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1.
Int J Mol Sci ; 22(11)2021 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-34206009

RESUMO

Toll-like receptor (TLR) signaling plays a critical role in the induction and progression of autoimmune diseases such as rheumatoid arthritis, systemic lupus erythematous, experimental autoimmune encephalitis, type 1 diabetes mellitus and neurodegenerative diseases. Deciphering antigen recognition by antibodies provides insights and defines the mechanism of action into the progression of immune responses. Multiple strategies, including phage display and hybridoma technologies, have been used to enhance the affinity of antibodies for their respective epitopes. Here, we investigate the TLR4 antibody-binding epitope by computational-driven approach. We demonstrate that three important residues, i.e., Y328, N329, and K349 of TLR4 antibody binding epitope identified upon in silico mutagenesis, affect not only the interaction and binding affinity of antibody but also influence the structural integrity of TLR4. Furthermore, we predict a novel epitope at the TLR4-MD2 interface which can be targeted and explored for therapeutic antibodies and small molecules. This technique provides an in-depth insight into antibody-antigen interactions at the resolution and will be beneficial for the development of new monoclonal antibodies. Computational techniques, if coupled with experimental methods, will shorten the duration of rational design and development of antibody therapeutics.


Assuntos
Anticorpos Monoclonais/imunologia , Artrite Reumatoide/imunologia , Encefalite/imunologia , Epitopos/genética , Doença de Hashimoto/imunologia , Doenças Neurodegenerativas/imunologia , Receptor 4 Toll-Like/genética , Sequência de Aminoácidos/genética , Anticorpos Monoclonais/genética , Anticorpos Monoclonais/uso terapêutico , Artrite Reumatoide/tratamento farmacológico , Artrite Reumatoide/genética , Técnicas de Visualização da Superfície Celular , Encefalite/genética , Encefalite/patologia , Mapeamento de Epitopos/métodos , Epitopos/imunologia , Doença de Hashimoto/genética , Doença de Hashimoto/patologia , Humanos , Doenças Neurodegenerativas/tratamento farmacológico , Doenças Neurodegenerativas/patologia , Ligação Proteica/genética , Receptor 4 Toll-Like/antagonistas & inibidores , Receptor 4 Toll-Like/imunologia
2.
Medicine (Baltimore) ; 100(24): e26297, 2021 Jun 18.
Artigo em Inglês | MEDLINE | ID: mdl-34128866

RESUMO

ABSTRACT: Previous studies have suggested that human T-cell leukemia virus type 1 (HTLV-1) might act as a pathogen in rheumatoid arthritis (RA), but epidemiological evidence of an association is scarce. We measured anti-HTLV-1 antibodies among Nagasaki atomic bomb survivors to determine whether HTLV-1 is related to RA and whether radiation exposure is associated with HTLV-1 and RA prevalence.This is a cross-sectional study among atomic bomb survivors who participated in biennial health examinations from 2006 to 2010. Serum levels of anti-HTLV-1 antibodies were measured using a chemiluminescent enzyme immunoassay and confirmed by Western blotting. Association between HTLV-1 and RA was analyzed by a logistic regression model.Of 2091 participants (women 61.5%; median age, 73 years), 215 (10.3%) had anti-HTLV-1 antibodies. HTLV-1 prevalence was higher among women (13.1% vs 5.8%; P < .001). Twenty-two participants (1.1%) were diagnosed with RA. HTLV-1 prevalence among RA participants was significantly higher than that among non-RA participants (27.3% vs 10.1%; P = .020). After adjustment for age, sex, and hepatitis C virus infection, HTLV-1 was significantly associated with prevalent RA (odds ratio, 2.89; 95% confidence interval, 1.06, 7.03). There was no association between radiation dose and either the prevalence of HTLV-1 or RA.This study, among a well-defined group of atomic bomb survivors, suggests that HTLV-1 is associated with RA.


Assuntos
Anticorpos Antivirais/imunologia , Artrite Reumatoide/imunologia , Sobreviventes de Bombas Atômicas/estatística & dados numéricos , Infecções por HTLV-I/imunologia , Vírus Linfotrópico T Tipo 1 Humano/imunologia , Idoso , Anticorpos Antivirais/sangue , Artrite Reumatoide/sangue , Artrite Reumatoide/virologia , Estudos Transversais , Feminino , Infecções por HTLV-I/sangue , Infecções por HTLV-I/epidemiologia , Humanos , Japão/epidemiologia , Masculino , Prevalência
3.
Sci Rep ; 11(1): 11462, 2021 06 01.
Artigo em Inglês | MEDLINE | ID: covidwho-1253984

RESUMO

An excessive immune response known as cytokine storm is the hallmark of severe COVID-19. The cause of this cytokine rampage is yet not known. Based on recent epidemiological evidence, we hypothesized that CD80/86 signaling is essential for this hyperinflammation, and that blocking this proinflammatory axis could be an effective therapeutic approach to protect against severe COVID-19. Here we provide exploratory evidence that abatacept, a drug that blocks CD80/86 co-stimulation, produces changes at the systemic level that are highly antagonistic of the proinflammatory processes elicited by COVID-19. Using RNA-seq from blood samples from a longitudinal cohort of n = 38 rheumatic patients treated with abatacept, we determined the immunological processes that are significantly regulated by this treatment. We then analyzed available blood RNA-seq from two COVID19 patient cohorts, a very early cohort from the epicenter of the pandemic in China (n = 3 COVID-19 cases and n = 3 controls), and a recent and larger cohort from the USA (n = 49 severe and n = 51 mild COVD-19 patients). We found a highly significant antagonism between SARS-CoV-2 infection and COVID-19 severity with the systemic response to abatacept. Analysis of previous single-cell RNA-seq data from bronchoalveolar lavage fluid from mild and severe COVID-19 patients and controls, reinforce the implication of the CD80/86 proinflammatory axis. Our functional results further support abatacept as a candidate therapeutic approach to prevent severe COVID-19.


Assuntos
Abatacepte/farmacologia , COVID-19/tratamento farmacológico , Síndrome da Liberação de Citocina/prevenção & controle , Imunossupressores/farmacologia , SARS-CoV-2/imunologia , Transdução de Sinais/efeitos dos fármacos , Abatacepte/uso terapêutico , Idoso , Artrite Reumatoide/sangue , Artrite Reumatoide/tratamento farmacológico , Artrite Reumatoide/imunologia , Antígeno B7-1/metabolismo , Antígeno B7-2/metabolismo , Líquido da Lavagem Broncoalveolar/citologia , COVID-19/sangue , COVID-19/complicações , COVID-19/imunologia , China , Síndrome da Liberação de Citocina/imunologia , Síndrome da Liberação de Citocina/virologia , Feminino , Humanos , Imunossupressores/uso terapêutico , Masculino , Pessoa de Meia-Idade , Estudos Observacionais como Assunto , RNA-Seq , Índice de Gravidade de Doença , Transdução de Sinais/imunologia , Análise de Célula Única , Espanha , Estados Unidos , Regulação para Cima/efeitos dos fármacos , Regulação para Cima/imunologia
4.
JCI Insight ; 6(13)2021 06 18.
Artigo em Inglês | MEDLINE | ID: mdl-34143756

RESUMO

We explored the potential link between chronic inflammatory arthritis and COVID-19 pathogenic and resolving macrophage pathways and their role in COVID-19 pathogenesis. We found that bronchoalveolar lavage fluid (BALF) macrophage clusters FCN1+ and FCN1+SPP1+ predominant in severe COVID-19 were transcriptionally related to synovial tissue macrophage (STM) clusters CD48hiS100A12+ and CD48+SPP1+ that drive rheumatoid arthritis (RA) synovitis. BALF macrophage cluster FABP4+ predominant in healthy lung was transcriptionally related to STM cluster TREM2+ that governs resolution of synovitis in RA remission. Plasma concentrations of SPP1 and S100A12 (key products of macrophage clusters shared with active RA) were high in severe COVID-19 and predicted the need for Intensive Care Unit transfer, and they remained high in the post-COVID-19 stage. High plasma levels of SPP1 were unique to severe COVID-19 when compared with other causes of severe pneumonia, and IHC localized SPP1+ macrophages in the alveoli of COVID-19 lung. Investigation into SPP1 mechanisms of action revealed that it drives proinflammatory activation of CD14+ monocytes and development of PD-L1+ neutrophils, both hallmarks of severe COVID-19. In summary, COVID-19 pneumonitis appears driven by similar pathogenic myeloid cell pathways as those in RA, and their mediators such as SPP1 might be an upstream activator of the aberrant innate response in severe COVID-19 and predictive of disease trajectory including post-COVID-19 pathology.


Assuntos
Artrite Reumatoide/imunologia , COVID-19/imunologia , Monócitos/imunologia , Neutrófilos/imunologia , Osteopontina/imunologia , Artrite Reumatoide/metabolismo , Antígeno B7-H1/imunologia , Líquido da Lavagem Broncoalveolar/imunologia , Antígeno CD48/imunologia , COVID-19/induzido quimicamente , COVID-19/metabolismo , Proteínas de Ligação a Ácido Graxo/imunologia , Humanos , Lectinas/imunologia , Receptores de Lipopolissacarídeos/imunologia , Receptores de Lipopolissacarídeos/metabolismo , Pulmão/diagnóstico por imagem , Pulmão/imunologia , Pulmão/metabolismo , Pulmão/patologia , Macrófagos/imunologia , Macrófagos/metabolismo , Glicoproteínas de Membrana/imunologia , Monócitos/metabolismo , Neutrófilos/metabolismo , Osteopontina/sangue , Receptores Proteína Tirosina Quinases/metabolismo , Receptores Imunológicos/imunologia , Proteína S100A12/imunologia , Proteína S100A12/metabolismo , Membrana Sinovial/imunologia , Tomografia Computadorizada por Raios X
5.
Sci Rep ; 11(1): 11462, 2021 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-34075090

RESUMO

An excessive immune response known as cytokine storm is the hallmark of severe COVID-19. The cause of this cytokine rampage is yet not known. Based on recent epidemiological evidence, we hypothesized that CD80/86 signaling is essential for this hyperinflammation, and that blocking this proinflammatory axis could be an effective therapeutic approach to protect against severe COVID-19. Here we provide exploratory evidence that abatacept, a drug that blocks CD80/86 co-stimulation, produces changes at the systemic level that are highly antagonistic of the proinflammatory processes elicited by COVID-19. Using RNA-seq from blood samples from a longitudinal cohort of n = 38 rheumatic patients treated with abatacept, we determined the immunological processes that are significantly regulated by this treatment. We then analyzed available blood RNA-seq from two COVID19 patient cohorts, a very early cohort from the epicenter of the pandemic in China (n = 3 COVID-19 cases and n = 3 controls), and a recent and larger cohort from the USA (n = 49 severe and n = 51 mild COVD-19 patients). We found a highly significant antagonism between SARS-CoV-2 infection and COVID-19 severity with the systemic response to abatacept. Analysis of previous single-cell RNA-seq data from bronchoalveolar lavage fluid from mild and severe COVID-19 patients and controls, reinforce the implication of the CD80/86 proinflammatory axis. Our functional results further support abatacept as a candidate therapeutic approach to prevent severe COVID-19.


Assuntos
Abatacepte/farmacologia , COVID-19/tratamento farmacológico , Síndrome da Liberação de Citocina/prevenção & controle , Imunossupressores/farmacologia , SARS-CoV-2/imunologia , Transdução de Sinais/efeitos dos fármacos , Abatacepte/uso terapêutico , Idoso , Artrite Reumatoide/sangue , Artrite Reumatoide/tratamento farmacológico , Artrite Reumatoide/imunologia , Antígeno B7-1/metabolismo , Antígeno B7-2/metabolismo , Líquido da Lavagem Broncoalveolar/citologia , COVID-19/sangue , COVID-19/complicações , COVID-19/imunologia , China , Síndrome da Liberação de Citocina/imunologia , Síndrome da Liberação de Citocina/virologia , Feminino , Humanos , Imunossupressores/uso terapêutico , Masculino , Pessoa de Meia-Idade , Estudos Observacionais como Assunto , RNA-Seq , Índice de Gravidade de Doença , Transdução de Sinais/imunologia , Análise de Célula Única , Espanha , Estados Unidos , Regulação para Cima/efeitos dos fármacos , Regulação para Cima/imunologia
6.
Genome Med ; 13(1): 64, 2021 04 20.
Artigo em Inglês | MEDLINE | ID: covidwho-1195928

RESUMO

BACKGROUND: Immunosuppressive and anti-cytokine treatment may have a protective effect for patients with COVID-19. Understanding the immune cell states shared between COVID-19 and other inflammatory diseases with established therapies may help nominate immunomodulatory therapies. METHODS: To identify cellular phenotypes that may be shared across tissues affected by disparate inflammatory diseases, we developed a meta-analysis and integration pipeline that models and removes the effects of technology, tissue of origin, and donor that confound cell-type identification. Using this approach, we integrated > 300,000 single-cell transcriptomic profiles from COVID-19-affected lungs and tissues from healthy subjects and patients with five inflammatory diseases: rheumatoid arthritis (RA), Crohn's disease (CD), ulcerative colitis (UC), systemic lupus erythematosus (SLE), and interstitial lung disease. We tested the association of shared immune states with severe/inflamed status compared to healthy control using mixed-effects modeling. To define environmental factors within these tissues that shape shared macrophage phenotypes, we stimulated human blood-derived macrophages with defined combinations of inflammatory factors, emphasizing in particular antiviral interferons IFN-beta (IFN-ß) and IFN-gamma (IFN-γ), and pro-inflammatory cytokines such as TNF. RESULTS: We built an immune cell reference consisting of > 300,000 single-cell profiles from 125 healthy or disease-affected donors from COVID-19 and five inflammatory diseases. We observed a CXCL10+ CCL2+ inflammatory macrophage state that is shared and strikingly abundant in severe COVID-19 bronchoalveolar lavage samples, inflamed RA synovium, inflamed CD ileum, and UC colon. These cells exhibited a distinct arrangement of pro-inflammatory and interferon response genes, including elevated levels of CXCL10, CXCL9, CCL2, CCL3, GBP1, STAT1, and IL1B. Further, we found this macrophage phenotype is induced upon co-stimulation by IFN-γ and TNF-α. CONCLUSIONS: Our integrative analysis identified immune cell states shared across inflamed tissues affected by inflammatory diseases and COVID-19. Our study supports a key role for IFN-γ together with TNF-α in driving an abundant inflammatory macrophage phenotype in severe COVID-19-affected lungs, as well as inflamed RA synovium, CD ileum, and UC colon, which may be targeted by existing immunomodulatory therapies.


Assuntos
COVID-19/imunologia , Citocinas/imunologia , Macrófagos/imunologia , SARS-CoV-2 , Artrite Reumatoide/genética , Artrite Reumatoide/imunologia , Líquido da Lavagem Broncoalveolar/citologia , Líquido da Lavagem Broncoalveolar/imunologia , COVID-19/genética , Colite Ulcerativa/genética , Colite Ulcerativa/imunologia , Colo/imunologia , Doença de Crohn/genética , Doença de Crohn/imunologia , Humanos , Inflamação/genética , Inflamação/imunologia , Pulmão/imunologia , Doenças Pulmonares Intersticiais/genética , Doenças Pulmonares Intersticiais/imunologia , Lúpus Eritematoso Sistêmico/genética , Lúpus Eritematoso Sistêmico/imunologia , Fenótipo , RNA-Seq
7.
Cell Mol Life Sci ; 78(12): 5095-5106, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33880615

RESUMO

Rheumatoid arthritis (RA) is a chronic autoimmune disease with joint and systemic inflammation that is accompanied by the production of autoantibodies, such as rheumatoid factor and anti-cyclic citrullinated peptide (anti-CCP) antibodies. Follicular helper T (Tfh) cells, which are a subset of CD4+ T cells, facilitate germinal center (GC) reactions by providing signals required for high-affinity antibody production and the generation of long-lived antibody-secreting plasma cells. Uncontrolled expansion of Tfh cells is observed in various systemic autoimmune diseases. Particularly, the frequencies of circulating Tfh-like (cTfh-like) cells, their subtypes and synovial-infiltrated T helper cells correlate with disease activity in RA patients. Therefore, reducing autoantibody production and restricting excessive Tfh cell responses are ideal ways to control RA pathogenesis. The present review summarizes current knowledge of the involvement of Tfh cells in RA pathogenesis and highlights the potential of these cells as therapeutic targets.


Assuntos
Antirreumáticos/farmacologia , Artrite Reumatoide/imunologia , Centro Germinativo/imunologia , Imunoterapia/métodos , Células T Auxiliares Foliculares/imunologia , Animais , Artrite Reumatoide/tratamento farmacológico , Centro Germinativo/efeitos dos fármacos , Humanos , Células T Auxiliares Foliculares/efeitos dos fármacos
8.
Nutrients ; 13(4)2021 Apr 13.
Artigo em Inglês | MEDLINE | ID: mdl-33924354

RESUMO

Anti-inflammatory potential of orally administrated bioflavonoid-robinin, active sub-stance of original drug Flaroninum™ (FL), was investigated in the combination with methotrexate (MTX) and in monotherapy in rats suffering from adjuvant-induced arthritis (AA). Robinin (kaempferol-3-O-robinoside-7-O-rhamnoside) was isolated from the aerial parts of Astragalus falcatus Lam. The monotherapy with robinin was not efficient in alleviating symptoms of AA. The combination of MTX with robinin was similarly active as MTX alone in reducing the hind paw volume and change of body weight during the whole experiment. The combination, however, reduced plasma levels of Interleukin-17Aand activity of gamma-glutamyl transferase in joint more efficiently then MTX alone. Our results demonstrate that the novel combination of robinin and MTX mildly improved the reduction of inflammation in experimental arthritis.


Assuntos
Anti-Inflamatórios/farmacologia , Artrite Experimental/tratamento farmacológico , Artrite Reumatoide/tratamento farmacológico , Flavonoides/farmacologia , Metotrexato/farmacologia , Animais , Anti-Inflamatórios/isolamento & purificação , Anti-Inflamatórios/uso terapêutico , Artrite Experimental/imunologia , Artrite Reumatoide/imunologia , Astrágalo (Planta)/química , Sinergismo Farmacológico , Quimioterapia Combinada , Flavonoides/isolamento & purificação , Flavonoides/uso terapêutico , Flores/química , Adjuvante de Freund/administração & dosagem , Adjuvante de Freund/imunologia , Humanos , Lipídeos/administração & dosagem , Lipídeos/imunologia , Masculino , Metotrexato/uso terapêutico , Folhas de Planta/química , Ratos
9.
Genome Med ; 13(1): 64, 2021 04 20.
Artigo em Inglês | MEDLINE | ID: mdl-33879239

RESUMO

BACKGROUND: Immunosuppressive and anti-cytokine treatment may have a protective effect for patients with COVID-19. Understanding the immune cell states shared between COVID-19 and other inflammatory diseases with established therapies may help nominate immunomodulatory therapies. METHODS: To identify cellular phenotypes that may be shared across tissues affected by disparate inflammatory diseases, we developed a meta-analysis and integration pipeline that models and removes the effects of technology, tissue of origin, and donor that confound cell-type identification. Using this approach, we integrated > 300,000 single-cell transcriptomic profiles from COVID-19-affected lungs and tissues from healthy subjects and patients with five inflammatory diseases: rheumatoid arthritis (RA), Crohn's disease (CD), ulcerative colitis (UC), systemic lupus erythematosus (SLE), and interstitial lung disease. We tested the association of shared immune states with severe/inflamed status compared to healthy control using mixed-effects modeling. To define environmental factors within these tissues that shape shared macrophage phenotypes, we stimulated human blood-derived macrophages with defined combinations of inflammatory factors, emphasizing in particular antiviral interferons IFN-beta (IFN-ß) and IFN-gamma (IFN-γ), and pro-inflammatory cytokines such as TNF. RESULTS: We built an immune cell reference consisting of > 300,000 single-cell profiles from 125 healthy or disease-affected donors from COVID-19 and five inflammatory diseases. We observed a CXCL10+ CCL2+ inflammatory macrophage state that is shared and strikingly abundant in severe COVID-19 bronchoalveolar lavage samples, inflamed RA synovium, inflamed CD ileum, and UC colon. These cells exhibited a distinct arrangement of pro-inflammatory and interferon response genes, including elevated levels of CXCL10, CXCL9, CCL2, CCL3, GBP1, STAT1, and IL1B. Further, we found this macrophage phenotype is induced upon co-stimulation by IFN-γ and TNF-α. CONCLUSIONS: Our integrative analysis identified immune cell states shared across inflamed tissues affected by inflammatory diseases and COVID-19. Our study supports a key role for IFN-γ together with TNF-α in driving an abundant inflammatory macrophage phenotype in severe COVID-19-affected lungs, as well as inflamed RA synovium, CD ileum, and UC colon, which may be targeted by existing immunomodulatory therapies.


Assuntos
COVID-19/imunologia , Citocinas/imunologia , Macrófagos/imunologia , SARS-CoV-2 , Artrite Reumatoide/genética , Artrite Reumatoide/imunologia , Líquido da Lavagem Broncoalveolar/citologia , Líquido da Lavagem Broncoalveolar/imunologia , COVID-19/genética , Colite Ulcerativa/genética , Colite Ulcerativa/imunologia , Colo/imunologia , Doença de Crohn/genética , Doença de Crohn/imunologia , Humanos , Inflamação/genética , Inflamação/imunologia , Pulmão/imunologia , Doenças Pulmonares Intersticiais/genética , Doenças Pulmonares Intersticiais/imunologia , Lúpus Eritematoso Sistêmico/genética , Lúpus Eritematoso Sistêmico/imunologia , Fenótipo , RNA-Seq
10.
Biomed Res Int ; 2021: 5538535, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33855071

RESUMO

Tumor necrosis factor alpha (TNF-α) plays a critical role in the progression of inflammation and affects the cells of the synovial membrane. Another key factor in the progression of rheumatoid inflammation is interleukin-6 (IL-6). Both TNF-α and IL-6 promote the proliferation of synovial membrane cells thus stimulating the production of matrix metalloproteinases and other cytotoxins and leading towards bone erosion and destruction of the cartilage. Growth differentiation factor-11 (GDF11) and growth differentiation factor-8 (GDF8) which is also known as myostatin are members of the transforming growth factor-ß family and could be used as antagonists to inflammatory responses which are associated with rheumatoid arthritis. In the current study, to elucidate the evolutionary relationships of GDF11 with its homologs from other closely related organisms, a comprehensive phylogenetic analysis was performed. From the phylogram, it was revealed that the clade of Primates that belong to superorder Euarchontoglires showed close evolutionary relationships with order Cetartiodactyla of the Laurasiatheria superorder. Fifty tetrapeptides were devised from conserved regions of GDF11 which served as ligands in protein-ligand docking against TNF-α and IL-6 followed by drug scanning and ADMET profiling of best selected ligands. The peptides SAGP showed strong interactions with IL-6, and peptides AFDP and AGPC showed strong interactions with TNF-α, and all three peptides fulfilled all the pharmacokinetic parameters which are important for bioavailability. The potential of GDF8 as an antagonist to TNF-α and IL-6 was also explored using a protein-protein docking approach. The binding patterns of GDF8 with TNF-α and IL-6 showed that GDF8 could be used as a potential inhibitor of TNF-α and IL-6 to treat rheumatoid arthritis.


Assuntos
Artrite Reumatoide/imunologia , Artrite Reumatoide/metabolismo , Proteínas Morfogenéticas Ósseas/metabolismo , Simulação por Computador , Fatores de Diferenciação de Crescimento/metabolismo , Inflamação/patologia , Interleucina-6/antagonistas & inibidores , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Sequência de Aminoácidos , Disponibilidade Biológica , Proteínas Morfogenéticas Ósseas/genética , Fatores de Diferenciação de Crescimento/genética , Humanos , Interleucina-6/metabolismo , Ligantes , Simulação de Acoplamento Molecular , Peptídeos/química , Peptídeos/metabolismo , Peptídeos/farmacocinética , Filogenia , Fator de Necrose Tumoral alfa/metabolismo
11.
Nutrients ; 13(4)2021 Apr 16.
Artigo em Inglês | MEDLINE | ID: mdl-33923766

RESUMO

Benefits and harms of different components of human diet have been known for hundreds of years. Alcohol is one the highest consumed, abused, and addictive substances worldwide. Consequences of alcohol abuse are increased risks for diseases of the cardiovascular system, liver, and nervous system, as well as reduced immune system function. Paradoxically, alcohol has also been a consistent protective factor against the development of autoimmune diseases such as type 1 diabetes, multiple sclerosis, systemic lupus erythematosus, and rheumatoid arthritis (RA). Here, we focused on summarizing current findings on the effects of alcohol, as well as of its metabolites, acetaldehyde and acetate, on the immune system and RA. Heavy or moderate alcohol consumption can affect intestinal barrier integrity, as well as the microbiome, possibly contributing to RA. Additionally, systemic increase in acetate negatively affects humoral immune response, diminishing TFH cell as well as professional antigen-presenting cell (APC) function. Hence, alcohol consumption has profound effects on the efficacy of vaccinations, but also elicits protection against autoimmune diseases. The mechanism of alcohol's negative effects on the immune system is multivariate. Future studies addressing alcohol and its metabolite acetate's effect on individual components of the immune system remains crucial for our understanding and development of novel therapeutic pathways.


Assuntos
Consumo de Bebidas Alcoólicas/imunologia , Artrite Reumatoide/imunologia , Etanol/farmacologia , Sistema Imunitário/efeitos dos fármacos , Substâncias Protetoras/farmacologia , Acetaldeído/imunologia , Acetaldeído/farmacologia , Acetatos/imunologia , Acetatos/farmacologia , Etanol/imunologia , Humanos
12.
Nat Commun ; 12(1): 2343, 2021 04 20.
Artigo em Inglês | MEDLINE | ID: mdl-33879788

RESUMO

In healthy joints, synovial fibroblasts (SFs) provide the microenvironment required to mediate homeostasis, but these cells adopt a pathological function in rheumatoid arthritis (RA). Carbohydrates (glycans) on cell surfaces are fundamental regulators of the interactions between stromal and immune cells, but little is known about the role of the SF glycome in joint inflammation. Here we study stromal guided pathophysiology by mapping SFs glycosylation pathways. Combining transcriptomic and glycomic analysis, we show that transformation of fibroblasts into pro-inflammatory cells is associated with glycan remodeling, a process that involves TNF-dependent inhibition of the glycosyltransferase ST6Gal1 and α2-6 sialylation. SF sialylation correlates with distinct functional subsets in murine experimental arthritis and remission stages in human RA. We propose that pro-inflammatory cytokines remodel the SF-glycome, converting the synovium into an under-sialylated and highly pro-inflammatory microenvironment. These results highlight the importance of glycosylation in stromal immunology and joint inflammation.


Assuntos
Artrite Reumatoide/metabolismo , Artrite Reumatoide/patologia , Ácidos Siálicos/metabolismo , Membrana Sinovial/metabolismo , Membrana Sinovial/patologia , Animais , Artrite Experimental/patologia , Artrite Reumatoide/imunologia , Linhagem Celular , Citocinas/metabolismo , Regulação para Baixo , Fibroblastos/imunologia , Fibroblastos/metabolismo , Fibroblastos/patologia , Glicosilação , Humanos , Inflamação/imunologia , Inflamação/metabolismo , Inflamação/patologia , Masculino , Redes e Vias Metabólicas , Camundongos , Camundongos Endogâmicos DBA , Fenótipo , RNA-Seq , Sialiltransferases/genética , Sialiltransferases/metabolismo , Membrana Sinovial/imunologia , Transcriptoma
13.
Int J Mol Sci ; 22(6)2021 Mar 13.
Artigo em Inglês | MEDLINE | ID: mdl-33805757

RESUMO

Tumor necrosis factor-alpha (TNF-α) is a multifunctional Th1 cytokine and one of the most important inflammatory cytokines. In pregnancy, TNF-α influences hormone synthesis, placental architecture, and embryonic development. It was also shown that increased levels of TNF-α are associated with pregnancy loss and preeclampsia. Increased TNF-α levels in complicated pregnancy draw attention to trophoblast biology, especially migratory activity, syncytialisation, and endocrine function. Additionally, elevated TNF-α levels may affect the maternal-fetal relationship by altering the secretory profile of placental immunomodulatory factors, which in turn affects maternal immune cells. There is growing evidence that metabolic/pro-inflammatory cytokines can program early placental functions and growth in the first trimester of pregnancy. Furthermore, early pregnancy placenta has a direct impact on fetal development and maternal immune system diseases that release inflammatory (e.g., TNF-α) and immunomodulatory factors, such as chronic inflammatory rheumatic, gastroenterological, or dermatological diseases, and may result in an abnormal release of cytokines and chemokines in syncytiotrophoblasts. Pregnancy poses a challenge in the treatment of chronic disease in patients who plan to have children. The activity of the disease, the impact of pregnancy on the course of the disease, and the safety of pharmacotherapy, including anti-rheumatic agents, in pregnancy should be considered.


Assuntos
Antirreumáticos/uso terapêutico , Artrite Reumatoide/tratamento farmacológico , Gastrite/tratamento farmacológico , Fármacos Gastrointestinais/uso terapêutico , Primeiro Trimestre da Gravidez/efeitos dos fármacos , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Adalimumab/uso terapêutico , Anticorpos Monoclonais/uso terapêutico , Artrite Reumatoide/imunologia , Artrite Reumatoide/patologia , Aleitamento Materno , Certolizumab Pegol/uso terapêutico , Etanercepte/uso terapêutico , Feminino , Gastrite/imunologia , Gastrite/patologia , Humanos , Infliximab/uso terapêutico , Parto/efeitos dos fármacos , Gravidez , Primeiro Trimestre da Gravidez/imunologia , Equilíbrio Th1-Th2/efeitos dos fármacos , Fator de Necrose Tumoral alfa/imunologia
14.
Int J Mol Sci ; 22(7)2021 Mar 29.
Artigo em Inglês | MEDLINE | ID: mdl-33805383

RESUMO

There is evidence that berberine (BBR), a clinically relevant plant compound, ameliorates clinically apparent collagen-induced arthritis (CIA) in vivo. However, to date, there are no studies involving the use of BBR which explore its prophylactic potential in this model of rheumatoid arthritis (RA). The aim of this study was to determine if prophylactic BBR use during the preclinical phase of collagen-induced arthritis would delay arthritic symptom onset, and to characterize the cellular mechanism underlying such an effect. DBA/1J mice were injected with an emulsion of bovine type II collagen (CII) and complete Freund's adjuvant (day 0) and a booster injection of CII in incomplete Freund's adjuvant (day 18) to induce arthritis. Mice were then given i.p. injections of 1 mg/kg/day of BBR or PBS (vehicle with 0.01% DMSO) from days 0 to 28, were left untreated (CIA control), or were in a non-arthritic control group (n = 15 per group). Incidence of arthritis in BBR-treated mice was 50%, compared to 90% in both the CIA and PBS controls. Populations of B and T cells from the spleens and draining lymph nodes of mice were examined on day 14 (n = 5 per group) and day 28 (n = 10 per group). BBR-treated mice had significantly reduced populations of CD4+Th and CD4+CXCR5+ Tfh cells, and an increased proportion of Foxp3+ Treg at days 14 and 28, as well as reduced expression of co-stimulatory molecules CD28 and CD154 at both endpoints. The effect seen on T cell populations and co-stimulatory molecule expression in BBR-treated mice was not mirrored in CD19+ B cells. Additionally, BBR-treated mice experienced reduced anti-CII IgG2a and anti-CII total IgG serum concentrations. These results indicate a potential role for BBR as a prophylactic supplement for RA, and that its effect may be mediated specifically through T cell suppression. However, the cellular effector involved raises concern for BBR prophylactic use in the context of vaccine efficacy and other primary adaptive immune responses.


Assuntos
Artrite Experimental/prevenção & controle , Berberina/farmacologia , Linfócitos T/efeitos dos fármacos , Animais , Artrite Experimental/induzido quimicamente , Artrite Experimental/imunologia , Artrite Reumatoide/induzido quimicamente , Artrite Reumatoide/imunologia , Artrite Reumatoide/prevenção & controle , Linfócitos B , Berberina/uso terapêutico , Colágeno Tipo II/toxicidade , Imunoglobulina G/sangue , Camundongos , Camundongos Endogâmicos DBA , Substâncias Protetoras/farmacologia , Substâncias Protetoras/uso terapêutico , Linfócitos T/imunologia
15.
Nat Rev Rheumatol ; 17(4): 224-237, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33674813

RESUMO

Rheumatoid arthritis (RA) is a chronic autoimmune inflammatory disorder that primarily affects the joints. One hypothesis for the pathogenesis of RA is that disease begins at mucosal sites as a consequence of interactions between the mucosal immune system and an aberrant local microbiota, and then transitions to involve the synovial joints. Alterations in the composition of the microbial flora in the lungs, mouth and gut in individuals with preclinical and established RA suggest a role for mucosal dysbiosis in the development and perpetuation of RA, although establishing whether these alterations are the specific consequence of intestinal involvement in the setting of a systemic inflammatory process, or whether they represent a specific localization of disease, is an ongoing challenge. Data from mouse models of RA and investigations into the preclinical stages of disease also support the hypothesis that these alterations to the microbiota predate the onset of disease. In addition, several therapeutic options widely used for the treatment of RA are associated with alterations in intestinal microbiota, suggesting that modulation of intestinal microbiota and/or intestinal barrier function might be useful in preventing or treating RA.


Assuntos
Artrite Reumatoide/imunologia , Artrite Reumatoide/microbiologia , Articulações/patologia , Microbiota/imunologia , Membrana Mucosa/imunologia , Animais , Antirreumáticos/efeitos adversos , Artrite Reumatoide/metabolismo , Artrite Reumatoide/patologia , Modelos Animais de Doenças , Disbiose/complicações , Disbiose/imunologia , Feminino , Microbioma Gastrointestinal/efeitos dos fármacos , Microbioma Gastrointestinal/imunologia , Humanos , Articulações/imunologia , Masculino , Camundongos , Microbiota/efeitos dos fármacos , Membrana Mucosa/microbiologia , Receptores de Superfície Celular/efeitos dos fármacos , Receptores de Superfície Celular/imunologia , Receptores de Superfície Celular/metabolismo , Líquido Sinovial/imunologia
16.
Cell Mol Gastroenterol Hepatol ; 12(1): 321-333, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33689803

RESUMO

The Inflammatory Bowel Diseases (IBD), Ulcerative Colitis (UC) and Crohn's Disease (CD) are characterised by chronic non-resolving gut mucosal inflammation involving innate and adaptive immune responses. Neutrophils, usually regarded as first responders in inflammation, are a key presence in the gut mucosal inflammatory milieu in IBD. Here, we review the role of neutrophil extracellular trap (NET) formation as a potential effector disease mechanism. NETs are extracellular webs of chromatin, microbicidal proteins and oxidative enzymes that are released by neutrophils to contain pathogens. NETs contribute to the pathogenesis of several immune-mediated diseases such as systemic lupus erythematosus and rheumatoid arthritis; and recently, as a major tissue damaging process involved in the host response to severe acute respiratory syndrome coronavirus 2 infection. NETs are pertinent as a defence mechanism at the gut mucosal interphase exposed to high levels of bacteria, viruses and fungi. On the other hand, NETs can also potentiate and perpetuate gut inflammation. In this review, we discuss the broad protective vs. pathogenic roles of NETs, explanatory factors that could lead to an increase in NET formation in IBD and how NETs may contribute to gut inflammation and IBD-related complications. Finally, we summarise therapeutic opportunities to target NETs in IBD.


Assuntos
Armadilhas Extracelulares/imunologia , Doenças Inflamatórias Intestinais/imunologia , Neutrófilos/imunologia , Pesquisa Médica Translacional , Artrite Reumatoide/imunologia , Artrite Reumatoide/patologia , Artrite Reumatoide/terapia , COVID-19/imunologia , COVID-19/patologia , COVID-19/terapia , Humanos , Doenças Inflamatórias Intestinais/patologia , Doenças Inflamatórias Intestinais/terapia , Lúpus Eritematoso Sistêmico/imunologia , Lúpus Eritematoso Sistêmico/patologia , Lúpus Eritematoso Sistêmico/terapia , Neutrófilos/patologia , SARS-CoV-2
17.
Curr Med Res Opin ; 37(6): 929-938, 2021 06.
Artigo em Inglês | MEDLINE | ID: covidwho-1146331

RESUMO

In March 2020, COVID-19 infection caused by SARS-CoV-2 has been declared to be a global pandemic, where its complications, severity and mortality are reported to be due to the released inflammatory cytokines or the so-called cytokine storm. This is quite similar to that observed in the autoimmune and chronic inflammatory rheumatic disease, rheumatoid arthritis (RA). It was hypothesized that RA patients are at a higher risk of acquiring COVID-19; however, recent studies reported that they are not when compared to the rest of the population. In this review, we aim to highlight the mutual pathological features, cytokine profiles and risk factors between COVID-19 and RA. Also, many researchers are currently working to explore therapeutic agents that could aid in the eradication of COVID-19 infection. Due to the similarity between the inflammation status in COVID-19 and RA, many anti-rheumatic drugs such as hydroxychloroquine, tocilizumab, baricitinib and anakinra were proposed to be therapeutic modalities for COVID-19 infection.


Assuntos
Artrite Reumatoide , COVID-19 , Síndrome da Liberação de Citocina , Antirreumáticos/uso terapêutico , Artrite Reumatoide/complicações , Artrite Reumatoide/tratamento farmacológico , Artrite Reumatoide/imunologia , COVID-19/complicações , COVID-19/tratamento farmacológico , COVID-19/imunologia , Síndrome da Liberação de Citocina/etiologia , Síndrome da Liberação de Citocina/imunologia , Citocinas/sangue , Humanos , Fatores de Risco
18.
Rheumatol Int ; 41(5): 903-909, 2021 05.
Artigo em Inglês | MEDLINE | ID: covidwho-1114295

RESUMO

To examine whether patients with inflammatory arthritis (IA) treated with conventional synthetic (cs) disease-modifying anti-rheumatic drugs (DMARDs) and/or biologic (b) DMARDs, could be affected from SARS-CoV-2 infection and to explore the COVID-19 disease course and outcome in this population. This is a prospective observational study. During the period February-December 2020, 443 patients with IA who were followed-up in the outpatient arthritis clinic were investigated. All patients were receiving cs and/or bDMARDs. During follow-up, the clinical, laboratory findings, comorbidities and drug side effects were all recorded and the treatment was adjusted or changed according to clinical manifestations and patient's needs. There were 251 patients with rheumatoid arthritis (RA), 101 with psoriatic arthritis (PsA) and 91 with ankylosing spondylitis (AS). We identified 32 patients who contracted COVID-19 (17 RA, 8 PsA, 7 AS). All were in remission and all drugs were discontinued. They presented mild COVID-19 symptoms, expressed mainly with systemic manifestations and sore throat, while six presented olfactory dysfunction and gastrointestinal disturbances, and all of them had a favorable disease course. However, three patients were admitted to the hospital, two of them with respiratory symptoms and pneumonia and were treated appropriately with excellent clinical response and outcome. Patients with IA treated with cs and/or bDMARDs have almost the same disease course with the general population when contract COVID-19.


Assuntos
Artrite Reumatoide/complicações , COVID-19/complicações , Adulto , Antirreumáticos/imunologia , Antirreumáticos/uso terapêutico , Artrite Reumatoide/tratamento farmacológico , Artrite Reumatoide/imunologia , Produtos Biológicos/imunologia , Produtos Biológicos/uso terapêutico , COVID-19/diagnóstico , COVID-19/tratamento farmacológico , COVID-19/imunologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , SARS-CoV-2 , Índice de Gravidade de Doença , Resultado do Tratamento
19.
Cell Mol Gastroenterol Hepatol ; 12(1): 321-333, 2021.
Artigo em Inglês | MEDLINE | ID: covidwho-1118539

RESUMO

The Inflammatory Bowel Diseases (IBD), Ulcerative Colitis (UC) and Crohn's Disease (CD) are characterised by chronic non-resolving gut mucosal inflammation involving innate and adaptive immune responses. Neutrophils, usually regarded as first responders in inflammation, are a key presence in the gut mucosal inflammatory milieu in IBD. Here, we review the role of neutrophil extracellular trap (NET) formation as a potential effector disease mechanism. NETs are extracellular webs of chromatin, microbicidal proteins and oxidative enzymes that are released by neutrophils to contain pathogens. NETs contribute to the pathogenesis of several immune-mediated diseases such as systemic lupus erythematosus and rheumatoid arthritis; and recently, as a major tissue damaging process involved in the host response to severe acute respiratory syndrome coronavirus 2 infection. NETs are pertinent as a defence mechanism at the gut mucosal interphase exposed to high levels of bacteria, viruses and fungi. On the other hand, NETs can also potentiate and perpetuate gut inflammation. In this review, we discuss the broad protective vs. pathogenic roles of NETs, explanatory factors that could lead to an increase in NET formation in IBD and how NETs may contribute to gut inflammation and IBD-related complications. Finally, we summarise therapeutic opportunities to target NETs in IBD.


Assuntos
Armadilhas Extracelulares/imunologia , Doenças Inflamatórias Intestinais/imunologia , Neutrófilos/imunologia , Pesquisa Médica Translacional , Artrite Reumatoide/imunologia , Artrite Reumatoide/patologia , Artrite Reumatoide/terapia , COVID-19/imunologia , COVID-19/patologia , COVID-19/terapia , Humanos , Doenças Inflamatórias Intestinais/patologia , Doenças Inflamatórias Intestinais/terapia , Lúpus Eritematoso Sistêmico/imunologia , Lúpus Eritematoso Sistêmico/patologia , Lúpus Eritematoso Sistêmico/terapia , Neutrófilos/patologia , SARS-CoV-2
20.
Front Immunol ; 12: 607315, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33679743

RESUMO

Dendritic cells (DCs) are professional antigen-presenting cells involved in the initiation of immune responses. We generated a tolerogenic DC (tolDC) line that constitutively secretes interleukin-10 (IL10-DCs), expressed lower levels of co-stimulatory and MHCII molecules upon stimulation, and induced antigen-specific proliferation of T cells. Vaccination with IL10-DCs combined with another tolDC line that secretes IL-35, reduced antigen-specific local inflammation in a delayed-type hypersensitivity assay independently on regulatory T cell differentiation. In an autoimmune model of rheumatoid arthritis, vaccination with the combined tolDCs after the onset of the disease impaired disease development and promoted recovery of mice. After stable memory was established, the tolDCs promoted CD4 downregulation and induced lymphocyte activation gene 3 (LAG-3) expression in reactivated memory T cells, reducing T cell activation. Taken together, our findings indicate the benefits of combining anti-inflammatory cytokines in an antigen-specific context to treat excessive inflammation when memory is already established.


Assuntos
Antígenos CD/genética , Células Dendríticas/imunologia , Células Dendríticas/metabolismo , Memória Imunológica , Interleucina-10/biossíntese , Subunidade p35 da Interleucina-12/biossíntese , Linfócitos T/imunologia , Linfócitos T/metabolismo , Animais , Artrite Reumatoide/imunologia , Artrite Reumatoide/metabolismo , Artrite Reumatoide/patologia , Artrite Reumatoide/terapia , Comunicação Celular/imunologia , Linhagem Celular , Citocinas/metabolismo , Feminino , Expressão Gênica , Antígenos de Histocompatibilidade Classe II/genética , Antígenos de Histocompatibilidade Classe II/imunologia , Tolerância Imunológica , Imunomodulação , Imunoterapia/métodos , Ativação Linfocitária/genética , Ativação Linfocitária/imunologia , Camundongos , Camundongos Knockout , Vacinas/administração & dosagem , Vacinas/imunologia
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