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1.
Protein Expr Purif ; 222: 106543, 2024 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-38971211

RESUMO

Dengue virus (DENV) is a considerable public health threat affecting millions of people globally. Vaccines for dengue are an important strategy to reduce the disease burden. We expressed capsid (C2) and envelope domain III of dengue virus serotype 2 (2EDIII) separately in the silkworm expression system. We conjugated them employing the monomeric streptavidin (mSA2) and biotin affinity to display the antigenic 2EDIII on the C2-forming capsid-like particle (CLP). Purified 2EDIII-displaying C2 (CLP/2EDIII) was immunogenic in BALB/c mice, eliciting neutralizing antibodies confirmed by a single-round infectious particle (SRIP) neutralization assay. Th1 cytokine levels were upregulated for the CLP/2EDIII group, and the anti-inflammatory IL-10 and pro-inflammatory IL-6 cytokine levels were also raised compared to the 2EDIII and the control groups. Elevated cytokine levels for CLP/2EDIII indicate the importance of displaying the 2EDIII as CLP/2EDIII rather than as an individual subunit. This study is the first to express the C2 protein as self-assembling CLP in vivo and 2EDIII separately in the silkworm expression system and conjugate them to form a monovalent CLP. Thus, this CLP/2EDIII display method may pave the way for an efficient tetravalent dengue vaccine candidate.


Assuntos
Anticorpos Neutralizantes , Bombyx , Vírus da Dengue , Camundongos Endogâmicos BALB C , Proteínas do Envelope Viral , Animais , Bombyx/genética , Bombyx/virologia , Bombyx/metabolismo , Vírus da Dengue/genética , Vírus da Dengue/imunologia , Camundongos , Proteínas do Envelope Viral/genética , Proteínas do Envelope Viral/imunologia , Proteínas do Envelope Viral/química , Proteínas do Envelope Viral/biossíntese , Anticorpos Neutralizantes/imunologia , Proteínas do Capsídeo/genética , Proteínas do Capsídeo/imunologia , Proteínas do Capsídeo/química , Proteínas do Capsídeo/biossíntese , Vacinas contra Dengue/imunologia , Vacinas contra Dengue/genética , Anticorpos Antivirais/imunologia , Dengue/imunologia , Dengue/virologia , Sorogrupo , Domínios Proteicos , Feminino
2.
Clin Exp Med ; 24(1): 153, 2024 Jul 08.
Artigo em Inglês | MEDLINE | ID: mdl-38972923

RESUMO

Rheumatoid arthritis (RA) is a common autoimmune rheumatic disease that causes chronic synovitis, bone erosion, and joint destruction. The autoantigens in RA include a wide array of posttranslational modified proteins, such as citrullinated proteins catalyzed by peptidyl arginine deiminase4a. Pathogenic anti-citrullinated protein antibodies (ACPAs) directed against a variety of citrullinated epitopes are abundant both in plasma and synovial fluid of RA patients. ACPAs play an important role in the onset and progression of RA. Intensive and extensive studies are being conducted to unveil the mechanisms of RA pathogenesis and evaluate the efficacy of some investigative drugs. In this review, we focus on the formation and pathogenic function of ACPAs.


Assuntos
Anticorpos Antiproteína Citrulinada , Artrite Reumatoide , Humanos , Artrite Reumatoide/imunologia , Anticorpos Antiproteína Citrulinada/imunologia , Autoantígenos/imunologia , Líquido Sinovial/imunologia , Líquido Sinovial/metabolismo
3.
J Nanobiotechnology ; 22(1): 400, 2024 Jul 08.
Artigo em Inglês | MEDLINE | ID: mdl-38972995

RESUMO

Considerable attention has been directed towards exploring the potential efficacy of miR-155 in the realm of cancer immunotherapy. Elevated levels of miR-155 in dendritic cells (DCs) have been shown to enhance their maturation, migration, cytokine secretion, and their ability to promote T cell activation. In addition, overexpression of mir155 in M2 macrophages boost the polarization towards the M1 phenotype. Conversely, miR-155 has the propensity to induce the accumulation of immunosuppressive cells like regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs) in the tumor tissue. To account for this discrepancy, it is imperative to get help from a drug that could deal with immunosuppressive effect. Curcumin (CUR) exhibits the capacity to prompt Tregs converse into T helper 1 cells, fostering the polarization of M2 tumor-associated macrophage towards the M1 phenotype, and impeding the recruitment and aggregation of MDSCs within the tumor microenvironment. Nonetheless, CUR is known to exert an immunosuppressive impact on DCs by hindering the expression of maturation markers, cytokines, and chemokines, thereby prevent DCs response to immunostimulatory agents. Hence, a reactive oxygen species/glutathione dual responsive drug conveyance platform (CUR/miR155@DssD-Hb NPs) was devised to co-deliver CUR and miR155, with the aim of exploring their synergistic potential in bolstering a sustained and robust anti-tumor immune response. In vitro and in vivo results have suggested that CUR/miR155@DssD-Hb NPs can effectively inhibit the viability of 4T1 and B16F10 tumor cells, trigger the release of damage associated molecular patterns, stimulate DCs maturation, subsequent activation of CD8+ T cells, diminish immunosuppressive cell populations (MDSCs, Tregs, M2 TAMs and exhausted T cells), promote the formation of long-term immunity and lessen the formation of metastatic nodules in the lungs. In summary, the co-delivery system integrating CUR and miR155 (CUR/miR155@DssD-Hb NPs) demonstrates promise as a promising strategy for the immunotherapy of melanoma and triple negative breast cancer.


Assuntos
Curcumina , Células Dendríticas , Imunoterapia , MicroRNAs , Nanopartículas , Espécies Reativas de Oxigênio , Curcumina/farmacologia , Curcumina/química , MicroRNAs/genética , Animais , Camundongos , Nanopartículas/química , Espécies Reativas de Oxigênio/metabolismo , Imunoterapia/métodos , Células Dendríticas/metabolismo , Células Dendríticas/imunologia , Células Dendríticas/efeitos dos fármacos , Linhagem Celular Tumoral , Feminino , Camundongos Endogâmicos C57BL , Microambiente Tumoral/efeitos dos fármacos , Camundongos Endogâmicos BALB C , Macrófagos/metabolismo , Macrófagos/efeitos dos fármacos , Humanos , Neoplasias/terapia , Neoplasias/tratamento farmacológico , Neoplasias/imunologia
4.
BMC Cancer ; 24(1): 811, 2024 Jul 07.
Artigo em Inglês | MEDLINE | ID: mdl-38972967

RESUMO

PURPOSE: There is mounting evidence that patients with liver cancer can benefit from Immune checkpoint inhibitors. However, due to the high cost and low efficacy, we aimed to explore new biomarkers for predicting the efficacy of immunotherapy. METHODS: Specimens and medical records of liver cancer patients treated at Drum Tower Hospital of Nanjing University were collected, and the expression of Kita-Kyushu lung cancer antigen-1 (KK-LC-1) in tissues as well as the corresponding antibodies in serum were examined to find biomarkers related to the prognosis of immunotherapy and to explore its mechanism in the development of liver cancer. RESULTS: KK-LC-1 expression was found to be 34.4% in histopathological specimens from 131 patients and was significantly correlated with Foxp3 expression (P = 0.0356). The expression of Foxp3 in the tissues of 24 patients who received immunotherapy was significantly correlated with overall survival (OS) (P = 0.0247), and there was also a tendency for prolonged OS in patients with high expression of KK-LC-1. In addition, the expression of KK-LC-1 antibody in the serum of patients who received immunotherapy with a first efficacy evaluation of stable disease (SD) was significantly higher than those with partial response (PR) (P = 0.0413). CONCLUSIONS: Expression of KK-LC-1 in both tissues and serum has been shown to correlate with the prognosis of patients treated with immunotherapy, and KK-LC-1 is a potential therapeutic target for oncological immunotherapy.


Assuntos
Biomarcadores Tumorais , Imunoterapia , Neoplasias Hepáticas , Humanos , Neoplasias Hepáticas/terapia , Neoplasias Hepáticas/imunologia , Masculino , Biomarcadores Tumorais/metabolismo , Biomarcadores Tumorais/sangue , Feminino , Prognóstico , Pessoa de Meia-Idade , Imunoterapia/métodos , Idoso , Antígenos de Neoplasias/imunologia , Fatores de Transcrição Forkhead/metabolismo , Adulto , Inibidores de Checkpoint Imunológico/uso terapêutico
5.
Elife ; 122024 Jul 08.
Artigo em Inglês | MEDLINE | ID: mdl-38973593

RESUMO

Pyrimidine nucleotide biosynthesis is a druggable metabolic dependency of cancer cells, and chemotherapy agents targeting pyrimidine metabolism are the backbone of treatment for many cancers. Dihydroorotate dehydrogenase (DHODH) is an essential enzyme in the de novo pyrimidine biosynthesis pathway that can be targeted by clinically approved inhibitors. However, despite robust preclinical anticancer efficacy, DHODH inhibitors have shown limited single-agent activity in phase 1 and 2 clinical trials. Therefore, novel combination therapy strategies are necessary to realize the potential of these drugs. To search for therapeutic vulnerabilities induced by DHODH inhibition, we examined gene expression changes in cancer cells treated with the potent and selective DHODH inhibitor brequinar (BQ). This revealed that BQ treatment causes upregulation of antigen presentation pathway genes and cell surface MHC class I expression. Mechanistic studies showed that this effect is (1) strictly dependent on pyrimidine nucleotide depletion, (2) independent of canonical antigen presentation pathway transcriptional regulators, and (3) mediated by RNA polymerase II elongation control by positive transcription elongation factor B (P-TEFb). Furthermore, BQ showed impressive single-agent efficacy in the immunocompetent B16F10 melanoma model, and combination treatment with BQ and dual immune checkpoint blockade (anti-CTLA-4 plus anti-PD-1) significantly prolonged mouse survival compared to either therapy alone. Our results have important implications for the clinical development of DHODH inhibitors and provide a rationale for combination therapy with BQ and immune checkpoint blockade.


Assuntos
Apresentação de Antígeno , Di-Hidro-Orotato Desidrogenase , Inibidores de Checkpoint Imunológico , Animais , Camundongos , Humanos , Apresentação de Antígeno/efeitos dos fármacos , Linhagem Celular Tumoral , Inibidores de Checkpoint Imunológico/farmacologia , Quinoxalinas/farmacologia , Inibidores Enzimáticos/farmacologia , Oxirredutases atuantes sobre Doadores de Grupo CH-CH/antagonistas & inibidores , Oxirredutases atuantes sobre Doadores de Grupo CH-CH/metabolismo , Camundongos Endogâmicos C57BL , Melanoma Experimental/tratamento farmacológico , Melanoma Experimental/imunologia , Compostos de Bifenilo , Quinaldinas
6.
J Korean Med Sci ; 39(26): e220, 2024 07 08.
Artigo em Inglês | MEDLINE | ID: mdl-38978490

RESUMO

During the coronavirus disease 2019 (COVID-19) pandemic, conclusively evaluating possible associations between COVID-19 vaccines and potential adverse events was of critical importance. The National Academy of Medicine of Korea established the COVID-19 Vaccine Safety Research Center (CoVaSC) with support from the Korea Disease Control and Prevention Agency to investigate the scientific relationship between COVID-19 vaccines and suspected adverse events. Although determining whether the COVID-19 vaccine was responsible for any suspected adverse event necessitated a systematic approach, traditional causal inference theories, such as Hill's criteria, encountered certain limitations and criticisms. To facilitate a systematic and evidence-based evaluation, the United States Institute of Medicine, at the request of the Centers for Disease Control and Prevention, offered a detailed causality assessment framework in 2012, which was updated in the recent report by the National Academies of Sciences, Engineering, and Medicine (NASEM) in 2024. This framework, based on a weight-of-evidence approach, allows the independent evaluation of both epidemiological and mechanistic evidence, culminating in a comprehensive conclusion about causality. Epidemiological evidence derived from population studies is categorized into four levels-high, moderate, limited, or insufficient-while mechanistic evidence, primarily from biological and clinical studies in animals and individuals, is classified as strong, intermediate, weak, or lacking. The committee then synthesizes these two types of evidence to draw a conclusion about the causal relationship, which can be described as "convincingly supports" ("evidence established" in the 2024 NASEM report), "favors acceptance," "favors rejection," or "inadequate to accept or reject." The CoVaSC has established an independent committee to conduct causality assessments using the weight-of-evidence framework, specifically for evaluating the causality of adverse events associated with COVID-19 vaccines. The aim of this study is to provide an overview of the weight-of-evidence framework and to detail the considerations involved in its practical application in the CoVaSC.


Assuntos
Vacinas contra COVID-19 , COVID-19 , SARS-CoV-2 , Humanos , Vacinas contra COVID-19/efeitos adversos , COVID-19/prevenção & controle , COVID-19/epidemiologia , SARS-CoV-2/imunologia , República da Coreia/epidemiologia , Causalidade , Estados Unidos
8.
Bull Exp Biol Med ; 177(1): 124-132, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38960961

RESUMO

Pregnancy-specific ß1-glycoprotein (PSG), one of the most important proteins of pregnancy, has a pronounced immunosuppressive effect. Short peptides of PSG, the so-called SLiMs (short linear motifs), are promising molecules for mild immunosuppression. We studied in vitro effect of short PSG peptides (YACS, YQCE, YVCS, and YECE) on differentiation and cytokine profile of human T-regulatory lymphocytes (Treg). T helpers isolated from the peripheral blood and polarized into the Treg phenotype with a T-cell activator (anti-CD2/3/28) and the cytokines IL-2 and transforming grown factor ß (TGFß) were used. PSG peptides were shown to have no direct modulatory effect on Treg differentiation in a culture of CD4+ cells polarized to the Treg phenotype. At the same time, PSG peptides had no effect on the viability and number of CD4+ cells in the in vitro culture. PSG peptides also had no effect on the levels of TNFα, IL-8, IL-2, macrophage inflammatory protein 1ß, IL-17, IL-10, IL-6, granulocyte-macrophage CSF, monocyte chemoattractant protein 1, IL-13, IL-5, IL-7, IL-12(p70), IL-1ß, granulocyte CSF, IL-4, but decreased IFNγ levels. The observed ability of the YQCE peptide to reduce the production of this proinflammatory Th1 cytokine by T helper cells can be interpreted as a positive effect. Our findings can be used for further development of safe peptide drugs based on SLiMs sequences.


Assuntos
Diferenciação Celular , Citocinas , Glicoproteínas beta 1 Específicas da Gravidez , Linfócitos T Reguladores , Humanos , Linfócitos T Reguladores/efeitos dos fármacos , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/citologia , Linfócitos T Reguladores/metabolismo , Diferenciação Celular/efeitos dos fármacos , Glicoproteínas beta 1 Específicas da Gravidez/metabolismo , Citocinas/metabolismo , Feminino , Gravidez , Peptídeos/farmacologia , Interleucina-2/metabolismo , Células Cultivadas
9.
J Agric Food Chem ; 72(28): 15715-15724, 2024 Jul 17.
Artigo em Inglês | MEDLINE | ID: mdl-38961631

RESUMO

Neohesperidin dihydrochalcone (NHDC) is a citrus-originated, seminatural sweetener. There is no investigation concerning the effect of NHDC on ulcerative colitis. The purpose of this study was to determine the therapeutic and protective effects of NHDC in Wistar Albino rats. NHDC was given for 7 days after or before colitis induction. The results showed that NHDC significantly reduced the interleukin-6 (IL-6), interleukin-10 (IL-10), transforming growth factor-ß1 (TGF-ß1), tumor necrosis factor-α (TNF-α), and interferon-γ (IFN-γ) levels. Catalase levels did not show a significant difference between the groups. NHDC provided a remarkable decrease in the expression levels of cyclooxygenase-2 (COX-2), myeloperoxidase (MPO), malondialdehyde (MDA), 8-hydroxy-2'-deoxyguanosine (8-OHdG), and nuclear factor kappa B (NF-κB). Total antioxidant status (TAS) levels were significantly elevated in NHDC treatment groups, while total oxidant status (TOS) and oxidative stress index (OSI) levels were significantly decreased. NHDC provided remarkable improvement in histological symptoms such as epithelial erosion, edema, mucosal necrosis, inflammatory cell infiltration, and hemorrhage. Also, caspase-3 expression levels were statistically decreased in NHDC treatment groups. The results indicated that NHDC might be a protection or alternative treatment for ulcerative colitis.


Assuntos
Anti-Inflamatórios , Antioxidantes , Apoptose , Chalconas , Hesperidina , NF-kappa B , Ratos Wistar , Animais , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/química , Anti-Inflamatórios/administração & dosagem , Ratos , Antioxidantes/farmacologia , Masculino , Apoptose/efeitos dos fármacos , Chalconas/farmacologia , Chalconas/administração & dosagem , Hesperidina/análogos & derivados , Hesperidina/farmacologia , Hesperidina/administração & dosagem , NF-kappa B/genética , NF-kappa B/metabolismo , Humanos , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Interleucina-6/genética , Interleucina-6/metabolismo , Colite/tratamento farmacológico , Colite/induzido quimicamente , Colite/metabolismo , Interleucina-10/genética , Interleucina-10/metabolismo , Ciclo-Oxigenase 2/metabolismo , Ciclo-Oxigenase 2/genética , Colite Ulcerativa/tratamento farmacológico , Colite Ulcerativa/metabolismo , Colite Ulcerativa/induzido quimicamente , Malondialdeído/metabolismo , Peroxidase/metabolismo , Interferon gama/genética , Interferon gama/metabolismo , Interferon gama/imunologia , Fator de Crescimento Transformador beta1/metabolismo , Fator de Crescimento Transformador beta1/genética
10.
Nanotechnology ; 35(40)2024 Jul 17.
Artigo em Inglês | MEDLINE | ID: mdl-38964289

RESUMO

Liver cancer, which is well-known to us as one of human most prevalent malignancies across the globe, poses a significant risk to live condition and life safety of individuals in every region of the planet. It has been shown that immune checkpoint treatment may enhance survival benefits and make a significant contribution to patient prognosis, which makes it a promising and popular therapeutic option for treating liver cancer at the current time. However, there are only a very few numbers of patients who can benefit from the treatment and there also exist adverse events such as toxic effects and so on, which is still required further research and discussion. Fortunately, the clustered regularly interspaced short palindromic repeat/CRISPR-associated nuclease 9 (CRISPR/Cas9) provides a potential strategy for immunotherapy and immune checkpoint therapy of liver cancer. In this review, we focus on elucidating the fundamentals of the recently developed CRISPR/Cas9 technology as well as the present-day landscape of immune checkpoint treatment which pertains to liver cancer. What's more, we aim to explore the molecular mechanism of immune checkpoint treatment in liver cancer based on CRISPR/Cas9 technology. At last, its encouraging and powerful potential in the future application of the clinic is discussed, along with the issues that already exist and the difficulties that must be overcome. To sum up, our ultimate goal is to create a fresh knowledge that we can utilize this new CRISPR/Cas9 technology for the current popular immune checkpoint therapy to overcome the treatment issues of liver cancer.


Assuntos
Sistemas CRISPR-Cas , Edição de Genes , Neoplasias Hepáticas , Humanos , Neoplasias Hepáticas/terapia , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/imunologia , Edição de Genes/métodos , Imunoterapia/métodos , Inibidores de Checkpoint Imunológico/uso terapêutico , Animais
11.
Nano Lett ; 24(28): 8723-8731, 2024 Jul 17.
Artigo em Inglês | MEDLINE | ID: mdl-38968148

RESUMO

Repolarizing tumor-associated macrophages (TAMs) into tumor-inhibiting M1 macrophages has been considered a promising strategy for enhanced cancer immunotherapy. However, several immunosuppressive ligands (e.g., LSECtin) can still be highly expressed on M1 macrophages, inducing unsatisfactory therapeutic outcomes. We herein developed an antibody-decorated nanoplatform composed of PEGylated iron oxide nanoparticles (IONPs) and LSECtin antibody conjugated onto the surface of IONPs via the hydrazone bond for enhanced cancer immunotherapy. After intravenous administration, the tumor microenvironment (TME) pH could trigger the hydrazone bond breakage and induce the disassociation of the nanoplatform into free LSECtin antibodies and IONPs. Consequently, the IONPs could repolarize TAMs into M1 macrophages to remodel immunosuppressive TME and provide an additional anticancer effect via secreting tumoricidal factors (e.g., interlukin-12). Meanwhile, the LSECtin antibody could further block the activity of LSECtin expressed on M1 macrophages and relieve its immunosuppressive effect on CD8+ T cells, ultimately leading to significant inhibition of tumor growth.


Assuntos
Imunoterapia , Microambiente Tumoral , Animais , Camundongos , Microambiente Tumoral/efeitos dos fármacos , Neoplasias/terapia , Neoplasias/imunologia , Humanos , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Linhagem Celular Tumoral , Macrófagos Associados a Tumor/imunologia , Macrófagos Associados a Tumor/efeitos dos fármacos , Nanopartículas Magnéticas de Óxido de Ferro/química , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/efeitos dos fármacos , Inibidores de Checkpoint Imunológico/farmacologia , Inibidores de Checkpoint Imunológico/química , Inibidores de Checkpoint Imunológico/uso terapêutico , Anticorpos/química , Anticorpos/imunologia , Anticorpos/uso terapêutico
12.
Immunol Cell Biol ; 102(6): 463-466, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38946158

RESUMO

In this article for the Highlight of 2023 series, we discuss recent advances in the fundamental biology of the germinal center response. These discoveries provide important insights as to how the germinal center contributes to protection against infection, and also highlights opportunities for future vaccine development.


Assuntos
Centro Germinativo , Animais , Humanos , Linfócitos B/imunologia , Centro Germinativo/imunologia , Desenvolvimento de Vacinas , Vacinas/imunologia
13.
Cell Host Microbe ; 32(7): 1114-1128.e10, 2024 Jul 10.
Artigo em Inglês | MEDLINE | ID: mdl-38955187

RESUMO

Plant immune homeostasis is achieved through a balanced immune activation and suppression, enabling effective defense while averting autoimmunity. In Arabidopsis, disrupting a mitogen-activated protein (MAP) kinase cascade triggers nucleotide-binding leucine-rich-repeat (NLR) SUPPRESSOR OF mkk1/2 2 (SUMM2)-mediated autoimmunity. Through an RNAi screen, we identify PUB5, a putative plant U-box E3 ligase, as a critical regulator of SUMM2-mediated autoimmunity. In contrast to typical E3 ligases, PUB5 stabilizes CRCK3, a calmodulin-binding receptor-like cytoplasmic kinase involved in SUMM2 activation. A closely related E3 ligase, PUB44, functions oppositely with PUB5 to degrade CRCK3 through monoubiquitylation and internalization. Furthermore, CRCK3, highly expressed in roots and conserved across plant species, confers resistance to Fusarium oxysporum, a devastating soil-borne fungal pathogen, in both Arabidopsis and cotton. These findings demonstrate the antagonistic role of an E3 ligase pair in fine-tuning kinase proteostasis for the regulation of NLR-mediated autoimmunity and highlight the function of autoimmune activators in governing plant root immunity against fungal pathogens.


Assuntos
Proteínas de Arabidopsis , Arabidopsis , Autoimunidade , Resistência à Doença , Fusarium , Doenças das Plantas , Imunidade Vegetal , Ubiquitina-Proteína Ligases , Arabidopsis/imunologia , Arabidopsis/microbiologia , Arabidopsis/genética , Ubiquitina-Proteína Ligases/metabolismo , Ubiquitina-Proteína Ligases/genética , Proteínas de Arabidopsis/metabolismo , Proteínas de Arabidopsis/genética , Doenças das Plantas/microbiologia , Doenças das Plantas/imunologia , Fusarium/imunologia , Proteínas NLR/metabolismo , Proteínas NLR/genética , Regulação da Expressão Gênica de Plantas , Ubiquitinação , Proteínas de Transporte
14.
EBioMedicine ; 105: 105231, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38959848

RESUMO

BACKGROUND: The clinical heterogeneity of myasthenia gravis (MG), an autoimmune disease defined by antibodies (Ab) directed against the postsynaptic membrane, constitutes a challenge for patient stratification and treatment decision making. Novel strategies are needed to classify patients based on their biological phenotypes aiming to improve patient selection and treatment outcomes. METHODS: For this purpose, we assessed the serum proteome of a cohort of 140 patients with anti-acetylcholine receptor-Ab-positive MG and utilised consensus clustering as an unsupervised tool to assign patients to biological profiles. For in-depth analysis, we used immunogenomic sequencing to study the B cell repertoire of a subgroup of patients and an in vitro assay using primary human muscle cells to interrogate serum-induced complement formation. FINDINGS: This strategy identified four distinct patient phenotypes based on their proteomic patterns in their serum. Notably, one patient phenotype, here named PS3, was characterised by high disease severity and complement activation as defining features. Assessing a subgroup of patients, hyperexpanded antibody clones were present in the B cell repertoire of the PS3 group and effectively activated complement as compared to other patients. In line with their disease phenotype, PS3 patients were more likely to benefit from complement-inhibiting therapies. These findings were validated in a prospective cohort of 18 patients using a cell-based assay. INTERPRETATION: Collectively, this study suggests proteomics-based clustering as a gateway to assign patients to a biological signature likely to benefit from complement inhibition and provides a stratification strategy for clinical practice. FUNDING: CN and CBS were supported by the Forschungskommission of the Medical Faculty of the Heinrich Heine University Düsseldorf. CN was supported by the Else Kröner-Fresenius-Stiftung (EKEA.38). CBS was supported by the Deutsche Forschungsgemeinschaft (DFG-German Research Foundation) with a Walter Benjamin fellowship (project 539363086). The project was supported by the Ministry of Culture and Science of North Rhine-Westphalia (MODS, "Profilbildung 2020" [grant no. PROFILNRW-2020-107-A]).


Assuntos
Autoanticorpos , Miastenia Gravis , Fenótipo , Proteômica , Receptores Colinérgicos , Humanos , Miastenia Gravis/sangue , Miastenia Gravis/diagnóstico , Miastenia Gravis/imunologia , Miastenia Gravis/metabolismo , Receptores Colinérgicos/imunologia , Receptores Colinérgicos/metabolismo , Autoanticorpos/sangue , Autoanticorpos/imunologia , Proteômica/métodos , Feminino , Masculino , Pessoa de Meia-Idade , Adulto , Análise por Conglomerados , Proteoma , Idoso , Linfócitos B/metabolismo , Linfócitos B/imunologia , Ativação do Complemento
15.
Ren Fail ; 46(2): 2373276, 2024 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-38967134

RESUMO

BACKGROUND: Podocytes, as intrinsic renal cells, can also express MHC-II and costimulatory molecules under inflammatory conditions, suggesting that they may act as antigen-presenting cells (APCs) to activate immune cell responses and then lead to immune-mediated renal injury. They are already recognized as main targets in the pathogenic mechanism of hepatitis B virus (HBV)-associated glomerulonephritis (HBV-GN). Previous studies also have indicated that inflammatory cells infiltration and immune-mediated tissue injury are evident in the kidney samples of patients with HBV-GN. However, the role of podocytes immune disorder in the pathogenic mechanism of HBV-GN remains unclear. METHODS: Renal function and inflammatory cells infiltration were measured in HBV transgenic (HBV-Tg) mice. In vitro, podocytes/CD4+ T cells or macrophages co-culture system was established. Then, the expression of HBx, CD4, and CD68 was determined by immunohistochemistry, while the expression of MHC-II, CD40, and CD40L was determined by immunofluorescence. Co-stimulatory molecules expression was examined by flow cytometry. The levels of inflammatory factors were detected by ELISA. RESULTS: In vivo, renal function was obviously impaired in HBV-Tg mice. HBx was significantly upregulated and immune cells infiltrated in the glomerulus of HBV-Tg mice. Expression of MHC-II and costimulatory molecule CD40 increased in the podocytes of HBV-Tg mice; CD4+ T cells exhibited increased CD40L expression in glomerulus. In vitro, CD40 expression was markedly elevated in HBx-podocytes. In co-culture systems, HBx-podocytes stimulated CD4+ T cells activation and caused the imbalance between IFN-γ and IL-4. HBx-podocytes also enhanced the adhesion ability of macrophages and induced the release of proinflammatory mediators. CONCLUSION: Taken together, these podocyte-related immune disorder may be involved in the pathogenic mechanism of HBV-GN.


Assuntos
Glomerulonefrite , Vírus da Hepatite B , Camundongos Transgênicos , Podócitos , Transativadores , Proteínas Virais Reguladoras e Acessórias , Animais , Podócitos/imunologia , Podócitos/patologia , Podócitos/metabolismo , Camundongos , Transativadores/metabolismo , Transativadores/genética , Glomerulonefrite/imunologia , Glomerulonefrite/patologia , Glomerulonefrite/virologia , Vírus da Hepatite B/imunologia , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/metabolismo , Macrófagos/imunologia , Macrófagos/metabolismo , Hepatite B/imunologia , Hepatite B/complicações , Humanos , Técnicas de Cocultura , Masculino , Modelos Animais de Doenças , Camundongos Endogâmicos C57BL
16.
Clin Exp Med ; 24(1): 156, 2024 Jul 13.
Artigo em Inglês | MEDLINE | ID: mdl-39003350

RESUMO

Tumor-associated macrophages (TAMs) represent one of the most abundant tumor-infiltrating stromal cells, and their normal function in tumor microenvironment (TME) is to suppress tumor cells by producing cytokines which trigger both direct cell cytotoxicity and antibody-mediated immune response. However, upon prolonged exposure to TME, the classical function of these so-called M1-type TAMs can be converted to another type, "M2-type," which are recruited by tumor cells so that they promote tumor growth and metastasis. This is the reason why the accumulation of TAMs in TME is correlated with poor prognosis in cancer patients. Both M1- and M2-types have high degree of plasticity, and M2-type cells can be reprogrammed to M1-type for therapeutic purposes. This characteristic introduces TAMs as promising target for developing novel cancer treatments. In addition, inhibition of M2-type cells and blocking their recruitment in TME, as well as their depletion by inducing apoptosis, are other approaches for effective immunotherapy of cancer. In this review, we summarize the potential of TAMs to be targeted for cancer immunotherapy and provide an up-to-date about novel strategies for targeting TAMs.


Assuntos
Imunoterapia , Neoplasias , Microambiente Tumoral , Macrófagos Associados a Tumor , Humanos , Macrófagos Associados a Tumor/imunologia , Macrófagos Associados a Tumor/metabolismo , Neoplasias/imunologia , Neoplasias/patologia , Neoplasias/terapia , Microambiente Tumoral/imunologia , Imunoterapia/métodos , Animais
17.
Sci Rep ; 14(1): 16201, 2024 Jul 13.
Artigo em Inglês | MEDLINE | ID: mdl-39003356

RESUMO

Immunoinflammation is associated with the development of post-stroke cognitive impairment (PSCI), however, peripheral immunity has not been fully explored. We aimed to investigate the association between PSCI and peripheral immune indicators, including neutrophil, lymphocyte, and mononuclear percentages and counts; the systemic immune inflammation index; platelet-to-lymphocyte ratio; neutrophil-to-lymphocyte ratio (NLR); and lymphocyte-to-monocyte ratio. A total of 224 patients with acute minor ischemic stroke or transient ischemic attack with 6-12 months of follow-up were included. PSCI was defined as a Montreal Cognitive Assessment score < 22 during the follow-up period. We performed logistic regression, subgroup analyses based on age and sex, and further established predictive models. We found that increased innate immunity indicators (neutrophils, neutrophil percentage) increased the risk of PSCI, whereas increased adaptive immunity indicator (lymphocytes) were protective against PSCI, especially in patients aged 50-65 years. Neutrophil percentage and NLR improved the predictive efficacy of the models that included demographic, clinical, and imaging information, with the area under the curve increased from 0.765 to 0.804 and 0.803 (P = 0.042 and 0.049, respectively). We conducted a comprehensive analysis of peripheral immunity in PSCI, providing a novel perspective on the early detection, etiology, and treatment of PSCI.


Assuntos
Disfunção Cognitiva , Ataque Isquêmico Transitório , AVC Isquêmico , Neutrófilos , Humanos , Masculino , Feminino , Ataque Isquêmico Transitório/imunologia , Ataque Isquêmico Transitório/complicações , Idoso , Pessoa de Meia-Idade , AVC Isquêmico/imunologia , AVC Isquêmico/complicações , Disfunção Cognitiva/imunologia , Disfunção Cognitiva/etiologia , Neutrófilos/imunologia , Linfócitos/imunologia , Imunidade Inata
18.
Bull Math Biol ; 86(9): 107, 2024 Jul 13.
Artigo em Inglês | MEDLINE | ID: mdl-39003370

RESUMO

Human immunodeficiency virus (HIV) infects CD4+ cells and causes progressive immune function failure, and CD8+ cells lyse infected CD4+ cell via recognising peptide presented by human leukocyte antigens (HLA). Variations in HLA allele lead to observed different HIV infection outcomes. Within-host HIV dynamics involves virus replication within infected cells and lysing of infected cells by CD8+ cells, but how variations in HLA alleles determine different infection outcomes was far from clear. Here, we used mathematical modelling and parameter inference with a new analysis of published virus inhibition assay data to estimate CD8+ cell lysing efficiency, and found that lysing efficiency fall in the gap between low bound (0.1-0.2 day-1 (Elemans et al. in PLoS Comput Biol 8(2):e1002381, 2012)) and upper boundary (6.5-8.4 day-1 (Wick et al. in J Virol 79(21):13579-13586, 2005)). Our outcomes indicate that both lysing efficiency and viral inoculum size jointly determine observed different infection outcomes. Low lysing rate associated with non-protective HLA alleles leads to monostable viral kinetic to high viral titre and oscillatory viral kinetics. High lysing rate associated with protective HLA alleles leads monostable viral kinetic to low viral titre and bistable viral kinetics; at a specific interval of CD8+ cell counts, small viral inoculum sizes are inhibited but not large viral inoculum sizes remain infectious. Further, with CD8+ cell recruitment, HIV kinetics always exhibit oscillatory kinetics, but lysing rate is negatively correlated with range of CD8+ cell count. Our finding highlights role of HLA allele determining different infection outcomes, thereby providing a potential mechanistic explanation for observed good and bad HIV infection outcomes induced by protective HLA allele.


Assuntos
Alelos , Linfócitos T CD4-Positivos , Linfócitos T CD8-Positivos , Infecções por HIV , Antígenos HLA , Conceitos Matemáticos , Modelos Imunológicos , Replicação Viral , Humanos , Infecções por HIV/imunologia , Infecções por HIV/genética , Infecções por HIV/virologia , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD4-Positivos/imunologia , Antígenos HLA/genética , Antígenos HLA/imunologia , Replicação Viral/imunologia , HIV-1/imunologia , HIV-1/fisiologia , Simulação por Computador , Carga Viral
19.
Respir Res ; 25(1): 275, 2024 Jul 13.
Artigo em Inglês | MEDLINE | ID: mdl-39003443

RESUMO

Pleurisy can be categorized as primary or secondary, arising from immunological, tumorous, or microbial conditions. It often results in lung structure damage and the development of various respiratory issues. Among the different types, tuberculous pleurisy has emerged as a prominent focus for both clinical and scientific investigations. The IL-10 family, known for its anti-inflammatory properties in the human immune system, is increasingly being studied for its involvement in the pathogenesis of pleurisy. This review aims to present a detailed overview of the intricate role of IL-10 family members (specifically IL-10, IL-22, and IL-26) in human and animal pleuritic diseases or relevant animal models. These insights could serve as valuable guidance and references for further studies on pleurisy and potential therapeutic strategies.


Assuntos
Interleucina-10 , Interleucina 22 , Interleucinas , Tuberculose Pleural , Humanos , Tuberculose Pleural/diagnóstico , Tuberculose Pleural/imunologia , Tuberculose Pleural/metabolismo , Tuberculose Pleural/tratamento farmacológico , Interleucinas/metabolismo , Interleucinas/imunologia , Animais , Interleucina-10/metabolismo , Pleurisia/imunologia , Pleurisia/diagnóstico , Pleurisia/metabolismo
20.
Int J Mol Sci ; 25(13)2024 Jul 02.
Artigo em Inglês | MEDLINE | ID: mdl-39000406

RESUMO

Diabetes mellitus (DM) poses a significant challenge to global health, with its prevalence projected to rise dramatically by 2045. This narrative review explores the bidirectional relationship between periodontitis (PD) and type 1 diabetes mellitus (T1DM), focusing on cellular and molecular mechanisms derived from the interplay between oral microbiota and the host immune response. A comprehensive search of studies published between 2008 and 2023 was conducted to elucidate the association between these two diseases. Preclinical and clinical evidence suggests a bidirectional relationship, with individuals with T1DM exhibiting heightened susceptibility to periodontitis, and vice versa. The review includes recent findings from human clinical studies, revealing variations in oral microbiota composition in T1DM patients, including increases in certain pathogenic species such as Porphyromonas gingivalis, Prevotella intermedia, and Aggregatibacter actinomycetemcomitans, along with shifts in microbial diversity and abundance. Molecular mechanisms underlying this association involve oxidative stress and dysregulated host immune responses, mediated by inflammatory cytokines such as IL-6, IL-8, and MMPs. Furthermore, disruptions in bone turnover markers, such as RANKL and OPG, contribute to periodontal complications in T1DM patients. While preventive measures to manage periodontal complications in T1DM patients may improve overall health outcomes, further research is needed to understand the intricate interactions between oral microbiota, host response, periodontal disease, and systemic health in this population.


Assuntos
Diabetes Mellitus Tipo 1 , Microbiota , Doenças Periodontais , Humanos , Diabetes Mellitus Tipo 1/microbiologia , Diabetes Mellitus Tipo 1/complicações , Doenças Periodontais/microbiologia , Periodontite/microbiologia , Periodontite/complicações , Periodontite/imunologia
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