneously detected in 3 patients, including 2 patients combined with pleural indentation. Calcification of nodules was detected in only one patient. Thirty-seven patients also had additional radiological abnormalities of lungs, including ground-glass opacity (21/50), thickening of pleura (9/50), thickening of interlobular septa (4/50), thickening of bronchial wall (3/50), pleural effusion (4/50), mass (3/50), interstitial changes (5/50), and mediastinal or hilar lymphadenopathy (32/50). Most patients (44/50) were treated with glucocorticoids alone or combined with immunosuppressive agents. Sixteen patients received a re-examination by chest computed tomography (CT) scan after treatment, 10 of whom showed a decrease in the size and/or the number of nodules. CONCLUSIONS: The incidence of lung nodules in IgG4-RD patients can be high. For an IgG4-RD patient with lung nodules, the possibility that the lung nodules related to IgG4-RLD is high. It is hard to differentiate IgG4 related lung nodules from other lung diseases, in particular, lung cancer. Radiological characteristics and positive responses to glucocorticoids and immunosuppressive agents can help with the differential diagnosis. For these patients, regular follow-up is also important.


Assuntos
Brônquios/patologia , Doença Relacionada a Imunoglobulina G4/complicações , Pneumopatias/diagnóstico , Linfadenopatia/diagnóstico , Mediastino/patologia , Adulto , China , Feminino , Glucocorticoides/uso terapêutico , Humanos , Doença Relacionada a Imunoglobulina G4/tratamento farmacológico , Imunossupressores/uso terapêutico , Pneumopatias/patologia , Linfadenopatia/patologia , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Tomografia Computadorizada por Raios X
12.
Int J Mol Sci ; 21(15)2020 Aug 04.
Artigo em Inglês | MEDLINE | ID: mdl-32759702

RESUMO

Vitamin A is an important regulator of immune protection, but it is often overlooked in studies of infectious disease. Vitamin A binds an array of nuclear receptors (e.g., retinoic acid receptor, peroxisome proliferator-activated receptor, retinoid X receptor) and influences the barrier and immune cells responsible for pathogen control. Children and adults in developed and developing countries are often vitamin A-deficient or insufficient, characteristics associated with poor health outcomes. To gain a better understanding of the protective mechanisms influenced by vitamin A, we examined immune factors and epithelial barriers in vitamin A deficient (VAD) mice, vitamin D deficient (VDD) mice, double deficient (VAD+VDD) mice, and mice on a vitamin-replete diet (controls). Some mice received insults, including intraperitoneal injections with complete and incomplete Freund's adjuvant (emulsified with PBS alone or with DNA + Fus-1 peptide) or intranasal inoculations with Sendai virus (SeV). Both before and after insults, the VAD and VAD+VDD mice exhibited abnormal serum immunoglobulin isotypes (e.g., elevated IgG2b levels, particularly in males) and cytokine/chemokine patterns (e.g., elevated eotaxin). Even without insult, when the VAD and VAD+VDD mice reached 3-6 months of age, they frequently exhibited opportunistic ascending bacterial urinary tract infections. There were high frequencies of nephropathy (squamous cell hyperplasia of the renal urothelium, renal scarring, and ascending pyelonephritis) and death in the VAD and VAD+VDD mice. When younger VAD mice were infected with SeV, the predominant lesion was squamous cell metaplasia of respiratory epithelium in lungs and bronchioles. Results highlight a critical role for vitamin A in the maintenance of healthy immune responses, epithelial cell integrity, and pathogen control.


Assuntos
Deficiência de Vitamina A/genética , Vitamina A/genética , Deficiência de Vitamina D/genética , Vitamina D/genética , Animais , Doenças Transmissíveis/genética , Doenças Transmissíveis/imunologia , Doenças Transmissíveis/metabolismo , Morte , Modelos Animais de Doenças , Humanos , Imunoglobulinas/genética , Imunoglobulinas/imunologia , Camundongos , Camundongos Knockout , Neoplasias de Células Escamosas/genética , Neoplasias de Células Escamosas/imunologia , Neoplasias de Células Escamosas/metabolismo , Proteínas Supressoras de Tumor/genética , Vitamina A/metabolismo , Deficiência de Vitamina A/imunologia , Deficiência de Vitamina A/metabolismo , Vitamina D/metabolismo , Deficiência de Vitamina D/imunologia , Deficiência de Vitamina D/metabolismo
13.
Medicine (Baltimore) ; 99(25): e20057, 2020 Jun 19.
Artigo em Inglês | MEDLINE | ID: mdl-32569156

RESUMO

INTRODUCTION: Gout is a worldwide chronic disease generally caused by high serum levels of uric acid. Using whole exome sequencing, we aimed to explore genetic alterations in hereditary gout. PATIENTS' CONCERNS: There were 9 direct descendants diagnosed with gout in total in this family. The patients concerned about the high incidence and inheritance of gout. DIAGNOSIS: The youngest propositus was diagnosed as gout in our hospital. Diagnoses of other patients in this family were made on the foundation of history and clinical tests. INTERVENTIONS: Six direct descendants and 3 healthy spouses in 1 family were recruited in our study. Whole-exome sequencing was conducted in all participants. OUTCOMES: Whole-exome sequencing and genetic analysis revealed 2 putative rare inherited deleterious variants, which were detected only in direct descendants. Twelve gout and uric acid (UC)-related nucleotide sequence variants previously reported by GWAS were detected among all subjects. CONCLUSIONS: In the case of this family, the GWAS identified gout and UC-related nucleotide sequence variants may increase the risk of developing gout, but penetrance was not complete. The rare sequence variants in low-density lipoprotein receptor-related protein 1 (LRP1) and oncoprotein induced transcript 3 (OIT3) may have contributed to inheritance of gout within the 5 generations of family members in this study.


Assuntos
Gota/genética , Proteína-1 Relacionada a Receptor de Lipoproteína de Baixa Densidade/genética , Proteínas de Membrana/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Sequenciamento do Exoma , Adulto Jovem
14.
Autoimmun Rev ; 19(8): 102530, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32240855

RESUMO

As a gigantic community in the human body, the microbiota exerts pleiotropic roles in human health and disease ranging from digestion and absorption of nutrients from food, defense against infection of pathogens, to regulation of immune system development and immune homeostasis. Recent advances in "omics" studies and bioinformatics analyses have broadened our insights of the microbiota composition of the inner and other surfaces of the body and their interactions with the host. Apart from the direct contact of microbes at the mucosal barrier, metabolites produced or metabolized by the gut microbes can serve as important immune regulators or initiators in a wide variety of diseases, including gastrointestinal diseases, metabolic disorders and systemic rheumatic diseases. This review focuses on the most recent understanding of how the microbiota and metabolites shape rheumatic diseases. Studies that explore the mechanistic interplay between microbes, metabolites and the host could thereby provide clues for novel methods in the diagnosis, therapy, and prevention of rheumatic diseases.


Assuntos
Microbioma Gastrointestinal , Microbiota , Doenças Reumáticas , Homeostase , Humanos , Doenças Reumáticas/microbiologia
15.
Front Cell Dev Biol ; 7: 285, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31799252

RESUMO

Mesenchymal stem cells (MSCs) have a potently immunosuppressive capacity in both innate and adaptive immune responses. Consequently, MSCs transplantation has emerged as a potential beneficial therapy for autoimmune diseases even though the mechanisms underlying the immunomodulatory activity of MSCs is incompletely understood. Transplanted MSCs from healthy individuals with no known history of autoimmune disease are immunosuppressive in systemic lupus erythematosus (SLE) patients and can ameliorate SLE disease symptoms in those same patients. In contrast, autologous MSCs from SLE patients are not immunosuppressive and do not ameliorate disease symptoms. Recent studies have shown that MSCs from SLE patients are dysfunctional in both proliferation and immunoregulation and phenotypically senescent. The senescent phenotype has been attributed to multiple genes and signaling pathways. In this review, we focus on the possible mechanisms for the defective phenotype and function of MSCs from SLE patients and summarize recent research on MSCs in autoimmune diseases.

16.
J Immunol Res ; 2019: 3560180, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30944832

RESUMO

Nanotechnology has become a novel subject with impact in many research and technology areas. Nanoparticles (NPs), as a key component in nanotechnology, are widely used in many areas such as optical, magnetic, electrical, and mechanical engineering. The biomedical and pharmaceutical industries have embraced NPs as a viable drug delivery modality. As such, the potential for NP-induced cytotoxicity has emerged as a major concern for NP drug delivery systems. Thus, it is important to understand how NPs affect the innate immune system. As the most abundant myeloid cell type in innate immune responses, neutrophils are critical for concerns about potentially toxic side effects of NPs. When activated by innate immune stimuli, neutrophils may initiate NETosis to release neutrophil extracellular traps (NETs). Herein, we have reviewed the relationship between NPs and the induction of NETosis and release of NETs.


Assuntos
Armadilhas Extracelulares/efeitos dos fármacos , Imunidade Inata/efeitos dos fármacos , Inflamação , Nanoestruturas/efeitos adversos , Neutrófilos/imunologia , Animais , Sistemas de Liberação de Medicamentos , Humanos , Nanopartículas Metálicas/efeitos adversos , Nanopartículas Metálicas/uso terapêutico , Camundongos , Neutrófilos/efeitos dos fármacos
18.
Sci Transl Med ; 11(482)2019 03 06.
Artigo em Inglês | MEDLINE | ID: mdl-30842314

RESUMO

The failure of anti-CD20 antibody (Rituximab) as therapy for lupus may be attributed to the transient and incomplete B cell depletion achieved in clinical trials. Here, using an alternative approach, we report that complete and sustained CD19+ B cell depletion is a highly effective therapy in lupus models. CD8+ T cells expressing CD19-targeted chimeric antigen receptors (CARs) persistently depleted CD19+ B cells, eliminated autoantibody production, reversed disease manifestations in target organs, and extended life spans well beyond normal in the (NZB × NZW) F1 and MRL fas/fas mouse models of lupus. CAR T cells were active for 1 year in vivo and were enriched in the CD44+CD62L+ T cell subset. Adoptively transferred splenic T cells from CAR T cell-treated mice depleted CD19+ B cells and reduced disease in naive autoimmune mice, indicating that disease control was cell-mediated. Sustained B cell depletion with CD19-targeted CAR T cell immunotherapy is a stable and effective strategy to treat murine lupus, and its effectiveness should be explored in clinical trials for lupus.


Assuntos
Antígenos CD19/metabolismo , Linfócitos B/imunologia , Imunoterapia Adotiva , Lúpus Eritematoso Sistêmico/imunologia , Lúpus Eritematoso Sistêmico/terapia , Depleção Linfocítica , Linfócitos T/metabolismo , Animais , Feminino , Lúpus Eritematoso Sistêmico/sangue , Camundongos , Fenótipo , Proteoma/metabolismo , Análise de Sobrevida
19.
Front Immunol ; 9: 2632, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30542343

RESUMO

Sepsis remains a serious and life-threatening condition with high morbidity and mortality due to uncontrolled inflammation together with immunosuppression with few therapeutic options. Macrophages are recognized to play essential roles throughout all phases of sepsis and affect both immune homeostasis and inflammatory processes, and macrophage dysfunction is considered to be one of the major causes for sepsis-induced immunosuppression. Currently, Parkinson disease protein 7 (Park 7) is known to play an important role in regulating the production of reactive oxygen species (ROS) through interaction with p47phox, a subunit of NADPH oxidase. ROS are key mediators in initiating toll-like receptor (TLR) signaling pathways to activate macrophages. Emerging evidence has strongly implicated Park 7 as an antagonist for sepsis-induced immunosuppression, which suggests that Park 7 may be a novel therapeutic target for reversing immunosuppression compromised by sepsis. Here, we review the main characteristics of sepsis-induced immunosuppression caused by macrophages and provide a detailed mechanism for how Park 7 antagonizes sepsis-induced immunosuppression initiated by the macrophage inflammatory response. Finally, we further discuss the most promising approach to develop innovative drugs that target Park 7 in patients whose initial presentation is at the late stage of sepsis.


Assuntos
Tolerância Imunológica , Ativação de Macrófagos , Macrófagos/imunologia , Proteína Desglicase DJ-1/imunologia , Sepse/imunologia , Transdução de Sinais/imunologia , Animais , Sistemas de Liberação de Medicamentos , Humanos , Macrófagos/patologia , NADPH Oxidases/imunologia , Espécies Reativas de Oxigênio/imunologia , Sepse/tratamento farmacológico , Sepse/patologia , Receptores Toll-Like/imunologia
20.
Medicine (Baltimore) ; 97(16): e0515, 2018 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-29668637

RESUMO

RATIONALE: Behçet disease (BD) is a recurrent vasculitis characterized by oral and genital mucous membrane ulcers, uveitis, and skin lesions but only rarely leg ulcers. To our knowledge, no efficacious therapy has been described for BD patients with complicating, destructive leg ulcers. PATIENT CONCERNS: Here, We report the case of a 55-year-old woman with generalized erythema nodosum-like, papulopustular lesions, recurrent oral and genital ulcers accompanied with recurrent leg ulcers and trouble walking. DIAGNOSES: Based upon the patient's clinical feature and positive pathergy test , BD was confirmed. INTERVENTIONS: Conventional immunosuppressive therapy and anti-tumor necrosis factor inhibitors, adalimumab and etanercept, had no demonstrable clinical effect. Mesenchymal stem cell (MSC) injection combined with low-dose prednisone and thalidomide, however, completely ameliorated the ulcers on one leg, significantly improved ulcers on the other leg, and returned normal function to both legs. OUTCOMES: The ulcerative lesions remained in remission, and the affected leg functioned normally after 34 months' follow-up. LESSONS: Our experience suggests that MSC infusion might be a potentially successful therapy for intractable drug-resistant BD patients with concomitant leg ulcer.


Assuntos
Síndrome de Behçet , Úlcera da Perna , Transplante de Células-Tronco Mesenquimais/métodos , Prednisona , Talidomida , Adalimumab/administração & dosagem , Adalimumab/efeitos adversos , Síndrome de Behçet/complicações , Síndrome de Behçet/diagnóstico , Relação Dose-Resposta a Droga , Resistência a Medicamentos , Substituição de Medicamentos/métodos , Etanercepte/administração & dosagem , Etanercepte/efeitos adversos , Feminino , Humanos , Imunossupressores/administração & dosagem , Imunossupressores/efeitos adversos , Úlcera da Perna/etiologia , Úlcera da Perna/fisiopatologia , Úlcera da Perna/terapia , Pessoa de Meia-Idade , Prednisona/administração & dosagem , Prednisona/efeitos adversos , Talidomida/administração & dosagem , Talidomida/efeitos adversos , Resultado do Tratamento
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...