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1.
Nature ; 585(7823): 102-106, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32848245

RESUMO

Accumulating evidence indicates that gut microorganisms have a pathogenic role in autoimmune diseases, including in multiple sclerosis1. Studies of experimental autoimmune encephalomyelitis (an animal model of multiple sclerosis)2,3, as well as human studies4-6, have implicated gut microorganisms in the development or severity of multiple sclerosis. However, it remains unclear how gut microorganisms act on the inflammation of extra-intestinal tissues such as the spinal cord. Here we show that two distinct signals from gut microorganisms coordinately activate autoreactive T cells in the small intestine that respond specifically to myelin oligodendrocyte glycoprotein (MOG). After induction of experimental autoimmune encephalomyelitis in mice, MOG-specific CD4+ T cells are observed in the small intestine. Experiments using germ-free mice that were monocolonized with microorganisms from the small intestine demonstrated that a newly isolated strain in the family Erysipelotrichaceae acts similarly to an adjuvant to enhance the responses of T helper 17 cells. Shotgun sequencing of the contents of the small intestine revealed a strain of Lactobacillus reuteri that possesses peptides that potentially mimic MOG. Mice that were co-colonized with these two strains showed experimental autoimmune encephalomyelitis symptoms that were more severe than those of germ-free or monocolonized mice. These data suggest that the synergistic effects that result from the presence of these microorganisms should be considered in the pathogenicity of multiple sclerosis, and that further study of these microorganisms may lead to preventive strategies for this disease.


Assuntos
Encefalomielite Autoimune Experimental/microbiologia , Microbioma Gastrointestinal/imunologia , Inflamação/patologia , Medula Espinal/patologia , Linfócitos T/imunologia , Linfócitos T/patologia , Animais , Modelos Animais de Doenças , Encefalomielite Autoimune Experimental/imunologia , Encefalomielite Autoimune Experimental/patologia , Encefalomielite Autoimune Experimental/prevenção & controle , Feminino , Vida Livre de Germes , Inflamação/imunologia , Intestino Delgado/imunologia , Intestino Delgado/microbiologia , Intestino Delgado/patologia , Limosilactobacillus reuteri/química , Limosilactobacillus reuteri/imunologia , Limosilactobacillus reuteri/patogenicidade , Masculino , Camundongos , Esclerose Múltipla/imunologia , Esclerose Múltipla/microbiologia , Esclerose Múltipla/patologia , Glicoproteína Mielina-Oligodendrócito/química , Glicoproteína Mielina-Oligodendrócito/imunologia , Medula Espinal/imunologia , Células Th17/imunologia , Células Th17/patologia
2.
Anim Microbiome ; 6(1): 33, 2024 Jun 20.
Artigo em Inglês | MEDLINE | ID: mdl-38902845

RESUMO

BACKGROUND: The gut microbiota plays an important role in the development of behavior and immunity in infants and juveniles. Early weaning (EW), a form of social stress in mice, leads to increased anxiety and an enhanced stress response in the hypothalamic-pituitary-adrenal axis during adulthood. Early life stress also modulates the immune system and increases vulnerability to infection. However, studies investigating the causal relationships among juvenile stress, microbiota changes, and immune and behavioral deficits are limited. Therefore, we hypothesized that EW alters gut microbiota composition and impairs the development of the nervous and immune systems. RESULTS: EW mice moved longer distances in the marble-burying test and had longer immobility times in the tail suspension test than normal weaning (NW) mice. In parallel, the gut microbiome composition differed between NW and EW mice, and the abundance of Erysipelotrichacea in EW mice at 8 weeks of age was lower than that in NW mice. In an empirical study, germ-free mice colonized with the gut microbiota of EW mice (GF-EW mice) demonstrated higher depressive behavior than GF mice colonized with normal weaning microbiota (GF-NW mice). Immune cell profiles were also affected by the EW microbiota colonization; the number of CD4 + T cells in the spleen was reduced in GF-EW mice. CONCLUSION: Our results suggest that EW-induced alterations in the gut microbiota cause depressive behaviors and modulate the immune system.

3.
J Virol ; 86(9): 5288-96, 2012 May.
Artigo em Inglês | MEDLINE | ID: mdl-22379101

RESUMO

Kaposi's sarcoma-associated herpesvirus (KSHV), a human tumor virus, encodes two homologous membrane-associated E3 ubiquitin ligases, modulator of immune recognition 1 (MIR1) and MIR2, to evade host immunity. Both MIR1 and MIR2 downregulate the surface expression of major histocompatibility complex class I (MHC I) molecules through ubiquitin-mediated endocytosis followed by lysosomal degradation. Since MIR2 additionally downregulates a costimulatory molecule (B7-2) and an integrin ligand (intercellular adhesion molecule 1 [ICAM-1]), MIR2 is thought to be a more important molecule for immune evasion than MIR1; however, the molecular basis of the MIR2 substrate specificity remains unclear. To address this issue, we determined which regions of B7-2 and MIR2 are required for MIR2-mediated B7-2 downregulation. Experiments with chimeras made by swapping domains between human B7-2 and CD8α, a non-MIR2 substrate, and between MIR1 and MIR2 demonstrated a significant contribution of the juxtamembrane (JM) region of B7-2 and the intertransmembrane (ITM) region of MIR2 to MIR2-mediated downregulation. Structure prediction and mutagenesis analyses indicate that Phe119 and Ser120 in the MIR2 ITM region and Asp244 in the B7-2 JM region contribute to the recognition of B7-2 by MIR2. This finding provides new insight into the molecular basis of substrate recognition by MIR family members.


Assuntos
Antígeno B7-2/metabolismo , Regulação para Baixo/imunologia , Herpesvirus Humano 8/imunologia , Proteínas Virais/metabolismo , Aminoácidos/química , Antígeno B7-2/química , Antígeno B7-2/genética , Linhagem Celular , Herpesvirus Humano 8/metabolismo , Humanos , Modelos Moleculares , Mutagênese Sítio-Dirigida , Estrutura Secundária de Proteína , Estrutura Terciária de Proteína , Proteínas Virais/química , Proteínas Virais/genética
4.
Sci Rep ; 12(1): 1758, 2022 02 02.
Artigo em Inglês | MEDLINE | ID: mdl-35110685

RESUMO

The bacterial composition of the gut lumen and mucosa is distinct and the mucosa-associated bacteria are thought to play a more critical role in interactions with the host immune system. However, limited studies of the gut mucosal microbiota in humans have been available due to methodological challenges. Here, we evaluated the potential use of colonic lavage samples for mucosal microbiota analysis in humans. Among the different types of colonic mucosal samples collected from healthy volunteers, the lavage samples contained a higher amount of bacterial DNA and were less contaminated with host DNA compared to mucosal brushing (brush) and biopsy. Although 16S gene amplicon sequencing showed that the bacterial composition of the lavage was intermediate between that of feces and biopsy, mucosal bacteria abundant in the biopsy were also enriched in lavage samples. Furthermore, differences in mucosal microbes between non-smokers and smokers were detectable in lavage samples. Our data emphasize that colonic lavage is suitable for analysis of the mucosal microbiota. Given its minimal invasiveness and high bacterial DNA content, the colonic lavage will promote research on the human mucosal microbiota, especially in gastrointestinal disorders.


Assuntos
Colo/microbiologia , Endoscopia , Microbioma Gastrointestinal/genética , Bactérias/genética , Bactérias/isolamento & purificação , Fumar Cigarros , DNA Bacteriano , Fezes/microbiologia , Humanos , Mucosa Intestinal/microbiologia , Metagenômica/métodos , RNA Ribossômico 16S/genética
5.
J Biol Chem ; 285(46): 35311-9, 2010 Nov 12.
Artigo em Inglês | MEDLINE | ID: mdl-20833710

RESUMO

The polyubiquitin chain is generated by the sequential addition of ubiquitin moieties to target molecules, a reaction between specific lysine residues that is catalyzed by E3 ubiquitin ligase. The Lys(48)-linked and Lys(63)-linked polyubiquitin chains are well established inducers of proteasome-dependent degradation and signal transduction, respectively. The concept has recently emerged that polyubiquitin chain-mediated regulation is even more complex because various types of atypical polyubiquitin chains have been discovered in vivo. Here, we demonstrate that a novel complex ubiquitin chain functions as an internalization signal for major histocompatibility complex class I (MHC I) membrane proteins in vivo. Using a tetracycline-inducible expression system and quantitative mass spectrometry, we show that the polyubiquitin chain generated by the viral E3 ubiquitin ligase of Kaposi sarcoma-associated herpesvirus, MIR2, is a Lys(11) and Lys(63) mixed-linkage chain. This novel ubiquitin chain can function as an internalization signal for MHC I through its association with epsin1, an adaptor molecule containing ubiquitin-interacting motifs.


Assuntos
Endocitose , Antígenos de Histocompatibilidade Classe I/metabolismo , Lisina/metabolismo , Proteínas Virais/metabolismo , Proteínas Adaptadoras de Transporte Vesicular/genética , Proteínas Adaptadoras de Transporte Vesicular/metabolismo , Western Blotting , Antígenos CD8/genética , Antígenos CD8/metabolismo , Clatrina/genética , Clatrina/metabolismo , Citometria de Fluxo , Proteínas de Fluorescência Verde/genética , Proteínas de Fluorescência Verde/metabolismo , Células HeLa , Antígenos de Histocompatibilidade Classe I/genética , Humanos , Espectrometria de Massas , Microscopia de Fluorescência , Interferência de RNA , Ubiquitinação , Ubiquitinas/genética , Ubiquitinas/metabolismo , Proteínas Virais/genética
6.
J Immunol ; 183(11): 6893-7, 2009 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-19917682

RESUMO

MARCH-I (membrane-associated RING-CH I) has been suggested as a physiological E3 ubiquitin ligase for both MHC class II (MHC II) and B7-2. In this study, we show that MARCH-I-mediated MHC II ubiquitination is necessary for the maintenance of conventional dendritic cell (cDC) functions in the steady state. MARCH-I-deficient cDCs accumulated MHC II and B7-2 and exhibited low Ag-presenting ability for exogenous Ags and low cytokine-producing ability upon stimulation in vivo. Importantly, MHC II, but not B7-2, was required for impaired cDC function induced by loss of MARCH-I in vivo. Moreover, MHC II knockin mice whose MHC II was not ubiquitinated showed dysfunction of cDC similar to that of MARCH-I knockout mice. These results suggest that the accumulation of MHC II resulting from loss of ubiquitination caused cDC abnormality; therefore, MARCH-I may function as a housekeeper of cDC in the steady state.


Assuntos
Células Dendríticas/imunologia , Regulação da Expressão Gênica/imunologia , Genes MHC da Classe II , Antígenos de Histocompatibilidade Classe II/imunologia , Ubiquitina-Proteína Ligases/imunologia , Ubiquitinação/fisiologia , Animais , Apresentação de Antígeno/imunologia , Antígeno B7-2/biossíntese , Antígeno B7-2/imunologia , Antígenos CD4/biossíntese , Antígenos CD4/imunologia , Antígenos CD8/biossíntese , Antígenos CD8/imunologia , Células Dendríticas/metabolismo , Citometria de Fluxo , Expressão Gênica , Técnicas de Introdução de Genes , Antígenos de Histocompatibilidade Classe II/genética , Antígenos de Histocompatibilidade Classe II/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Ubiquitina-Proteína Ligases/genética , Ubiquitina-Proteína Ligases/metabolismo
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