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1.
Adv Exp Med Biol ; 1172: 79-96, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31628652

RESUMO

The Interleukin (IL)-10 cytokine family includes IL-10, IL-19, IL-20, IL-22, IL-24, and IL-26, which are considered as Class 2α-helical cytokines. IL-10 is the most important cytokine in suppressing pro-inflammatory responses in all kinds of autoimmune diseases and limiting excessive immune responses. Due to protein structure homology and shared usage of receptor complexes as well as downstream signaling pathway, other IL-10 family cytokines also show indispensable functions in immune regulation, tissue homeostasis, and host defense. In this review, we focus on immune functions and structures of different cytokines in this family and try to better understand how their molecular mechanisms connect to their biological functions. The molecular details regarding their actions also provide useful information in developing candidate immune therapy reagents for a variety of diseases.


Assuntos
Interleucina-10 , Doenças Autoimunes/imunologia , Humanos , Imunoterapia , Interleucina-10/química , Interleucina-10/imunologia , Transdução de Sinais/imunologia , Relação Estrutura-Atividade
2.
Isr Med Assoc J ; 21(7): 444-448, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31507118

RESUMO

BACKGROUND: Although cross-reactions between Epstein-Barr virus (EBV) and human systemic lupus erythematosus (SLE) autoantigens occur, a complete analysis of the potential EBV peptide cross-reactome has not been performed. OBJECTIVES: To analyze the whole EBV proteome searching for peptides common to SLE-related proteins and endowed with an immunological potential. METHODS: Fifty-one SLE-related proteins were analyzed for hexapeptide sharing with EBV proteome using publicly available databases. RESULTS: An extremely high number of hexapeptides are shared between 34 human SLE autoantigens and EBV proteins. The peptide sharing mostly occurs with complement components C4 and Interleukin-10 (IL-10). CONCLUSIONS: This study thoroughly describes the EBV vs. SLE autoantigens peptide overlap and powerfully supports cross-reactivity as a major mechanism in EBV-associated SLE etiopathogenesis.


Assuntos
Autoantígenos/imunologia , Infecções por Vírus Epstein-Barr/imunologia , Lúpus Eritematoso Sistêmico/imunologia , Peptídeos/imunologia , Proteoma , Complemento C4/imunologia , Reações Cruzadas/imunologia , Bases de Dados Factuais , Herpesvirus Humano 4/imunologia , Humanos , Interleucina-10/imunologia
4.
Vet Immunol Immunopathol ; 212: 38-42, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31213250

RESUMO

Food allergen-specific sublingual immunotherapy (FA-SLIT) is a novel, safe and effective approach in dogs with adverse food reactions (AFR) to reduce their clinical symptoms. However, little is known about the specific immune components which mediate this reduction in clinical symptoms. In humans, regulatory T cells seem to play an important role in this desensitisation process. Here, we investigated changes in peripheral T cell responses of dogs with AFR upon FA-SLIT. Five dogs received a dose escalation of FA-SLIT over a six-month period. An oral food challenge was performed at the beginning and end of the study to assess the efficacy of the FA-SLIT. Using in vitro allergen-recall assays, we assessed the proliferation of T cell subsets before and at the end of the treatment. FA-SLIT significantly increased the percentage of proliferating CD4-CD8- double-negative (DN) T cells, while the percentage of allergen-specific CD4-CD8+ and CD4+CD8+ double-positive (DP) T cells decreased upon treatment. These findings indicate that sublingual immunotherapy in dogs activates DN T cells, which might be important for the desensitisation of dogs with adverse food reactions. However, further research is needed to corroborate these findings and to further elucidate the mechanism of action of FA-SLIT in dogs with AFR.


Assuntos
Hipersensibilidade Alimentar/imunologia , Hipersensibilidade Alimentar/terapia , Imunoterapia Sublingual , Linfócitos T Reguladores/imunologia , Animais , Linfócitos T CD4-Positivos/imunologia , Dessensibilização Imunológica/métodos , Cães , Imunoglobulina E/sangue , Imunoglobulina E/imunologia , Interleucina-10/imunologia , Ativação Linfocitária
5.
Virol J ; 16(1): 79, 2019 06 13.
Artigo em Inglês | MEDLINE | ID: mdl-31196204

RESUMO

BACKGROUND: The increased levels of blood cytokines is the main immunopathological process that were attributed to severe clinical outcomes in cases of influenza A, influenza B and people with influenza-like illness (ILI). Functional genetic polymorphisms caused by single nucleotide polymorphisms (SNPs) in inflammatory cytokines genes can influence their functions either qualitatively or quantitatively, which is associated with the possibility of severe influenza infections. The aim of the present case-control study was to investigate the association of polymorphisms in inflammatory cytokines genes with influenza patients and ILI group in an Iranian population. METHODS: Total number of 30 influenza B, 50 influenza A (H1N1) and 96 ILI inpatient individuals were confirmed by Real-time RT-PCR and HI assays. The genotype determination was assessed for defined SNPs in IL-1ß, IL-17, IL-10 and IL-28 genes. RESULTS: The frequencies of the IL-1ß rs16944 (P = 0.007) and IL-17 rs2275913 (P = 0.006) genotypes were associated with severe influenza disease, while the frequencies of IL-10 rs1800872 and IL-28 rs8099917 were not associated with the disease (P > 0.05). Also, the absence of A allele in IL-17 rs2275913 SNP increased the risk of influenza A (H1N1) infection (P = 0.008). CONCLUSIONS: This study demonstrated that influenza A- (H1N1) and B-infected patients and also ILI controls have different profiles of immune parameters, and individuals carrying the specific cytokine-derived polymorphisms may show different immune responses towards severe outcome.


Assuntos
Citocinas/genética , Influenza Humana/epidemiologia , Influenza Humana/imunologia , Polimorfismo de Nucleotídeo Único , Adulto , Alelos , Estudos de Casos e Controles , Citocinas/imunologia , Feminino , Frequência do Gene , Predisposição Genética para Doença , Genótipo , Humanos , Vírus da Influenza A Subtipo H1N1 , Vírus da Influenza B , Interleucina-10/genética , Interleucina-10/imunologia , Interleucina-17/genética , Interleucina-17/imunologia , Interleucina-1beta/genética , Interleucina-1beta/imunologia , Irã (Geográfico)/epidemiologia , Masculino , Pessoa de Meia-Idade , Adulto Jovem
6.
Mol Immunol ; 112: 175-181, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31170628

RESUMO

Regulatory B cells (Bregs) have critical roles as a negative regulator of immunity, mainly due to the fact that it secrets high a level of interleukin 10 (IL-10). Recently, a new subset of Bregs was identified as a key source of IL-35, which is an immunosuppressive cytokine and conventionally thought to be secreted by regulatory T cells (Tregs). Our previous study showed that the level of IL-35 in serum was elevated in the patients with active tuberculosis (ATB). However, none of the studies reported that IL-35 is secreted by B cells in ATB patients. In the current study, we found that the mRNA expressions of the both subunits (p35 and Ebi3) of IL-35 by circulating B cells were increased in ATB patients. By using immunohistochemistry and immunofluorescence staining, we found a subset of B cells infiltrated into the tuberculous granuloma of ATB patients also expressed IL-35. Moreover, Mycobacterium tuberculosis (MTB) lysate stimulation assay also demonstrated higher levels of IL-35 were exerted by MTB lysate within purified B cells from healthy control group (HC). Flow cytometry analysis further showed that the IL-35-producing B cells from ATB patients produced a higher level of IL-10. Taken together, IL-35-producing B cells may play a regulatory role during MTB infection by producing IL-10.


Assuntos
Linfócitos B Reguladores/imunologia , Interleucina-10/imunologia , Interleucinas/imunologia , Mycobacterium tuberculosis/imunologia , Tuberculose Pulmonar/imunologia , Adolescente , Adulto , Idoso , Feminino , Humanos , Interferon gama/imunologia , Pulmão/imunologia , Pulmão/microbiologia , Masculino , Pessoa de Meia-Idade , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/microbiologia , Tuberculose Pulmonar/microbiologia , Adulto Jovem
7.
Mol Immunol ; 112: 233-239, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31181422

RESUMO

BACKGROUND: Regulatory B cells participate in the pathogenesis of autoimmune disease. This study aimed to examine the putative contribution of regulatory B cells to the pathogenesis of DN. The number of circulating CD19+CD24hiCD38hi B cells, CD19+CD24hiCD38hiCD5+ B cells, and CD19+CD24hiCD38hiIL-10+ B cells were significantly lower in DN patients (p < 0.05) than the control group. The number of circulating CD19+CD24hiCD38hi B cells was positively correlated with the levels of eGFR and serum IL-10 levels, but negatively correlated with urinary protein levels in DN patients. Treatment significantly increased the number of CD19+CD24hiCD38hi B cells, CD19+CD24hiCD38hiCD5+ B cells, CD19+CD24hiCD38hiIL-10+ B cells, and the levels of serum IL-10 (p < 0.05). We conclude that regulatory B cells may present new targets for intervention of DN.


Assuntos
ADP-Ribosil Ciclase 1/imunologia , Antígenos CD19/imunologia , Linfócitos B Reguladores/imunologia , Antígeno CD24/imunologia , Nefropatias Diabéticas/imunologia , Glicoproteínas de Membrana/imunologia , Adulto , Idoso , Contagem de Células/métodos , Feminino , Humanos , Interleucina-10/imunologia , Masculino , Pessoa de Meia-Idade
8.
Vet Microbiol ; 233: 124-132, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31176398

RESUMO

Leptospirosis is a zoonosis, caused by pathogenic spirochetes of the genus Leptospira. Although cattle are usually the maintenance hosts of serovar Hardjo, Pomona is the most frequent serovar circulating in Argentina. The understanding of bovine innate immune response and the virulence of this serovar is important for future control measures. This work compares infection of bovine macrophages with the virulent L. interrogans sv Pomona strain AKRFB (P1) and its attenuated counterpart (P19). First, we confirmed attenuation in the hamster model. Mortality and lung hemorrhages occurred after P1 inoculation, while the survival rate was 100% in P19-infected animals. Cells infected with both strains showed statistically upregulated gene expression of pro-inflammatory cytokines, IL-1ß, IL-6 and TNFα. The level of expression of anti-inflammatory cytokine IL-10 was statistically different between strains. Increased expression of IL-10 was observed only in P1-infected cells. For the first time, we describe macrophages extracellular traps induced by infection of bovine macrophages (bMETs) with both, the virulent and attenuated Leptospira interrogans Pomona strains. P1 was found higher internalized when the phagocytosis was inhibited, suggesting a cell entrance of this strain also by an independent-phagocytosis pathway. Furthermore, P1 was higher colocalized with acidic and late endosomal compartments compared with P19. This data emphasizes the importance to deepen in Leptospira bovine macrophages particular invasion mechanisms and, furthermore, underline the value of studying the main hosts.


Assuntos
Imunidade Inata , Leptospira interrogans serovar pomona/patogenicidade , Macrófagos/imunologia , Macrófagos/microbiologia , Animais , Argentina , Bovinos , Células Cultivadas , Cricetinae , Citocinas/genética , Citocinas/imunologia , Interleucina-10/genética , Interleucina-10/imunologia , Leptospirose/imunologia , Pulmão/microbiologia , Pulmão/patologia , Sorogrupo , Virulência
9.
Infect Immun ; 87(7)2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31036600

RESUMO

Enterococcus faecalis strains are resident intestinal bacteria associated with invasive infections, inflammatory bowel diseases, and colon cancer. Although factors promoting E. faecalis colonization of intestines are not fully known, one implicated pathway is a phosphotransferase system (PTS) in E. faecalis strain OG1RF that phosphorylates gluconate and contains the genes OG1RF_12399 to OG1RF_12402 (OG1RF_12399-12402). We hypothesize that this PTS permits growth in gluconate, facilitates E. faecalis intestinal colonization, and exacerbates colitis. We generated E. faecalis strains containing deletions/point mutations in this PTS and measured bacterial growth and PTS gene expression in minimal medium supplemented with selected carbohydrates. We show that E. faecalis upregulates OG1RF_12399 transcription specifically in the presence of gluconate and that E. faecalis strains lacking, or harboring a single point mutation in, OG1RF_12399-12402 are unable to grow in minimal medium containing gluconate. We colonized germfree wild-type and colitis-prone interleukin-10-deficient mice with defined bacterial consortia containing the E. faecalis strains and measured inflammation and bacterial abundance in the colon. We infected macrophage and intestinal epithelial cell lines with the E. faecalis strains and measured intracellular bacterial survival and proinflammatory cytokine secretion. The presence of OG1RF_12399-12402 is not required for E. faecalis colonization of the mouse intestine but is associated with an accelerated onset of experimental colitis in interleukin-10-deficient mice, altered bacterial composition in the colon, enhanced E. faecalis survival within macrophages, and increased proinflammatory cytokine secretion by colon tissue and macrophages. Further studies of bacterial carbohydrate metabolism in general, and E. faecalis PTS-gluconate in particular, during inflammation may identify new mechanisms of disease pathogenesis.


Assuntos
Proteínas de Bactérias/metabolismo , Colite/microbiologia , Enterococcus faecalis/enzimologia , Macrófagos/imunologia , Fosfotransferases/metabolismo , Animais , Proteínas de Bactérias/genética , Colite/genética , Colite/imunologia , Enterococcus faecalis/genética , Enterococcus faecalis/crescimento & desenvolvimento , Feminino , Gluconatos/metabolismo , Humanos , Interleucina-10/genética , Interleucina-10/imunologia , Intestinos/imunologia , Intestinos/microbiologia , Macrófagos/microbiologia , Masculino , Camundongos , Óperon , Fosfotransferases/genética
10.
PLoS Negl Trop Dis ; 13(5): e0007375, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-31050676

RESUMO

BACKGROUND: The Mayaro virus (MAYV) is an endemic arbovirus in South American countries, where it is responsible for sporadic outbreaks of Mayaro fever. Clinical manifestations include fever, headache, ocular pain, rash, myalgia, and debilitating and persistent polyarthralgia. Understanding the mechanisms associated with MAYV-induced arthritis is of great importance due to the potential for its emergence, urbanization and dispersion to other regions. METHODS: 15-day old Balb/c mice were infected by two distinct pathways, below the forelimb and in the rear footpad. Animals were observed for a period of 21 days. During this time, they were monitored every 24 hours for disease signs, such as weight loss and muscle weakness. Histological damage in the muscles and joints was evaluated 3, 7, 10, 15 and 20 days post-infection. The cytokine profile in serum and muscles during MAYV infection was evaluated by flow cytometry at different post-infection times. For pain analysis, the animals were submitted to the von Frey test and titre in different organs was evaluated throughout the study to obtain viral kinetics. FINDINGS: Infection by two distinct pathways, below the forelimb and in the rear footpad, resulted in a homogeneous viral spread and the development of acute disease in animals. Clinical signs were observed such as ruffled fur, hunched posture, eye irritation and slight gait alteration. In the physical test, both groups presented loss of resistance, which was associated with histopathological damage, including myositis, arthritis, tenosynovitis and periostitis. The immune response was characterized by a strong inflammatory response mediated by the cytokines TNF-α, IL-6 and INF-γ and chemokine MCP-1, followed by the action of IL-10 and IL-4 cytokines. INTERPRETATION: The results showed that Balb/c mice represent a promising model to study mechanisms involved in MAYV pathogenesis and for future antiviral testing.


Assuntos
Infecções por Arbovirus/virologia , Arbovirus/fisiologia , Artrite/virologia , Modelos Animais de Doenças , Miosite/virologia , Animais , Arbovirus/genética , Arbovirus/isolamento & purificação , Feminino , Humanos , Interferon gama/genética , Interferon gama/imunologia , Interleucina-10/genética , Interleucina-10/imunologia , Interleucina-6/genética , Interleucina-6/imunologia , Masculino , Camundongos Endogâmicos BALB C , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/imunologia
11.
PLoS Negl Trop Dis ; 13(5): e0007354, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-31067234

RESUMO

BACKGROUND: Toll-like receptors (TLRs) are sentinel receptors of the innate immune system. TLR4 detects bacterial lipopolysaccharide (LPS) and TLR5 detects bacterial flagellin. A common human nonsense polymorphism, TLR5:c.1174C>T, results in a non-functional TLR5 protein. Individuals carrying this variant have decreased mortality from melioidosis, infection caused by the flagellated Gram-negative bacterium Burkholderia pseudomallei. Although impaired flagellin-dependent signaling in carriers of TLR5:c.1174C>T is well established, this study tested the hypothesis that a functional effect of TLR5:c.1174C>T is flagellin-independent and involves LPS-TLR4 pathways. METHODOLOGY/PRINCIPAL FINDINGS: Whole blood from two independent cohorts of individuals genotyped at TLR5:c.1174C>T was stimulated with wild type or aflagellated B. pseudomallei or purified bacterial motifs followed by plasma cytokine measurements. Blood from individuals carrying the TLR5:c.1174C>T variant produced less IL-6 and IL-10 in response to an aflagellated B. pseudomallei mutant and less IL-8 in response to purified B. pseudomallei LPS than blood from individuals without the variant. TLR5 expression in THP1 cells was silenced using siRNA; these cells were stimulated with LPS before cytokine levels in cell supernatants were quantified by ELISA. In these cells following LPS stimulation, silencing of TLR5 with siRNA reduced both TNF-α and IL-8 levels. These effects were not explained by differences in TLR4 mRNA expression or NF-κB or IRF activation. CONCLUSIONS/SIGNIFICANCE: The effects of the common nonsense TLR5:c.1174C>T polymorphism on the host inflammatory response to B. pseudomallei may not be restricted to flagellin-driven pathways. Moreover, TLR5 may modulate TLR4-dependent cytokine production. While these results may have broader implications for the role of TLR5 in the innate immune response in melioidosis and other conditions, further studies of the mechanisms underlying these observations are required.


Assuntos
Burkholderia pseudomallei/imunologia , Flagelina/imunologia , Melioidose/genética , Melioidose/imunologia , Polimorfismo Genético , Receptor 5 Toll-Like/genética , Adolescente , Adulto , Idoso , Burkholderia pseudomallei/genética , Códon sem Sentido , Estudos de Coortes , Feminino , Flagelina/genética , Humanos , Imunidade Inata , Interleucina-10/genética , Interleucina-10/imunologia , Masculino , Melioidose/microbiologia , Pessoa de Meia-Idade , NF-kappa B/genética , NF-kappa B/imunologia , Mutação Puntual , Receptor 5 Toll-Like/imunologia , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/imunologia , Adulto Jovem
12.
PLoS Negl Trop Dis ; 13(5): e0007436, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-31120872

RESUMO

Despite worldwide mass drug administration, it is estimated that 68 million individuals are still infected with lymphatic filariasis with 19 million hydrocele and 17 million lymphedema reported cases. Despite the staggering number of pathology cases, the majority of LF-infected individuals do not develop clinical symptoms and present a tightly regulated immune system characterized by higher frequencies of regulatory T cells (Treg), suppressed proliferation and Th2 cytokine responses accompanied with increased secretion of IL-10, TGF-ß and infection-specific IgG4. Nevertheless, the filarial-induced modulation of the host`s immune system and especially the role of regulatory immune cells like regulatory B (Breg) and Treg during an ongoing LF infection remains unknown. Thus, we analysed Breg and Treg frequencies in peripheral blood from Ghanaian uninfected endemic normals (EN), lymphedema (LE), asymptomatic patent (CFA+MF+) and latent (CFA+MF-) W. bancrofti-infected individuals as well as individuals who were previously infected with W. bancrofti (PI) but had cleared the infection due to the administration of ivermectin (IVM) and albendazole (ALB). In summary, we observed that IL-10-producing CD19+CD24highCD38dhigh Breg were specifically increased in patently infected (CFA+MF+) individuals. In addition, CD19+CD24highCD5+CD1dhigh and CD19+CD5+CD1dhighIL-10+ Breg as well as CD4+CD127-FOXP3+ Treg frequencies were significantly increased in both W. bancrofti-infected cohorts (CFA+MF+ and CFA+MF-). Interestingly, the PI cohort presented frequency levels of all studied regulatory immune cell populations comparable with the EN group. In conclusion, the results from this study show that an ongoing W. bancrofti infection induces distinct Breg and Treg populations in peripheral blood from Ghanaian volunteers. Those regulatory immune cell populations might contribute to the regulated state of the host immune system and are probably important for the survival and fertility (microfilaria release) of the helminth.


Assuntos
Anti-Helmínticos/administração & dosagem , Linfócitos B Reguladores/imunologia , Filariose Linfática/tratamento farmacológico , Filariose Linfática/imunologia , Interleucina-10/imunologia , Linfócitos T Reguladores/imunologia , Wuchereria bancrofti/fisiologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Albendazol/administração & dosagem , Animais , Filariose Linfática/genética , Filariose Linfática/parasitologia , Feminino , Gana , Humanos , Interleucina-10/genética , Ivermectina/administração & dosagem , Masculino , Pessoa de Meia-Idade , Células Th2/imunologia , Adulto Jovem
13.
Mem Inst Oswaldo Cruz ; 114: e180571, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31116244

RESUMO

BACKGROUND: TcP21 is a ubiquitous secreted protein of Trypanosoma cruzi and its recombinant form (rP21) promotes parasite cell invasion and acts as a phagocytosis inducer by activating actin polymerisation in the host cell. OBJECTIVE: Our goal was to evaluate if the additional supplementation of rP21 during a prime/boost/challenge scheme with T. cruzi TCC attenuated parasites could modify the well-known protective behavior conferred by these parasites. METHODS: The humoral immune response was evaluated through the assessment of total anti-T. cruzi antibodies as well as IgG subtypes. IFN-γ, TNF-α and IL-10 were measured in supernatants of splenic cells stimulated with total parasite homogenate or rP21. FINDINGS: Our results demonstrated that, when comparing TCC+rP21 vs. TCC vaccinated animals, the levels of IFN-γ were significantly higher in the former group, while the levels of IL-10 and TNF-α were significantly lower. Further, the measurement of parasite load after lethal challenge showed an exacerbated infection and parasite load in heart and skeletal muscle after pre-treatment with rP21, suggesting the important role of this protein during parasite natural invasion process. MAIN CONCLUSION: Our results demonstrated that rP21 may have adjuvant capacity able to modify the cytokine immune profile elicited by attenuated parasites.


Assuntos
Anticorpos Antiprotozoários/imunologia , Antígenos de Protozoários/imunologia , Doença de Chagas/imunologia , Proteínas de Protozoários/imunologia , Trypanosoma cruzi/imunologia , Vacinas Atenuadas/imunologia , Animais , Doença de Chagas/prevenção & controle , Modelos Animais de Doenças , Imunoglobulina G/sangue , Imunoglobulina G/imunologia , Interferon-alfa/sangue , Interferon-alfa/imunologia , Interferon gama/sangue , Interferon gama/imunologia , Interleucina-10/sangue , Interleucina-10/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Fagocitose , Vacinas Atenuadas/administração & dosagem
14.
Nat Commun ; 10(1): 2153, 2019 05 14.
Artigo em Inglês | MEDLINE | ID: mdl-31089128

RESUMO

The gut commensal Bacteroides fragilis or its capsular polysaccharide A (PSA) can prevent various peripheral and CNS sterile inflammatory disorders. Fatal herpes simplex encephalitis (HSE) results from immune pathology caused by uncontrolled invasion of the brainstem by inflammatory monocytes and neutrophils. Here we assess the immunomodulatory potential of PSA in HSE by infecting PSA or PBS treated 129S6 mice with HSV1, followed by delayed Acyclovir (ACV) treatment as often occurs in the clinical setting. Only PSA-treated mice survived, with dramatically reduced brainstem inflammation and altered cytokine and chemokine profiles. Importantly, PSA binding by B cells is essential for induction of regulatory CD4+ and CD8+ T cells secreting IL-10 to control innate inflammatory responses, consistent with the lack of PSA mediated protection in Rag-/-, B cell- and IL-10-deficient mice. Our data reveal the translational potential of PSA as an immunomodulatory symbiosis factor to orchestrate robust protective anti-inflammatory responses during viral infections.


Assuntos
Bacteroides fragilis/imunologia , Encefalite por Herpes Simples/imunologia , Microbioma Gastrointestinal/imunologia , Herpesvirus Humano 1/imunologia , Polissacarídeos Bacterianos/imunologia , Aciclovir/uso terapêutico , Animais , Antivirais/uso terapêutico , Linfócitos B/imunologia , Linfócitos B/metabolismo , Bacteroides fragilis/metabolismo , Cercopithecus aethiops , Modelos Animais de Doenças , Encefalite por Herpes Simples/tratamento farmacológico , Encefalite por Herpes Simples/virologia , Feminino , Herpesvirus Humano 1/patogenicidade , Interações entre Hospedeiro e Microrganismos/imunologia , Humanos , Interleucina-10/genética , Interleucina-10/imunologia , Interleucina-10/metabolismo , Masculino , Camundongos , Camundongos Knockout , Polissacarídeos Bacterianos/metabolismo , Simbiose/imunologia , Linfócitos T/imunologia , Linfócitos T/metabolismo , Células Vero
15.
Immunity ; 50(4): 871-891, 2019 04 16.
Artigo em Inglês | MEDLINE | ID: mdl-30995504

RESUMO

Cytokines are among the most important effector and messenger molecules in the immune system. They profoundly participate in immune responses during infection and inflammation, protecting against or contributing to diseases such as allergy, autoimmunity, and cancer. Manipulating cytokine pathways, therefore, is one of the most effective strategies to treat various diseases. IL-10 family cytokines exert essential functions to maintain tissue homeostasis during infection and inflammation through restriction of excessive inflammatory responses, upregulation of innate immunity, and promotion of tissue repairing mechanisms. Their important functions in diseases are supported by data from many preclinical models, human genetic studies, and clinical interventions. Despite significant efforts, however, there is still no clinically approved therapy through manipulating IL-10 family cytokines. Here, we summarize the recent progress in understanding the biology of this family of cytokines, suggesting more specific strategies to maneuver these cytokines for the effective treatment of inflammatory diseases and cancers.


Assuntos
Imunidade Inata , Interleucina-10/imunologia , Interleucinas/imunologia , Animais , Doenças Autoimunes/imunologia , Doenças Autoimunes/terapia , Citocinas/classificação , Citocinas/genética , Regulação da Expressão Gênica , Humanos , Infecção/imunologia , Infecção/terapia , Inflamação/imunologia , Inflamação/terapia , Interleucina-10/genética , Interleucinas/genética , Subpopulações de Linfócitos/imunologia , Camundongos , Família Multigênica , Células Mieloides/imunologia , Neoplasias/imunologia , Neoplasias/terapia , Transdução de Sinais , Fatores de Transcrição/fisiologia
16.
J Immunol Res ; 2019: 2816498, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30944830

RESUMO

Regulatory T-cells (Tregs) are a very important subtype of lymphocytes when it comes to self-control in the human immunological system. Tregs are decisive not only in the protection against destruction of own tissues by autoimmune immunocompetent cells but also in the immunological answer to developing cancers. On the other hand, Tregs could be responsible for the progression of acute and chronic leukemias. In our study, we review publications available in the PUMED database concerning acute leukemia, with a particular emphasis on child's leukemias. The percentage of regulatory T-lymphocytes in peripheral blood and bone marrow was elevated compared to those in healthy individuals and correlated with progressive disease. Regulatory T-cells taken from children diagnosed with leukemia showed a higher suppressive capability, which was confirmed by detecting elevated levels of secreted IL-10 and TGF-beta. The possibility of pharmacological intervention in the self-control of the immunological system is now under extensive investigation in many human cancers. Presumably, Treg cells could be a vital part of targeted therapies. Routine Treg determination could be used to assess the severity of disease and prognosis in children with acute lymphoblastic leukemia. This proposition results from the fact that in some studies, higher percentage of Treg cells in peripheral blood was demonstrated. However, observations confirming these facts are scarce; thus, extrapolating them to the population of children with hematological malignancies needs to be verified in additional studies.


Assuntos
Leucemia Mieloide Aguda/imunologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/imunologia , Linfócitos T Reguladores/imunologia , Progressão da Doença , Citometria de Fluxo , Fatores de Transcrição Forkhead/imunologia , Humanos , Imunofenotipagem , Interleucina-10/imunologia , Linfócitos T Reguladores/classificação , Fator de Crescimento Transformador beta/imunologia
17.
Bull Exp Biol Med ; 166(6): 770-773, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31028583

RESUMO

Plant lipid transfer proteins and homologues of the main birch pollen allergen Bet v 1 are involved in the development of allergic reactions of varying severity to plant foods and pollen. In this study, the sera from patients with tree and weed pollen allergies in the Moscow region were examined. The levels of IL-4, IL-5, IL-9, IL-10, IL-13, IL-17A, IFNγ, TNFα, and TNFß cytokines were determined in the sera of patients with specific IgE antibodies to Bet v 1 and Pru p 3 allergens. It was confirmed that patients with pollen allergy are often characterized by Th2 response of the immune system, though other mechanisms of allergy development occurred in some cases. The data obtained demonstrate the necessity of detailed analysis of the individual mechanism of allergic reactions and patient-centered approach to the personalized allergy treatment.


Assuntos
Antígenos de Plantas/imunologia , Proteínas de Transporte/imunologia , Imunoglobulina E/sangue , Proteínas de Plantas/imunologia , Rinite Alérgica Sazonal/sangue , Adulto , Antígenos de Plantas/química , Proteínas de Transporte/química , Estudos de Casos e Controles , Feminino , Expressão Gênica , Humanos , Imunoglobulina E/genética , Interferon gama/sangue , Interferon gama/imunologia , Interleucina-10/sangue , Interleucina-10/imunologia , Interleucina-13/sangue , Interleucina-13/imunologia , Interleucina-17/sangue , Interleucina-17/imunologia , Interleucina-4/sangue , Interleucina-4/imunologia , Interleucina-5/sangue , Interleucina-5/imunologia , Interleucina-9/sangue , Interleucina-9/imunologia , Linfotoxina-alfa/sangue , Linfotoxina-alfa/imunologia , Masculino , Pessoa de Meia-Idade , Moscou , Proteínas de Plantas/química , Medicina de Precisão , Proteínas Recombinantes/química , Proteínas Recombinantes/imunologia , Rinite Alérgica Sazonal/genética , Rinite Alérgica Sazonal/imunologia , Rinite Alérgica Sazonal/fisiopatologia , Células Th1/imunologia , Células Th17/imunologia , Células Th2/imunologia , Fator de Necrose Tumoral alfa/sangue , Fator de Necrose Tumoral alfa/imunologia
18.
Appl Microbiol Biotechnol ; 103(13): 5193-5213, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31025073

RESUMO

There is an urgent need to discover new active drugs to combat methicillin-resistant Staphylococcus aureus, which is a serious threat to humans and animals and incompletely eliminated by antibiotics due to its intracellular accumulation in host cells, production of biofilms, and persisters. Fungal defensin-like peptides (DLPs) are emerging as a potential source of new antibacterial drugs due to their potent antibacterial activity. In this study, nine novel fungal DLPs were firstly identified by querying against UniProt databases and expressed in Pichia pastoris, and their antibacterial and anti-biofilm ability were tested against multidrug-resistant (MDR) S. aureus. Results showed that among them, P2, the highest activity and expression level, showed low toxicity, no resistance, and high stability. Minimal inhibitory concentrations (MICs) of P2 against Gram-positive bacteria were < 2 µg/mL. P2 exhibited the potent activity against intracellular MDR S. aureus (bacterial reduction in 80-97%) in RAW264.7 macrophages. P2 bound to/disrupted bacterial DNA, wrinkled outer membranes and permeabilized cytoplasmic membranes, but maintained the integrity of bacterial cells. P2 inhibited/eradicated the biofilm and killed 99% persister bacteria, which were resistant to 100× MIC vancomycin. P2 upregulated the anti-inflammatory cytokine (IL-10) and downregulated pro-inflammatory cytokines (TNF-α/IL-1ß) and chemokine (MCP-1) levels in RAW 264.7 macrophages and in mice, respectively. Five milligram per kilogram P2 enhanced the survival of S. aureus-infected mice (100%), superior to vancomycin (30 mg/kg), inhibited the bacterial translocation, and alleviated multiple-organ injuries (liver, spleen, kidney, and lung). These data suggest that P2 may be a candidate for novel antimicrobial agents against MDR staphylococcal infections.


Assuntos
Antibacterianos/farmacologia , Biofilmes/efeitos dos fármacos , Defensinas/farmacologia , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Animais , Quimiocina CCL2/genética , Quimiocina CCL2/imunologia , Defensinas/genética , Descoberta de Drogas , Farmacorresistência Bacteriana Múltipla , Feminino , Interleucina-10/genética , Interleucina-10/imunologia , Camundongos , Testes de Sensibilidade Microbiana , Peritonite/tratamento farmacológico , Peritonite/microbiologia , Pichia/genética , Células RAW 264.7 , Infecções Estafilocócicas , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/imunologia , Vancomicina/farmacologia
19.
J Dairy Sci ; 102(6): 4783-4797, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30954261

RESUMO

The aims of this study were to investigate the effects of Lactobacillus plantarum DR7 isolated from bovine milk against upper respiratory tract infections (URTI) and elucidate the possible mechanisms underlying immunomodulatory properties. The DR7 strain (9 log cfu/d) was administered for 12 wk in a randomized, double-blind, and placebo-controlled human study involving 109 adults (DR7, n = 56; placebo, n = 53). Subjects were assessed for health conditions monthly via questionnaires, and blood samples were evaluated for cytokine concentrations, peroxidation and oxidative stress, and gene expression in T cells and natural killer (NK) cells. The administration of DR7 reduced the duration of nasal symptoms (mean difference 5.09 d; 95% CI: 0.42-9.75) and the frequency of URTI (mean difference 0.32; 95% CI: 0.01-0.63) after 12 and 4 wk, respectively, compared with the placebo. The DR7 treatment suppressed plasma proinflammatory cytokines (IFN-γ, TNF-α) in middle-aged adults (30 to 60 yr old), while enhancing anti-inflammatory cytokines (IL-4, IL-10) in young adults (<30 yr old), accompanied by reduced plasma peroxidation and oxidative stress levels compared with the placebo. Young adults who received DR7 showed higher expression of plasma CD44 and CD117 by 4.50- and 2.22-fold, respectively, compared with the placebo. Meanwhile, middle-aged adults showed lower expression of plasma CD4 and CD8 by 11.26- and 1.80-fold, respectively, compared with the placebo, indicating less T-cell activation. In contrast, both young and middle-aged adults who received DR7 showed enhanced presence of nonresting and mature NK cells compared with those who received the placebo. We postulate that DR7 alleviated the symptoms of URTI by improving inflammatory parameters and enhancing immunomodulatory properties.


Assuntos
Lactobacillus plantarum/imunologia , Leite/microbiologia , Probióticos/uso terapêutico , Infecções Respiratórias/terapia , Adolescente , Adulto , Animais , Bovinos , Citocinas/imunologia , Método Duplo-Cego , Feminino , Humanos , Interleucina-10/imunologia , Células Matadoras Naturais/imunologia , Masculino , Pessoa de Meia-Idade , Infecções Respiratórias/imunologia , Adulto Jovem
20.
Nat Commun ; 10(1): 1685, 2019 04 11.
Artigo em Inglês | MEDLINE | ID: mdl-30976008

RESUMO

Neonatal sepsis is characterized by hyperinflammation causing enhanced morbidity and mortality compared to adults. This suggests differences in the response towards invading threats. Here we investigate activated cord blood macrophages (CBMΦ) in comparison to adult macrophages (PBMΦ), indicating incomplete interferon gamma (IFN-γ) and interleukin 10 (IL-10)-induced activation of CBMΦ. CBMΦ show reduced expression of phagocytosis receptors and cytokine expression in addition to altered energy metabolism. In particular, IFN-γ as well as IL-10-activated CBMΦ completely fail to increase glycolysis and furthermore show reduced activation of the mTOR pathway, which is important for survival in sepsis. MTOR inhibition by rapamycin equalizes cytokine production in CBMΦ and PBMΦ. Finally, incubation of PBMΦ with cord blood serum or S100A8/A9, which is highly expressed in neonates, suppresses mTOR activation, prevents glycolysis and the expression of an PBMΦ phenotype. Thus, a metabolic alteration is apparent in CBMΦ, which might be dependent on S100A8/A9 expression.


Assuntos
Citotoxicidade Imunológica , Metabolismo Energético/imunologia , Macrófagos/metabolismo , Adulto , Fatores Etários , Calgranulina A/imunologia , Calgranulina A/metabolismo , Calgranulina B/imunologia , Calgranulina B/metabolismo , Diferenciação Celular/imunologia , Células Cultivadas , Sangue Fetal/citologia , Glicólise/imunologia , Voluntários Saudáveis , Humanos , Recém-Nascido , Interferon gama/imunologia , Interferon gama/metabolismo , Interleucina-10/imunologia , Interleucina-10/metabolismo , Macrófagos/imunologia , Cultura Primária de Células , Sepse/imunologia , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/imunologia , Sirolimo/farmacologia , Serina-Treonina Quinases TOR/imunologia , Serina-Treonina Quinases TOR/metabolismo
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