RESUMO
BACKGROUND: Coronavirus disease-2019 (COVID-19) is a worldwide pandemic. We present the clinical characteristics and outcomes of 28 COVID-19 patients treated in our hospital in Taiwan. METHODS: Patients with COVID-19, confirmed by positive real-time reverse-transcriptase polymerase chain reaction results for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) viral nucleic acids from oropharyngeal swab specimens between February 4, 2020 and July 6, 2020, were enrolled. Their clinical characteristics and outcomes were reviewed. RESULTS: Seventeen of the 28 patients (60.7%) had pneumonia. The most frequent symptoms were cough (n = 23, 82.1%) and fever (n = 17, 60.7%). The development of pneumonia was associated with age ≥40 years (p < 0.024), body mass index (BMI) ≥25 kg/m2 (p = 0.014), fever (p = 0.007), shortness of breath (p = 0.036), chills ((p = 0.047), and lower platelet counts (<200,000/µL) (p = 0.007). Increased quarantine duration was associated with age ≥40 years (p = 0.026), Charlson index ≥1 (p = 0.037), lower lymphocyte (<1500/uL; p = 0.028) or platelet counts (<200,000/µL) (p = 0.016), lower serum sodium (<140 mEq/L; p = 0.006), and higher C-reactive protein (CRP) level (≥1 mg/dl; p = 0.04). Treatment with hydroxychloroquine or in combination with other medicines did not reduce the quarantine duration. All 28 patients recovered with a median quarantine duration of 27.2 days. CONCLUSION: COVID-19 patients with older age, higher BMI, fever, chills or shortness of breath, lower serum sodium level, lower platelet or lymphocyte count, and higher CRP level may be associated with developing pneumonia or longer quarantine duration.
Assuntos
Teste de Ácido Nucleico para COVID-19/métodos , COVID-19 , Pneumonia Viral , SARS-CoV-2/isolamento & purificação , Adulto , Fatores Etários , Contagem de Células Sanguíneas/métodos , Índice de Massa Corporal , Proteína C-Reativa/análise , COVID-19/sangue , COVID-19/epidemiologia , COVID-19/fisiopatologia , COVID-19/terapia , Feminino , Hospitalização/estatística & dados numéricos , Humanos , Masculino , Pessoa de Meia-Idade , Avaliação de Resultados em Cuidados de Saúde , Pneumonia Viral/diagnóstico , Pneumonia Viral/epidemiologia , Pneumonia Viral/etiologia , Quarentena , Fatores de Risco , Avaliação de Sintomas/métodos , Taiwan/epidemiologiaAssuntos
Cegueira/diagnóstico , Infecções por HIV/complicações , Sífilis/complicações , Administração Intravenosa , Adulto , Fármacos Anti-HIV/uso terapêutico , Coinfecção , Infecções por HIV/tratamento farmacológico , Humanos , Masculino , Exame Neurológico , Oftalmoscopia , Paresia/etiologia , Penicilina G/administração & dosagem , Penicilina G/uso terapêutico , Sífilis/diagnóstico , Sífilis/tratamento farmacológico , Sorodiagnóstico da Sífilis , Resultado do TratamentoRESUMO
Atopic dermatitis (AD) is a persistent skin disease typified by symptoms of dry skin and recurrent eczema. Patients with AD are at heightened risk for Staphylococcus aureus infection. Group 2 innate lymphoid cells (ILC2s) are mainly activated by epithelial cell-derived cytokines IL-33 and involved in the pathogenesis of AD. However, little is known about the effect of skin delipidization on the epithelial cell-derived cytokines and dermal ILC2s in AD. In our study, we investigated the mechanism by which S. aureus infection modulates and exacerbates the pathogenesis of dry skin, leading to type 2 inflammation in the context of innate immunity. In vivo, we found that S. aureus infection aggravated delipidization-induced dermal IL-33 release and dermal ILC2 accumulation, which exacerbated skin inflammation. We also noticed that Il33fl/fl K14cre mice and Tlr2-/- mice exhibited attenuated skin inflammation. In vitro, treatment with necroptosis inhibitors reduced IL-33 release from S. aureus-infected keratinocytes. Mechanistically, we observed an increase in the necroptosis-associated kinases, MLKL and RIPK3, in S. aureus-infected mice, indicating that IL-33 release was associated with necroptotic cell death responses. Our results reveal that S. aureus infection-elicited keratinocyte necroptosis contributes to IL-33-mediated type 2 inflammation, which exacerbates the pathogenesis of dry skin.
Assuntos
Dermatite Atópica , Ictiose , Infecções Estafilocócicas , Humanos , Camundongos , Animais , Imunidade Inata , Staphylococcus aureus , Interleucina-33/metabolismo , Necroptose , Linfócitos , Inflamação/patologia , Citocinas/metabolismo , Proteína Serina-Treonina Quinases de Interação com Receptores/metabolismo , Proteínas Quinases/metabolismoAssuntos
Proteínas do Sistema Complemento/deficiência , Infecções por Vírus Epstein-Barr/complicações , Síndrome do Desconforto Respiratório/virologia , Urticária/imunologia , Vasculite/imunologia , Diagnóstico Precoce , Humanos , Masculino , Pessoa de Meia-Idade , Síndrome do Desconforto Respiratório/diagnóstico por imagem , Tomografia Computadorizada por Raios X , Urticária/virologia , Vasculite/virologiaRESUMO
In this study, we selected bacteremic Klebsiella pneumoniae isolates from the Taiwan Surveillance of Antimicrobial Resistance program. A total of 521 isolates were collected over a period of 2 decades, including 121 from 1998, 197 from 2008, and 203 from 2018. Seroepidemiology showed that the top five capsular polysaccharide types were serotypes K1, K2, K20, K54, and K62, constituting 48.5% of the total isolates, and the respective ratios at each time point have remained similar over the past 2 decades. The antibacterial susceptibility tests showed that K1, K2, K20, and K54 were susceptible to most antibiotics, while K62 was relatively resistant compared to other typeable and nontypeable strains. In addition, six virulence-associated genes, clbA, entB, iroN, rmpA, iutA, and iucA, were predominant in K1 and K2 isolates of K. pneumoniae. In conclusion, serotypes K1, K2, K20, K54, and K62 of K. pneumoniae are the most prevalent serotypes and carry more virulence determinants in bacteremia patients, which may indicate their invasiveness. If further serotype-specific vaccine development is performed, these five serotypes should be included. Since the antibiotic susceptibility profiles were stable over a long duration, empirical treatment may be predicted according to serotype if rapid diagnosis from direct clinical specimens is available, such as PCR or antigen serotyping for serotype K1 and K2. IMPORTANCE This is the first nationwide study to examine the seroepidemiology of Klebsiella pneumoniae using blood culture isolates collected over a period of 20 years. The study found that the prevalence of serotypes remained consistent over the 20-year period, with high-prevalence serotypes associated with invasive types. Nontypeable isolates had fewer virulence determinants than other serotypes. With the exception of serotype K62, the other high-prevalence serotypes were highly susceptible to antibiotics. If rapid diagnosis using direct clinical specimens, such as PCR or antigen serotyping, is available, empirical treatment can be predicted based on serotype, particularly for K1 and K2. The results of this seroepidemiology study could also help the development of future capsule polysaccharide vaccines.
Assuntos
Bacteriemia , Infecções por Klebsiella , Humanos , Virulência/genética , Klebsiella pneumoniae , Taiwan/epidemiologia , Estudos Soroepidemiológicos , Fatores de Virulência/genética , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Polissacarídeos , Bacteriemia/epidemiologia , Bacteriemia/tratamento farmacológico , Infecções por Klebsiella/microbiologiaRESUMO
BACKGROUND/PURPOSE: Clinical characteristics of patients in the first community outbreak of coronavirus disease 2019 (COVID-19) by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variant B.1.1.7 in Taiwan have not been characterized. METHODS: SARS-CoV-2 positive specimens from inpatients between May 7 and June 15 in 2021were screen for SARS-CoV-2 B.1.1.7 lineage by VirSNiP assay. Clinical characteristics were reviewed and compared with those from Feb 1 to April 30, 2020 and from Jan 1 to March 31, 2022. RESULTS: One hundred forty-one inpatients from May 7 to June 15, 2021 infected with SARS-CoV-2 B.1.1.7 lineage were included. The major presenting symptoms were fever (88.7%) and cough (59.6%). Incidence of relevant complications including pulmonary embolism, simultaneous infections with bacteria, virus, and fungi were 0.7%, 12.8%, 13.5%, and 2.1%, respectively. Old age, high Charlson comorbidity index, short of breath, and initial critical illness were independently associated with 28-day mortality (all p < 0.05). In comparison to COVID-19 inpatients from Feb 1 to April 30, 2020, patients from the outbreak by SARS-CoV-2 B.1.1.7 lineage were older, more severe in disease condition, higher mortality but less obvious initial presenting symptoms. After implementation of nationwide vaccination campaign in the next half year of 2021, COVID-19 inpatients from Jan 1 to March 31 in 2022 indicated less severe diseases than those infected with SARS-CoV-2 B.1.1.7 lineage. CONCLUSION: COVID-19 inpatients by SARS-CoV-2 variant B.1.1.7 with old age, multiple comorbidities, and more severe disease conditions were associated with increased mortality. Vaccination for this vulnerable populations may be helpful.
Assuntos
COVID-19 , SARS-CoV-2 , Humanos , SARS-CoV-2/genética , COVID-19/diagnóstico , COVID-19/epidemiologia , Taiwan/epidemiologia , Surtos de DoençasRESUMO
BACKGROUND: Coronavirus disease 2019 (COVID-19) inpatients may acquire infections from other pathogens during hospital admission. This is the first research on this subject to be reported from Taiwan. METHODS: Confirmed COVID-19 inpatients were enrolled in this study from January 1, 2020 to July 31, 2021. Various types of pathogens in COVID-19 inpatients, with hospital-acquired infections, were identified and analyzed. The clinical characteristics of COVID-19 patients with and without hospital-acquired infections were reviewed and compared. RESULTS: Of the 204 patients included in the study, 32 (15.7%) patients experienced at least one infectious episode. Of 113 recorded episodes of infection, the predominant type was bacterial (88 of 113 infections, 77.9%); the most frequently isolated bacteria were Acinetobacter spp., followed by Stenotrophomonas maltophilia . With regard to viral infections (19 of 113, 16.8%), the Epstein-Barr virus ranked first place among the identified viruses. Four (3.5%) and 2 (1.8%) of 113 infectious episodes were caused by fungi and atypical pathogens. A multivariate analysis revealed that steroid use was an independent factor in hospital-acquired infections (odds ratio [OR], 6.97; 95% confidence interval [CI], 1.15-42.43; p = 0.035). Patients with hospital-acquired infections were associated with increased 28-day and in-hospital mortality (18.8% vs 5.8% and 31.3% and 5.8%; p = 0.023 and <0.01, respectively), and a longer hospital stay (34 vs 19 days; p < 0.001), compared to those without hospital-acquired infections. CONCLUSION: Our study revealed the unique local epidemiology of hospital-acquired infections among COVID-19 inpatients in Taiwan. These patients were associated with increased mortality and prolonged hospital admissions.
Assuntos
COVID-19 , Infecção Hospitalar , Infecções por Vírus Epstein-Barr , Infecção Hospitalar/epidemiologia , Herpesvirus Humano 4 , Hospitais , Humanos , Estudos Retrospectivos , Esteroides , Taiwan/epidemiologiaRESUMO
Numerous studies have implicated a connection between schizophrenia and autoimmune disorders. However, the precise relationship and underlying mechanism are still obscure. To further identify the association between autoimmune disorders and schizophrenia, the mRNA expressions of various cytokines and Toll-like receptors (TLRs) in monocytes are examined by using RT-PCR. Additionally, ELISA and zymography were performed to determine the anti-cardiolipin antibody (aCL) and MMP9 activity in serum form schizophrenic patients. Notably, significantly increased interleukin (IL)-6 and IL-10 mRNA were observed in schizophrenic patients, whereas significant reductions of TLR-3 and TLR-5 mRNA were detected. Moreover, significantly increased levels of aCL antibody and a higher frequency of positive-MMP9 activity were detected in serum from patients with schizophrenia. Meanwhile, no significant association was found between each of the medications and aCL activity. These findings demonstrated autoimmune-related phenomena in schizophrenic patients and further suggested a connection between schizophrenia and autoimmune disorders.
Assuntos
Anticorpos Anticardiolipina/sangue , Citocinas/metabolismo , Esquizofrenia/sangue , Esquizofrenia/imunologia , Receptores Toll-Like/genética , Adulto , Análise de Variância , Citocinas/genética , Ensaio de Imunoadsorção Enzimática , Regulação da Expressão Gênica/fisiologia , Humanos , Masculino , Metaloproteinase 9 da Matriz/sangue , Pessoa de Meia-Idade , Monócitos/metabolismo , RNA Mensageiro/metabolismo , Esquizofrenia/patologia , Receptores Toll-Like/metabolismoRESUMO
Both cell-mediated and humoral immunity have been widely investigated for the roles in pathogenesis of human parvovirus B19 (B19) infection. However, little is known about the effects of B19 infection on innate immunity. In the current study, expression of alpha-human neutrophil peptides (HNP) 1-3, alpha-human defensin (HD) 5, HD6, beta-human defensin (hBD)-1, hBD-3, toll-like receptor (TLR) 4, TLR5, TLR7 and TLR9 in B19-nonstructural protein (NS)-1 or B19-viral protein (VP)-2 transfected COS-7 cells was investigated by reverse transcription (RT)-PCR or by western blots. Significantly increased HNP1-3, HD5, HD6, hBD1 and hBD3 mRNA levels were detected at both 24 h and 20 days post-transfection in COS-7 cells transfected with pEGFP-NS1. In pEGFP-VP2-transfected COS-7 cells, significantly increased HNP1-3, HD5, HD6, hBD-1 and hBD-3 mRNA expression levels were observed on day 20, albeit only hBD3 mRNA increased significantly at 24 h post-transfection. Additionally, TLR4, TLR5 and TLR7 proteins decreased significantly in COS-7 cells transfected with pEGFP-NS1 or pEGFP-VP2 at 48 h but significantly increased on day 20. Notably, only TLR9 protein increased significantly in the cells transfected with pEGFP-NS1 on day 20. No significant variation of TLRs was observed in cells transfected with pEGFP-NS1K334E, a single substitution mutantation of B19-NS1 protein without original cytotoxicity, at both 48 h and on day 20. These novel findings revealed the different effects of B19-NS1 and VP2 on the stimulation of defensins and TLRs and could provide a clue in understanding the roles of B19-NS1 and VP2 on innate immunity.
Assuntos
Defensinas/genética , Parvovirus B19 Humano , Receptores Toll-Like/genética , Animais , Células COS , Chlorocebus aethiops , Imunidade Inata , RNA Mensageiro/análiseRESUMO
BACKGROUND: Human parvovirus B19 (B19) is known to induce apoptosis that has been associated with a variety of autoimmune disorders. Although we have previously reported that B19 non-structural protein (NS1) induces mitochondrial-dependent apoptosis in COS-7 cells, the precise mechanism of B19-NS1 in developing autoimmunity is still obscure. METHODS: To further examine the effect of B19-NS1 in presence of autoantigens, COS-7 cells were transfected with pEGFP, pEGFP-B19-NS1 and pEGFP-NS1K334E, a mutant form of B19-NS1, and detected the expressions of autoantigens by various autoantibodies against Sm, U1 small nuclear ribonucleoprotein (U1-snRNP), SSA/Ro, SSB/La, Scl-70, Jo-1, Ku, and centromere protein (CENP) A/B by using Immunoblotting. RESULTS: Significantly increased apoptosis was detected in COS-7 cells transfected with pEGFP-B19-NS1 compared to those transfected with pEGFP. Meanwhile, the apoptotic 70 kDa U1-snRNP protein in COS-7 cells transfected with pEGFP-B19-NS1 is cleaved by caspase-3 and converted into a specific 40 kDa product, which were recognized by anti-U1-snRNP autoantibody. In contrast, significantly decreased apoptosis and cleaved 40 kDa product were observed in COS-7 cells transfected with pEGFP-NS1K334E compared to those transfected with pEGFP-B19-NS1. CONCLUSIONS: These findings suggested crucial association of B19-NS1 in development of autoimmunity by inducing apoptosis and specific cleavage of 70 kDa U1-snRNP.
Assuntos
Autoantígenos/metabolismo , Parvovirus B19 Humano/metabolismo , Ribonucleoproteína Nuclear Pequena U1/imunologia , Ribonucleoproteína Nuclear Pequena U1/metabolismo , Proteínas não Estruturais Virais/metabolismo , Animais , Apoptose/imunologia , Doenças Autoimunes/etiologia , Doenças Autoimunes/imunologia , Doenças Autoimunes/patologia , Sequência de Bases , Células COS , Chlorocebus aethiops , Primers do DNA/genética , DNA Viral/genética , Proteínas de Fluorescência Verde/genética , Proteínas de Fluorescência Verde/metabolismo , Humanos , Mutagênese Sítio-Dirigida , Infecções por Parvoviridae/etiologia , Infecções por Parvoviridae/imunologia , Infecções por Parvoviridae/patologia , Parvovirus B19 Humano/genética , Parvovirus B19 Humano/patogenicidade , Proteínas Recombinantes de Fusão/genética , Proteínas Recombinantes de Fusão/metabolismo , Transfecção , Proteínas não Estruturais Virais/genéticaRESUMO
BACKGROUND: Human parvovirus B19 infection has been postulated to the anti-phospholipid syndrome (APS) in autoimmunity. However, the influence of anti-B19-VP1u antibody in autoimmune diseases is still obscure. METHODS: To elucidate the effect of anti-B19-VP1u antibodies in systemic lupus erythematosus (SLE), passive transfer of rabbit anti-B19-VP1u IgG was injected intravenously into NZB/W F1 mice. RESULTS: Significant reduction of platelet count and prolonged thrombocytopenia time were detected in anti-B19-VP1u IgG group as compared to other groups, whereas significant increases of anti-B19-VP1u, anti-phospholipid (APhL), and anti-double strand DNA (dsDNA) antibody binding activity were detected in anti-B19-VP1u group. Additionally, significant increases of matrix metalloproteinase-9 (MMP9) activity and protein expression were detected in B19-VP1u IgG group. Notably, phosphatidylinositol 3-phosphate kinase (PI3K) and phosphorylated extracellular signal-regulated kinase (ERK) proteins were involved in the induction of MMP9. CONCLUSION: These experimental results firstly demonstrated the aggravated effects of anti-B19-VP1u antibody in disease activity of SLE.
Assuntos
Autoanticorpos/imunologia , Fígado/enzimologia , Lúpus Eritematoso Sistêmico/imunologia , Metaloproteinase 2 da Matriz/metabolismo , Metaloproteinase 9 da Matriz/metabolismo , Parvovirus B19 Humano , Proteínas Virais/imunologia , Animais , Síndrome Antifosfolipídica/imunologia , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Feminino , Humanos , Metaloproteinase 2 da Matriz/genética , Metaloproteinase 9 da Matriz/genética , Camundongos , Parvovirus B19 Humano/genética , Parvovirus B19 Humano/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Coelhos , Proteínas Virais/genéticaRESUMO
BACKGROUND: Activity of secreted phospholipase A (sPLA2) has been implicated in a wide range of cellular responses. However, little is known about the function of human parvovirus B19-VP1 unique region (VP1u) with sPLA2 activity on macrophage. METHODS: To investigate the roles of B19-VP1u in response to macrophage, phospholipase A2 activity, cell migration assay, phagocytosis activity, metalloproteinase assay, RT-PCR and immunoblotting were performed. RESULTS: In the present study, we report that migration, phagocytosis, IL-6, IL-1beta mRNA, and MMP9 activity are significantly increased in RAW264.7 cells by B19-VP1u protein with sPLA2 activity, but not by B19-VP1uD175A protein that is mutated and lacks sPLA2 activity. Additionally, significant increases of phosphorylated ERK1/2 and JNK proteins were detected in macrophages that were treated with B19-VP1u protein, but not when they were treated with B19-VP1uD175A protein. CONCLUSION: Taken together, our experimental results suggest that B19-VP1u with sPLA2 activity affects production of IL-6, IL-1beta mRNA, and MMP9 activity, possibly through the involvement of ERK1/2 and JNK signaling pathways. These findings could provide clues in understanding the role of B19-VP1u and its sPLA2 enzymatic activity in B19 infection and B19-related diseases.
Assuntos
Macrófagos/fisiologia , Parvovirus B19 Humano/enzimologia , Parvovirus B19 Humano/imunologia , Fosfolipases A/metabolismo , Animais , Linhagem Celular , Movimento Celular/fisiologia , MAP Quinases Reguladas por Sinal Extracelular/genética , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Humanos , Interleucina-1beta/genética , Interleucina-1beta/metabolismo , Interleucina-6/genética , Interleucina-6/metabolismo , Proteínas Quinases JNK Ativadas por Mitógeno/genética , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Macrófagos/citologia , Metaloproteinase 9 da Matriz/genética , Metaloproteinase 9 da Matriz/metabolismo , Camundongos , Parvovirus B19 Humano/genética , Fagocitose/fisiologia , Fosfolipases A/genética , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/metabolismoRESUMO
BACKGROUND: Human parvovirus B19 infection has been frequently described as a cause or trigger of various autoimmune diseases. In previous studies, we have postulated the association among human parvovirus B19 (B19)-VP1 unique region (VP1u), production of anti-beta2-glycoprotein I (anti-beta2GPI) antibody and anti-phospholipid syndrome (APS)-like autoimmunity. However, the precise role of B19-VP1u in induction of APS is still obscure. METHODS: To further elucidate the pathogenic roles of VP1u in B19 infection and autoimmunity, we examined the effect of anti-B19-VP1u IgG antibodies on endothelial cells that is recognized to play crucial roles in APS. Human vascular endothelial cells, ECV-304, were incubated with various preparations of purified human or rabbit IgG. The activation of endothelial cells and production of cytokines were assessed by flow cytometry and ELISA, respectively. RESULTS: Purified IgG from rabbits immunized with recombinant B19-VP1u proteins can up-regulate ICAM-1 (CD54), VCAM-1 (CD106), E-selectin (CD62E), MHC class II (HLA-DR, DP, DQ) molecule expression, and TNF-alpha production in endothelial cells as compared to those endothelial cells cultured with control IgG. Additionally, significantly increased phosphorylated-P38 mitogen-activated protein kinase (P38 MAPK) and iNOS were observed in both human anti-beta2GPI IgG and rabbit anti-B19-VP1u IgG treated-ECV-304 cells, respectively. CONCLUSIONS: These experimental results imply that antibodies against B19-VP1u play important roles in the immunopathological processes as well as human anti-beta2GPI IgG that leads to development of APS by involving p38 phosphorylation and iNOS activation. It could provide a clue in understanding the role of anti-B19-VP1u antibodies in APS manifestations.
Assuntos
Proteínas do Capsídeo/imunologia , Moléculas de Adesão Celular/biossíntese , Endotélio Vascular/imunologia , Imunoglobulina G/sangue , Parvovirus B19 Humano/imunologia , Fator de Necrose Tumoral alfa/biossíntese , Animais , Células Cultivadas , Endotélio Vascular/citologia , Endotélio Vascular/virologia , Humanos , Óxido Nítrico Sintase Tipo II/metabolismo , Infecções por Parvoviridae/imunologia , Fosforilação , Coelhos , Regulação para Cima , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismoRESUMO
Increased population with hepatic diseases and apoptosis were found in patients with SLE and implicated in the pathogenesis of SLE. Since cystamine has been demonstrated to be beneficial to NZB/W F1 mice in our previous report, this study intends to investigate the effects of cystamine in liver from NZB/W F1 mice. Decreased apoptosis was detected in liver from NZB/W F1 mice given cystamine as compared to those given PBS by TUNEL and caspase-3 activity assay. Fas-dependent apoptotic proteins including Fas, cleaved caspase-8 and tBid were reduced in liver from NZB/W F1 mice given cystamine as compared to those given PBS. Additionally, the mitochondria-dependent apoptotic proteins including cytochrome c and Apaf-1 were reduced in liver from NZB/W F1 mice given cystamine as compared to those given PBS. Moreover, increased BCL-2 protein was observed in liver from both mice. Notably, increased NF-kappaB protein was detected in liver from NZB/W F1 mice given cystamine as compared to those given PBS. These experimental results suggest the effect of cystamine in reducing apoptosis in liver from NZB/W F1 mice through Fas-dependent and mitochondrial-dependent pathways. The phosphorylation of NF-kappaB (p65) could be a possible mechanism involving anti-apoptotic effects of cystamine in liver from NZB/W F1 mice.
Assuntos
Apoptose/efeitos dos fármacos , Cistamina/farmacologia , Fígado/efeitos dos fármacos , Lúpus Eritematoso Sistêmico/patologia , Animais , Proteína Agonista de Morte Celular de Domínio Interatuante com BH3/metabolismo , Caspase 3/metabolismo , Caspase 8/metabolismo , Inibidores Enzimáticos/farmacologia , Feminino , Fígado/citologia , Fígado/metabolismo , Fígado/patologia , Camundongos , Camundongos Endogâmicos NZB , Proteínas Serina-Treonina Quinases/metabolismo , Transdução de Sinais , Fator de Transcrição RelA/metabolismo , Proteína de Morte Celular Associada a bcl/metabolismo , Receptor fas/metabolismo , Quinase Induzida por NF-kappaBRESUMO
Mounting evidence suggests a connection between human parvovirus B19 (B19) and autoimmune diseases, and especially an association between the B19-VP1 unique region (VP1u) and anti-phospholipid syndrome (APS). However, little is known about the antigenicity of B19-VP1u in the induction of APS-like syndrome. To elucidate the antigenicity of B19-VP1u in the induction of APS, N-terminal truncated B19-VP1u (tVP1u) proteins were prepared to immunize Balb/c mice to generate antibodies against B19-tVP1u proteins. The secreted phospholipase A2 (sPLA2) activities and binding specificity of mice anti-B19-tVP1u antibodies with cardiolipin (CL) and beta-2-glycoprotein I (ß2GPI) were evaluated by performing immunoblot, ELISA and absorption experiments. A mice model of passively induced APS was adopted. Although sPLA2 activities were identified in all B19-tVP1u proteins, only amino acid residues 61-227 B19-tVP1u exhibited a higher sPLA2 activity. Autoantibodies against CL and ß2GPI exhibited binding activities with all B19-tVP1u proteins. IgG that was purified from mice that had been immunized with amino acid residues 21-227 to 121-227 B19-tVP1u proteins exhibited significantly higher binding activity with CL. IgG that was purified from mice that had been immunized with amino acid residues 21-227, 31-227, 82-227 and 91-227 B19-tVP1u proteins exhibited significantly higher binding activity with ß2GPI. Accordingly, significantly higher binding inhibition of CL was detected in the presence of amino acid residues 61-227 and 101-227 B19-tVP1u. Significantly higher binding inhibition of ß2GPI was detected in the presence of amino acid residues 21-227, 31-227, 82-227 and 91-227 B19-tVP1u. The mice that received amino acid residues 31-227 or 61-227 anti-tB19-VP1u IgG revealed significant thrombocytopenia and those that received amino acid residues 21-227, 31-227, 61-227, 71-227, 82-227, 91-227, 101-227 or 114-227 anti-tB19-VP1u IgG exhibited significantly prolonged aPTT. These findings provide further information concerning the role of B19-VP1u antigenicity in APS-like autoimmunity.
Assuntos
Síndrome Antifosfolipídica/imunologia , Proteínas do Capsídeo/química , Proteínas do Capsídeo/imunologia , Parvovirus B19 Humano/imunologia , Animais , Autoantígenos/metabolismo , Proteínas do Capsídeo/antagonistas & inibidores , Cardiolipinas/metabolismo , Modelos Animais de Doenças , Feminino , Imunoglobulina G/sangue , Imunoglobulina G/imunologia , Imunoglobulina G/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Fosfolipases A2 Secretórias/análise , Ligação Proteica , beta 2-Glicoproteína I/metabolismoRESUMO
BACKGROUND: Previous studies have postulated a connection between human parvovirus B19 (B19) infection and anti-phospholipid antibodies (APhL). B19 infection and anti-phospholipid syndrome (APS) exhibit congruent symptoms. Recently, phospholipase A2 (PLA2)-like activity has been linked to the VP1 unique region (VP1u) of B19. However, the precise role of B19-VP1u in pathogenesis of autoimmunity is still obscure. METHODS: To elucidate the roles of VP1u in B19 infection and autoimmunity, the reactivity of B19-VP1u proteins with various autoantibodies were evaluated by ELISA and immunoblotting. Rabbits were immunized with purified recombinant B19-VP1u protein to generate anti-sera. Absorption experiments were conducted to determine the binding specificity of rabbit anti-sera against B19-VP1u, cardiolipin (CL) and beta-2-glycoprotein I (beta2GPI). Moreover, the effects of passive transfer of polyclonal rabbit anti-B19-VP1u IgG antibodies on platelets, activated partial thromboplastin time (aPTT), and autoantibodies were assessed. RESULTS: Autoantibodies against CL, beta2GPI, and phospholipid (PhL) in sera from patients with B19 infection, were cross-reactive with B19-VP1u. Consistently, sera from rabbits immunized with recombinant B19-VP1u protein displayed raised detectable immunoglobulins against B19-VP1u, CL, beta2GPI and PhL. Additionally, the mice immunized with anti-B19-VP1u IgG developed thrombocytopenia, prolongation of aPTT, and autoantibody against beta2GPI and PhL. CONCLUSIONS: These experimental results suggested the association between B19-VP1u and production of anti-beta2GPI antibodies, APhL, and APS-like autoimmunity. Altogether, it may provide a clue in understanding the role of B19-VP1u in inducing autoantibodies and B19-associated APS manifestations.
Assuntos
Anticorpos Antifosfolipídeos/imunologia , Especificidade de Anticorpos/imunologia , Síndrome Antifosfolipídica/imunologia , Autoimunidade/imunologia , Proteínas do Capsídeo/imunologia , Parvovirus B19 Humano/imunologia , Animais , Anticorpos Antifosfolipídeos/metabolismo , Formação de Anticorpos , Síndrome Antifosfolipídica/virologia , Autoanticorpos , Modelos Animais de Doenças , Feminino , Camundongos , Camundongos Endogâmicos BALB C , CoelhosRESUMO
Atopic dermatitis is a complex chronic inflammatory skin disorder that results from intimate interactions among genetic predisposition, host environment, skin barrier defects, and immunological factors. However, a clear genetic roadmap leading to atopic dermatitis remains to be fully explored. From a genome-wide mutagenesis screen, deficiency of ZDHHC13, a palmitoylacyl transferase, has previously been associated with skin and multitissue inflammatory phenotypes. Here, we report that ZDHHC13 is required for skin barrier integrity and that deficiency of ZDHHC13 renders mice susceptible to environmental bacteria, resulting in persistent skin inflammation and an atopic dermatitis-like disease. This phenotype is ameliorated in a germ-free environment and is also attenuated by antibiotic treatment, but not by deletion of the Rag1 gene, suggesting that a microbial factor triggers inflammation rather than intrinsic adaptive immunity. Furthermore, skin from ZDHHC13-deficient mice has both elevated levels of IL-33 and type 2 innate lymphoid cells, reinforcing the role of innate immunity in the development of atopic dermatitis. In summary, our study suggests that loss of ZDHHC13 in skin impairs the integrity of multiple barrier functions and leads to a dermatitis lesion in response to microbial encounters.
Assuntos
Aciltransferases/genética , Citocinas/metabolismo , Dermatite Atópica/genética , Dermatite Atópica/imunologia , Dermatite/microbiologia , Imunidade Inata/genética , Animais , Biomarcadores/análise , Biópsia por Agulha , Citocinas/imunologia , Dermatite/patologia , Dermatite Atópica/patologia , Modelos Animais de Doenças , Ensaio de Imunoadsorção Enzimática , Regulação da Expressão Gênica , Humanos , Imuno-Histoquímica , Lipoilação/genética , Camundongos , Camundongos Mutantes , Distribuição Aleatória , Reação em Cadeia da Polimerase em Tempo RealRESUMO
Lactoferrin (LF) has beneficial effects against various diseases. However, the effects of LF on liver fibrosis in systematic lupus erythematosus (SLE) are unknown. In this study, NZB/W F1 mice were utilized to investigate the effects of LF on SLE. Experiments reveal that LF significantly increases glutathione and 1,1-diphenyl-2-picryl-hydrazyl levels and significantly decreased malondialdehyde levels in both serum and liver in NZB/W F1 mice. LF also lowered matrix metalloproteinase-9 activity and liver inflammatory indices, such as aminotransferase and alanine aminotransferase. Notably, significantly decreased expression of fibrotic related molecules, including transforming growth factor (TGF)-ß1, tumor necrosis factor-α, interleukin-1ß, and TGF-ß1 receptor, were observed in the livers of NZB/W F1 mice that had been treated with LF. Significantly, suppressed Smad2/3 signaling, α-smooth muscle actin, and collagen deposition were also detected. These findings reveal that LF has beneficial effects on SLE by increasing antioxidant activities and ameliorating liver inflammation and fibrosis, suggesting the therapeutic effectiveness of LF against SLE.
Assuntos
Antioxidantes/análise , Colesterol na Dieta/administração & dosagem , Cirrose Hepática/tratamento farmacológico , Cirrose Hepática/etiologia , Lúpus Eritematoso Sistêmico/complicações , Alanina Transaminase/análise , Animais , Aspartato Aminotransferases/análise , Citocinas/análise , Glutationa/análise , Glutationa/sangue , Lactoferrina , Fígado/química , Fígado/enzimologia , Lúpus Eritematoso Sistêmico/tratamento farmacológico , Metaloproteinase 9 da Matriz/metabolismo , Camundongos , Camundongos Endogâmicos NZB , Transdução de Sinais/efeitos dos fármacos , Proteína Smad2 , Proteína Smad3RESUMO
Systemic lupus erythematosus (SLE) is an autoimmune disorder with unknown etiology that impacts various organs including liver. Recently, human parvovirus B19 (B19) is recognized to exacerbate SLE. However, the effects of B19 on liver in SLE are still unclear. Herein we aimed to investigate the effects of B19 on liver in NZB/W F1 mice by injecting subcutaneously with PBS, recombinant B19 NS1, VP1u or VP2, respectively. Our experimental results revealed that B19 NS1 protein significantly enhanced the TGF-ß/Smad fibrotic signaling by increasing the expressions of TGF-ß, Smad2/3, phosphorylated Smad2/3, Smad4 and Sp1. The consequent fibrosis-related proteins, PAI-1 and α-SMA, were also significantly induced in livers of NZB/W F1 mice receiving B19 NS1 protein. Accordingly, markedly increased collagen deposition was also observed in livers of NZB/W F1 mice receiving B19 NS1 protein. However, no significant difference was observed in livers of NZB/W F1 mice receiving B19 VP1u or VP2 as compared to the controls. These findings indicate that B19 NS1 plays a crucial role in exacerbating liver fibrosis in NZB/W F1 mice through enhancing the TGF-â/Smad fibrotic signaling.
Assuntos
Cirrose Hepática/genética , Cirrose Hepática/virologia , Fígado/patologia , Parvovirus B19 Humano/genética , Parvovirus B19 Humano/metabolismo , Actinas/genética , Actinas/metabolismo , Animais , Colágeno/genética , Colágeno/metabolismo , Receptores ErbB/genética , Receptores ErbB/metabolismo , Feminino , Humanos , Fígado/metabolismo , Fígado/virologia , Cirrose Hepática/metabolismo , Camundongos , Camundongos Endogâmicos NZB , Fosforilação/genética , Inibidor 1 de Ativador de Plasminogênio/genética , Inibidor 1 de Ativador de Plasminogênio/metabolismo , Transdução de Sinais/genética , Proteínas Smad/genética , Proteínas Smad/metabolismo , Fator de Crescimento Transformador beta/genética , Fator de Crescimento Transformador beta/metabolismoRESUMO
Human parvovirus B19 (B19) has been associated with a variety of diseases. However, the influence of B19 viral proteins on hepatic injury in SLE is still obscure. To elucidate the effects of B19 viral proteins on livers in SLE, recombinant B19 NS1, VP1u or VP2 proteins were injected subcutaneously into NZB/W F1 mice, respectively. Significant expressions of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) were detected in NZB/W F1 mice receiving B19 NS1 as compared to those mice receiving PBS. Markedly hepatocyte disarray and lymphocyte infiltration were observed in livers from NZB/WF 1 mice receiving B19 NS1 as compared to those mice receiving PBS. Additionally, significant increases of Tumor Necrosis Factor -α (TNF-α), TNF-α receptor, IκB kinase -α (IKK-α), nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor (IκB) and nuclear factor-kappa B (NF-κB) were detected in livers from NZB/W F1 mice receiving B19 NS1 as compared to those mice receiving PBS. Accordingly, significant increases of matrix metalloproteinase-9 (MMP9) and U-plasminogen activator (uPA) were also detected in livers from NZB/W F1 mice receiving B19 NS1 as compared to those mice receiving PBS. Contrarily, no significant variation on livers from NZB/W F1 mice receiving B19 VP1u or VP2 was observed as compared to those mice receiving PBS. These findings firstly demonstrated the aggravated effects of B19 NS1 but not VP1u or VP2 protein on hepatic injury and provide a clue in understanding the role of B19 NS1 on hepatic injury in SLE.