RESUMO
Gut dysbiosis might underlie the pathogenesis of type 1 diabetes. In mice of the non-obese diabetic (NOD) strain, we found that key features of disease correlated inversely with blood and fecal concentrations of the microbial metabolites acetate and butyrate. We therefore fed NOD mice specialized diets designed to release large amounts of acetate or butyrate after bacterial fermentation in the colon. Each diet provided a high degree of protection from diabetes, even when administered after breakdown of immunotolerance. Feeding mice a combined acetate- and butyrate-yielding diet provided complete protection, which suggested that acetate and butyrate might operate through distinct mechanisms. Acetate markedly decreased the frequency of autoreactive T cells in lymphoid tissues, through effects on B cells and their ability to expand populations of autoreactive T cells. A diet containing butyrate boosted the number and function of regulatory T cells, whereas acetate- and butyrate-yielding diets enhanced gut integrity and decreased serum concentration of diabetogenic cytokines such as IL-21. Medicinal foods or metabolites might represent an effective and natural approach for countering the numerous immunological defects that contribute to T cell-dependent autoimmune diseases.
Assuntos
Acetatos/metabolismo , Linfócitos B/imunologia , Butiratos/metabolismo , Colo/metabolismo , Diabetes Mellitus Tipo 1/dietoterapia , Disbiose/dietoterapia , Linfócitos T Reguladores/imunologia , Animais , Autoimunidade , Linfócitos B/microbiologia , Células Cultivadas , Colo/patologia , Dietoterapia , Microbioma Gastrointestinal , Interleucinas/sangue , Camundongos , Camundongos Endogâmicos NOD , Linfócitos T Reguladores/microbiologiaRESUMO
The skin is a site of constant dialog between the immune system and commensal bacteria. However, the molecular mechanisms that allow us to tolerate the presence of skin commensals without eliciting destructive inflammation are unknown. Using a model system to study the antigen-specific response to S. epidermidis, we demonstrated that skin colonization during a defined period of neonatal life was required for establishing immune tolerance to commensal microbes. This crucial window was characterized by an abrupt influx of highly activated regulatory T (Treg) cells into neonatal skin. Selective inhibition of this Treg cell wave completely abrogated tolerance. Thus, the host-commensal relationship in the skin relied on a unique Treg cell population that mediated tolerance to bacterial antigens during a defined developmental window. This suggests that the cutaneous microbiome composition in neonatal life is crucial in shaping adaptive immune responses to commensals, and disrupting these interactions might have enduring health implications.
Assuntos
Animais Recém-Nascidos/imunologia , Pele/imunologia , Pele/microbiologia , Infecções Estafilocócicas/imunologia , Staphylococcus epidermidis/imunologia , Linfócitos T Reguladores/imunologia , Animais , Animais Recém-Nascidos/microbiologia , Antígenos de Bactérias/imunologia , Interações Hospedeiro-Patógeno/imunologia , Tolerância Imunológica/imunologia , Inflamação/imunologia , Inflamação/microbiologia , Camundongos , Camundongos Endogâmicos C57BL , Microbiota/imunologia , Dados de Sequência Molecular , Infecções Estafilocócicas/microbiologia , Linfócitos T Reguladores/microbiologiaRESUMO
BACKGROUND & AIMS: Fecal microbiota transplantation (FMT) is an emerging treatment modality for ulcerative colitis (UC). Several randomized controlled trials have shown efficacy for FMT in the treatment of UC, but a better understanding of the transferable microbiota and their immune impact is needed to develop more efficient microbiome-based therapies for UC. METHODS: Metagenomic analysis and strain tracking was performed on 60 donor and recipient samples receiving FMT for active UC. Sorting and sequencing of immunoglobulin (Ig) A-coated microbiota (called IgA-seq) was used to define immune-reactive microbiota. Colonization of germ-free or genetically engineered mice with patient-derived strains was performed to determine the mechanism of microbial impact on intestinal immunity. RESULTS: Metagenomic analysis defined a core set of donor-derived transferable bacterial strains in UC subjects achieving clinical response, which predicted response in an independent trial of FMT for UC. IgA-seq of FMT recipient samples and gnotobiotic mice colonized with donor microbiota identified Odoribacter splanchnicus as a transferable strain shaping mucosal immunity, which correlated with clinical response and the induction of mucosal regulatory T cells. Colonization of mice with O splanchnicus led to an increase in Foxp3+/RORγt+ regulatory T cells, induction of interleukin (IL) 10, and production of short chain fatty acids, all of which were required for O splanchnicus to limit colitis in mouse models. CONCLUSIONS: This work provides the first evidence of transferable, donor-derived strains that correlate with clinical response to FMT in UC and reveals O splanchnicus as a key component promoting both metabolic and immune cell protection from colitis. These mechanistic features will help enable strategies to enhance the efficacy of microbial therapy for UC. Clinicaltrials.gov ID NCT02516384.
Assuntos
Bacteroidetes/imunologia , Colite/terapia , Colo/microbiologia , Transplante de Microbiota Fecal , Microbioma Gastrointestinal , Imunoglobulina A/imunologia , Mucosa Intestinal/microbiologia , Animais , Bacteroidetes/genética , Bacteroidetes/metabolismo , Ensaios Clínicos como Assunto , Colite/imunologia , Colite/metabolismo , Colite/microbiologia , Colite Ulcerativa/diagnóstico , Colite Ulcerativa/imunologia , Colite Ulcerativa/metabolismo , Colite Ulcerativa/microbiologia , Colo/imunologia , Colo/metabolismo , Modelos Animais de Doenças , Fatores de Transcrição Forkhead/metabolismo , Microbioma Gastrointestinal/genética , Microbioma Gastrointestinal/imunologia , Vida Livre de Germes , Humanos , Imunidade nas Mucosas , Imunoglobulina A/genética , Imunoglobulina A/metabolismo , Mucosa Intestinal/imunologia , Mucosa Intestinal/metabolismo , Linfócitos Intraepiteliais/imunologia , Linfócitos Intraepiteliais/metabolismo , Linfócitos Intraepiteliais/microbiologia , Metagenoma , Metagenômica , Camundongos Endogâmicos C57BL , Camundongos Knockout , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/metabolismo , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/metabolismo , Linfócitos T Reguladores/microbiologia , Resultado do TratamentoRESUMO
The building evidence for the contribution of microbiota to human disease has spurred an effort to develop therapies that target the gut microbiota. This is particularly evident in inflammatory bowel diseases (IBDs), where clinical trials of fecal microbiota transplantation have shown some efficacy. To aid the development of novel microbiota-targeted therapies and to better understand the biology underpinning such treatments, we have used gnotobiotic mice to model microbiota manipulations in the context of microbiotas from humans with inflammatory bowel disease. Mice colonized with IBD donor-derived microbiotas exhibit a stereotypical set of phenotypes, characterized by abundant mucosal Th17 cells, a deficit in the tolerogenic RORγt+ regulatory T (Treg) cell subset, and susceptibility to disease in colitis models. Transplanting healthy donor-derived microbiotas into mice colonized with human IBD microbiotas led to induction of RORγt+ Treg cells, which was associated with an increase in the density of the microbiotas following transplant. Microbiota transplant reduced gut Th17 cells in mice colonized with a microbiota from a donor with Crohn's disease. By culturing strains from this microbiota and screening them in vivo, we identified a specific strain that potently induces Th17 cells. Microbiota transplants reduced the relative abundance of this strain in the gut microbiota, which was correlated with a reduction in Th17 cells and protection from colitis.
Assuntos
Transplante de Microbiota Fecal , Doenças Inflamatórias Intestinais/microbiologia , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/imunologia , Linfócitos T Reguladores/imunologia , Células Th17/imunologia , Animais , Colite/prevenção & controle , Colo/microbiologia , Doença de Crohn/metabolismo , Doença de Crohn/microbiologia , Citocinas/imunologia , Modelos Animais de Doenças , Fezes/microbiologia , Feminino , Microbioma Gastrointestinal/imunologia , Humanos , Doenças Inflamatórias Intestinais/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Linfócitos T Reguladores/microbiologia , Células Th17/microbiologiaRESUMO
Thymically derived Foxp3⺠regulatory T (Treg) cells have a propensity to recognize self-peptide:MHC complexes, but their ability to respond to epitope-defined foreign antigens during infectious challenge has not been demonstrated. Here we show that pulmonary infection with Mycobacterium tuberculosis (Mtb), but not Listeria monocytogenes (Lm), induced robust lymph node expansion of a highly activated population of pathogen-specific Treg cells from the pre-existing pool of thymically derived Treg cells. These antigen-specific Treg cells peaked in numbers 3 weeks after infection but subsequently underwent selective elimination driven, in part, by interleukin-12-induced intrinsic expression of the Th1-cell-promoting transcription factor T-bet. Thus, the initial Mtb-induced inflammatory response promotes pathogen-specific Treg cell proliferation, but these cells are actively culled later, probably to prevent suppression during later stages of infection. These findings have important implications for the prevention and treatment of tuberculosis and other chronic diseases in which antigen-specific Treg cells restrict immunity.
Assuntos
Fatores de Transcrição Forkhead/metabolismo , Interleucina-12/imunologia , Mycobacterium tuberculosis/imunologia , Proteínas com Domínio T/metabolismo , Linfócitos T Reguladores/imunologia , Células Th1/imunologia , Tuberculose Pulmonar/imunologia , Animais , Antígenos de Bactérias/imunologia , Proteínas de Bactérias/imunologia , Proliferação de Células , Células Cultivadas , Deleção Clonal , Epitopos de Linfócito T/imunologia , Fatores de Transcrição Forkhead/genética , Evasão da Resposta Imune , Ativação Linfocitária , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fragmentos de Peptídeos/imunologia , Proteínas com Domínio T/genética , Linfócitos T Reguladores/microbiologia , Timo/patologiaRESUMO
The intracellular signaling molecule TRAF6 is critical for Toll-like receptor (TLR)-mediated activation of dendritic cells (DCs). We now report that DC-specific deletion of TRAF6 (TRAF6ΔDC) resulted, unexpectedly, in loss of mucosal tolerance, characterized by spontaneous development of T helper 2 (Th2) cells in the lamina propria and eosinophilic enteritis and fibrosis in the small intestine. Loss of tolerance required the presence of gut commensal microbiota but was independent of DC-expressed MyD88. Further, TRAF6ΔDC mice exhibited decreased regulatory T (Treg) cell numbers in the small intestine and diminished induction of iTreg cells in response to model antigen. Evidence suggested that this defect was associated with diminished DC expression of interleukin-2 (IL-2). Finally, we demonstrate that aberrant Th2 cell-associated responses in TRAF6ΔDC mice could be mitigated via restoration of Treg cell activity. Collectively, our findings reveal a role for TRAF6 in directing DC maintenance of intestinal immune tolerance through balanced induction of Treg versus Th2 cell immunity.
Assuntos
Células Dendríticas/imunologia , Enterite/imunologia , Eosinofilia/imunologia , Eosinófilos/imunologia , Gastrite/imunologia , Intestinos/imunologia , Linfócitos T Reguladores/imunologia , Fator 6 Associado a Receptor de TNF/metabolismo , Células Th2/imunologia , Animais , Células Cultivadas , Células Dendríticas/microbiologia , Enterite/genética , Eosinofilia/genética , Gastrite/genética , Regulação da Expressão Gênica/genética , Regulação da Expressão Gênica/imunologia , Tolerância Imunológica/genética , Interleucina-2/genética , Interleucina-2/metabolismo , Intestinos/microbiologia , Intestinos/patologia , Ativação Linfocitária/genética , Metagenoma/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fator 88 de Diferenciação Mieloide/genética , Fator 88 de Diferenciação Mieloide/metabolismo , Transdução de Sinais/genética , Linfócitos T Reguladores/microbiologia , Fator 6 Associado a Receptor de TNF/genética , Fator 6 Associado a Receptor de TNF/imunologia , Células Th2/microbiologiaRESUMO
The gut is the biggest immune organ in the body that encloses commensal microbiota which aids in food digestion. Paneth cells, positioned at the frontline of host-microbiota interphase, can modulate the composition of microbiota. Paneth cells achieve this via the delivery of microbicidal substances, among which enteric α-defensins play the primary role. If microbiota is dysregulated, it can impact the function of the local mucosal immune system. Importantly, this system is also exposed to an enormous number of antigens which are derived from the gut-resident microbiota and processed food, and may potentially trigger undesirable local inflammatory responses. To understand the intricate regulations and liaisons between Paneth cells, microbiota and the immune system in this intestinal-specific setting, one must consider their mode of interaction in a wider context of regulatory processes which impose immune tolerance not only to self, but also to microbiota and food-derived antigens. These include, but are not limited to, tolerogenic mechanisms of central tolerance in the thymus and peripheral tolerance in the secondary lymphoid organs, and the intestine itself. Defects in these processes can compromise homeostasis in the intestinal mucosal immunity. In this review, which is focused on tolerance to intestinal antigens and its relevance for the pathogenesis of gut immune diseases, we provide an outline of such multilayered immune control mechanisms and highlight functional links that underpin their cooperative nature.
Assuntos
Disbiose/prevenção & controle , Trato Gastrointestinal/imunologia , Celulas de Paneth/imunologia , Tolerância Periférica , alfa-Defensinas/imunologia , Animais , Tolerância Central , Disbiose/imunologia , Disbiose/microbiologia , Microbioma Gastrointestinal/imunologia , Trato Gastrointestinal/efeitos dos fármacos , Trato Gastrointestinal/microbiologia , Expressão Gênica/imunologia , Homeostase/imunologia , Humanos , Imunidade nas Mucosas/efeitos dos fármacos , Inflamação , Celulas de Paneth/efeitos dos fármacos , Celulas de Paneth/microbiologia , Simbiose/imunologia , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/microbiologia , alfa-Defensinas/biossíntese , alfa-Defensinas/farmacologiaRESUMO
Treg deficiency causes a lethal, CD4+ T cell-driven autoimmune disease called IPEX syndrome (immunodysregulation, polyendocrinopathy, and enteropathy, with X-linked inheritance) in humans and in the scurfy (SF) mouse, a mouse model of the disease. Feeding Limosilactobacillus reuteri DSM 17938 (LR 17938, LR) to SF mice reprograms the gut microbiota, reduces disease progression, and prolongs lifespan. However, the efficacy and mechanism of LR, compared with other probiotics, in producing these effects is unknown. We compared LR with Lacticaseibacillus rhamnosus GG (LGG), an extensively investigated probiotic. LR was more effective than LGG in prolonging survival. Both probiotics restored the fecal microbial alpha diversity, but they produced distinct fecal bacterial clusters and differentially modulated microbial relative abundance (RA). LR increased the RA of phylum_Firmicutes, genus_Oscillospira whereas LR reduced phylum_Bacteroidetes, genus_Bacteroides and genus_Parabacteroides, reversing changes attributed to the SF phenotype. LGG primarily reduced the RA of genus_Bacteroides. Both LR and LGG reduced the potentially pathogenic taxon class_γ-proteobacteria. Plasma metabolomics revealed substantial differences among 696 metabolites. We observed similar changes of many clusters of metabolites in SF mice associated with treatment with either LR or LGG. However, a unique effect of LR was to increase the abundance of plasma adenosine metabolites such as inosine, which we previously showed had immune modulatory effects. In conclusion: 1) different probiotics produce distinct signatures in the fecal microbial community in mice with Treg deficiency; and 2) when comparing different probiotics, there are strain-specific microbial products with different anti-inflammatory properties, reinforcing the concept that "one size does not fit all" in the treatment of autoimmune disease.NEW & NOTEWORTHY In the treatment of Treg-deficiency-induced autoimmunity, Limosilactobacillus reuteri DSM 17938 (LR) showed greater efficacy than Lacticaseibacillus rhamnosus GG (LGG). The study demonstrated that two different probiotics produce distinct signatures in the fecal microbial community in mice with Treg deficiency, but with many similarities in global plasma metabolites in general. However, there are strain-specific microbial products with different anti-inflammatory properties, reinforcing the concept that "one size does not fit all" in the treatment of autoimmune disease.
Assuntos
Diabetes Mellitus Tipo 1/congênito , Diarreia/microbiologia , Microbioma Gastrointestinal/imunologia , Doenças Genéticas Ligadas ao Cromossomo X/microbiologia , Doenças do Sistema Imunitário/congênito , Lacticaseibacillus rhamnosus , Limosilactobacillus reuteri , Linfócitos T Reguladores/imunologia , Animais , Diabetes Mellitus Tipo 1/metabolismo , Diabetes Mellitus Tipo 1/microbiologia , Diarreia/metabolismo , Doenças Genéticas Ligadas ao Cromossomo X/metabolismo , Doenças do Sistema Imunitário/metabolismo , Doenças do Sistema Imunitário/microbiologia , Camundongos , Camundongos Transgênicos , Probióticos , Linfócitos T Reguladores/metabolismo , Linfócitos T Reguladores/microbiologiaRESUMO
The gastric lamina propria of mice that have been experimentally infected with the pathobiont Helicobacter pylori hosts a dense network of myeloid cells that includes BATF3-dependent CD103+ dendritic cells (DCs). We show here that CD103+ DCs are strictly required for gastric Th1 responses to H. pylori and for H. pylori infection control. A similar dependence of type 1 immunity on CD103+ DCs is observed in a Mycobacterium bovis BCG infection model, and in a syngeneic colon cancer model. Strikingly, we find that not only the expansion and/or recruitment of Th1 cells, but also of peripherally induced, neuropilin-negative regulatory T-cells to sites of infection requires BATF3-dependent DCs. A shared feature of the examined models is the strongly reduced production of the chemokines and CXCR3 ligands CXCL9, 10 and 11 in BATF3-deficient mice. The results implicate BATF3-dependent DCs in the recruitment of CXCR3+ effector and regulatory T-cells to target tissues and in their local expansion.
Assuntos
Fatores de Transcrição de Zíper de Leucina Básica/imunologia , Células Dendríticas/imunologia , Infecções por Helicobacter/imunologia , Helicobacter pylori/imunologia , Mycobacterium bovis/imunologia , Proteínas Repressoras/imunologia , Linfócitos T Reguladores/imunologia , Tuberculose/imunologia , Animais , Fatores de Transcrição de Zíper de Leucina Básica/genética , Linhagem Celular Tumoral , Quimiocinas CXC/genética , Quimiocinas CXC/imunologia , Células Dendríticas/microbiologia , Células Dendríticas/patologia , Infecções por Helicobacter/genética , Infecções por Helicobacter/patologia , Camundongos , Camundongos Knockout , Receptores CXCR3/genética , Receptores CXCR3/imunologia , Proteínas Repressoras/genética , Linfócitos T Reguladores/microbiologia , Linfócitos T Reguladores/patologia , Tuberculose/genética , Tuberculose/patologiaRESUMO
A fracture-related infection (FRI) is a serious complication that can occur after surgical fixation of bone fractures. Affected patients may encounter delayed healing and functional limitations. Although it is well established that Staphylococcus aureus (S. aureus) is the main causative pathogen of an FRI, the pathophysiology of an S. aureus-induced FRI is not well characterised over time. Therefore, an experimental study in mice comparing S. aureus-inoculated and non-inoculated groups was performed that particularly focused on staphylococcal abscess communities (SACs) and host cellular response. C57Bl/6N female mice received a double osteotomy of the femur, which was stabilised using a titanium 6-hole MouseFix locking plate and four screws. Animals were either S. aureus-inoculated or non-inoculated and euthanised between 1 and 28 d post-surgery. Histopathological evaluation showed normal bone healing for non-inoculated mice, whereas inoculated mice had no fracture consolidation and severe osteolysis. Within the bone marrow of inoculated mice, SACs were observed from 7 d, which increased in size and number over time. A fibrin pseudocapsule enclosed the SACs, which were surrounded by many Ly6G+ neutrophils with some Ly6C+ monocytes and F4/80+ macrophages, the majority of which were viable. The abscesses were encapsulated by fibrin(ogen), collagen and myofibroblasts, with regulatory T cells and M2 macrophages at the periphery. Only bone marrow monocytes and neutrophils of inoculated mice displayed functional suppression of T cells, indicative of myeloid-derived suppressor cells. The present study revealed that an FRI in mice is persistent over time and associated with osteolysis, SAC formation and an immunosuppressive environment.
Assuntos
Abscesso/microbiologia , Fraturas Ósseas/microbiologia , Células Supressoras Mieloides/microbiologia , Infecções Estafilocócicas/etiologia , Infecções Estafilocócicas/microbiologia , Animais , Biofilmes/crescimento & desenvolvimento , Modelos Animais de Doenças , Macrófagos/microbiologia , Camundongos , Camundongos Endogâmicos C57BL , Monócitos/microbiologia , Neutrófilos/microbiologia , Osteólise/microbiologia , Staphylococcus aureus/patogenicidade , Linfócitos T Reguladores/microbiologiaRESUMO
Chronic T cell activation is a hallmark of pulmonary tuberculosis (PTB). The mechanisms underpinning this important phenomenon are however, poorly elucidated, though known to rely on control of T effector cells (Teff) by regulatory T cells (Treg). Our studies show that circulating natural Treg cells in adults with PTB preserve their suppressive potential but Teff cells from such subjects are resistant to Treg-mediated suppression. We found this to be due to expansion of an activated Teff subset identified by Human Leukocyte Antigen (HLA)-DR expression. Sensitivity to suppression was restored to control levels by depletion of this subset. Comparative transcriptome analysis of Teff cells that contain HLA-DR+ cells versus the fraction depleted of this population identified putative resistance mechanisms linked to IFNG, IL17A, IL22, PD-L1 and ß-chemokines CCL3L3, CCL4 expression. Antibody blocking experiments confirmed HLA-DR+ Teff cells, but not the fraction depleted of HLA-DR+ effectors, to be resistant to Treg suppression mediated via CCR5 and PD-L1 associated pathways. In the presence of HLA-DR+ Teff cells, activation of NFκB downstream of CCR5 and PD-L1 was perturbed. In addition, HLA-DR+ Teff cells expressed significantly higher levels of Th1/Th17 cytokines that may regulate Treg function through a reciprocal counter-balancing relationship. Taken together, our study provides novel insight on how activated HLA-DR+CD4+ T cells may contribute to disease associated inflammation by compromising Treg-mediated suppression in PTB.
Assuntos
Antígeno B7-H1/metabolismo , Linfócitos T CD4-Positivos/imunologia , Receptores CCR5/metabolismo , Linfócitos T Reguladores/imunologia , Tuberculose Pulmonar/imunologia , Adulto , Antígeno B7-H1/antagonistas & inibidores , Linfócitos T CD4-Positivos/microbiologia , Citocinas/genética , Citocinas/metabolismo , Feminino , Antígenos HLA-DR/metabolismo , Interações Hospedeiro-Patógeno/imunologia , Humanos , Tolerância Imunológica , Memória Imunológica , Tuberculose Latente/imunologia , Tuberculose Latente/microbiologia , Ativação Linfocitária , Masculino , Pessoa de Meia-Idade , Mycobacterium tuberculosis/imunologia , Mycobacterium tuberculosis/patogenicidade , Linfócitos T Reguladores/microbiologia , Tuberculose Pulmonar/genética , Tuberculose Pulmonar/microbiologia , Regulação para CimaRESUMO
The delineation of the pathogenic interaction between the host skin immune responses and dermatophytes has remained indigent. The obscure enigma in host-dermatophyte immunopathogenic interactions is the T regulatory (Treg) and T-helper (Th) 17 cell role in maintaining immune homeostasis. We attempted to understand the regulation and recognition of lineage-specific response in chronic dermatophytic skin infection patients. The percentages of Th17 (CD4+CD161+IL23R+) and Treg (CD4+CD25+FoxP3+) cell subpopulations in the peripheral circulation of thirty chronic dermatophytic skin infection patients and twenty healthy individuals was determined. The serum cytokine levels were estimated for disease correlation. The mean duration of the disease was 10.68 ± 8.72 months, with Trichophyton mentagrophytes complex as the major pathogen. Total serum IgE level of patients was significantly higher compared to healthy controls (305 ± 117 vs 98.53 ± 54.55 IU/ml; p < 0.01). Expression of Th17 and Treg cell markers on CD4+ T cells was significantly elevated in patients than controls (p < 0.05). Comparatively, serum interleukin (IL)-4 and interferon (IFN)-γ levels were increased, with low IL-10 levels in patients. Our data envisages a complex immune dysfunction in chronic dermatophytosis, arising either as a result of dermatophyte exposure or paradoxical precedence of disease establishment. Designing new treatment strategies and preventing recurrences are challenges for future research.
Assuntos
Arthrodermataceae/fisiologia , Dermatomicoses/imunologia , Linfócitos T Reguladores/imunologia , Células Th17/imunologia , Adolescente , Adulto , Doença Crônica , Dermatomicoses/sangue , Dermatomicoses/microbiologia , Feminino , Humanos , Interferon gama/sangue , Interleucina-10/sangue , Interleucina-4/sangue , Masculino , Linfócitos T Reguladores/microbiologia , Células Th17/microbiologia , Adulto JovemRESUMO
Septic arthritis is a condition of bone disorder caused predominantly by Staphylococcus aureus. Following the bacterial entry activated immune cells specially macrophages and dendritic cells release pro-inflammatory mediators such as IL-6, TNF-α, IL-1ß etc., which not only create an inflammatory microenvironment but also play crucial roles in the proliferation of different CD+ T cell subsets. Among them, Th17 and Tregs are of major concern in recent times because of their potential roles in regulating the ongoing inflammation in many diseases including experimental arthritis. But the downstream signalling mechanism of these cells in regulating the severity of inflammation in case of septic arthritis is not known yet. So, here we have established a murine model of S. aureus induced septic arthritis and kept the animal upto 15â¯days post-infection. To examine the signalling mechanism, Th17 and Treg cells were isolated from blood, spleen and synovial joints of control and infected mice and observed the expression of JNK, NFκB and RANKL in the lysate of isolated Th17 and Tregs. We have also estimated the levels of serum IL-21 and TGF-ß. NFκB, JNK and RANKL expression was found to be higher at 3 and 15â¯days post-infection along with serum IL-21 levels. On the other hand, maximum TGF-ß level was observed at 9â¯days post-infection along with increased Treg population. In conclusion it was hypothesized that bone resorption is related with downstream signalling pathways of Th17 cells, which stimulate osteoclast generation via NFκB/JNK-RANKL axis and helps in the persistence of the disease.
Assuntos
Artrite Infecciosa/imunologia , Inflamação/imunologia , Infecções Estafilocócicas/imunologia , Linfócitos T Reguladores/imunologia , Células Th17/imunologia , Animais , Artrite Experimental/genética , Artrite Experimental/imunologia , Artrite Experimental/microbiologia , Artrite Experimental/patologia , Artrite Infecciosa/genética , Artrite Infecciosa/microbiologia , Artrite Infecciosa/patologia , Regulação da Expressão Gênica/genética , Humanos , Inflamação/genética , Inflamação/microbiologia , Inflamação/patologia , Interleucina-1beta/genética , Articulações/imunologia , Articulações/microbiologia , Articulações/patologia , MAP Quinase Quinase 4/genética , Camundongos , Osteoclastos/imunologia , Osteoclastos/microbiologia , Osteoclastos/patologia , Ligante RANK/genética , Transdução de Sinais/genética , Infecções Estafilocócicas/genética , Infecções Estafilocócicas/microbiologia , Infecções Estafilocócicas/patologia , Staphylococcus aureus/patogenicidade , Linfócitos T Reguladores/microbiologia , Células Th17/microbiologia , Fator de Crescimento Transformador beta/genética , Fator de Necrose Tumoral alfa/genéticaRESUMO
Psoriasis is a chronic inflammatory cutaneous disease, characterized by activated plasmacytoid dendritic cells, myeloid dendritic cells, Th17 cells, and hyperproliferating keratinocytes. Recent studies revealed skin-resident cells have pivotal roles in developing psoriatic skin lesions. The balance in effector T cells and regulatory T cells is disturbed, leading Foxp3-positive regulatory T cells to produce proinflammatory IL-17. Not only acquired but also innate immunity is important in psoriasis pathogenesis, especially in triggering the disease. Group 3 innate lymphoid cell are considered one of IL-17-producing cells in psoriasis. Short chain fatty acids produced by gut microbiota stabilize expression of Foxp3 in regulatory T cells, thereby stabilizing their function. The composition of gut microbiota influences the systemic inflammatory status, and associations been shown with diabetes mellitus, cardiovascular diseases, psychomotor diseases, and other systemic inflammatory disorders. Psoriasis has been shown to frequently comorbid with diabetes mellitus, cardiovascular diseases, psychomotor disease and obesity, and recent report suggested the similar abnormality in gut microbiota as the above comorbid diseases. However, the precise mechanism and relation between psoriasis pathogenesis and gut microbiota needs further investigation. This review introduces the recent advances in psoriasis research and tries to provide clues to solve the mysterious relation of psoriasis and gut microbiota.
Assuntos
Microbioma Gastrointestinal/imunologia , Psoríase/imunologia , Linfócitos T Reguladores/microbiologia , Animais , Fatores de Transcrição Forkhead , Humanos , Inflamação , Linfócitos T Reguladores/imunologiaRESUMO
The aims of this study were to explore intestinal microbial composition and functionality in primary Sjögren's syndrome (pSS) and to relate these findings to inflammation, permeability and the transcription factor Forkhead box protein P3 (FOXP3) gene expression in peripheral blood. The study included 19 pSS patients and 19 healthy controls matched for age, sex, and body mass index. Fecal bacterial DNA was extracted and analyzed by 16S rRNA sequencing using an Ion S5 platform followed by a bioinformatics analysis using Quantitative Insights into Microbial Ecology (QIIME II) and Phylogenetic Investigation of Communities by Reconstruction of Unobserved States (PICRUSt). Our data suggest that the gut microbiota of pSS patients differs at both the taxonomic and functional levels with respect to healthy controls. The gut microbiota profile of our pSS patients was characterized by a lower diversity and richness and with Bacteroidetes dominating at the phylum level. The pSS patients had less beneficial or commensal butyrate-producing bacteria and a higher proportion of opportunistic pathogens with proinflammatory activity, which may impair intestinal barrier function and therefore contribute to inflammatory processes associated with pSS by increasing the production of proinflammatory cytokines and decreasing the release of the anti-inflammatory cytokine IL-10 and the peripheral FOXP3 mRNA expression, implicated in the development and function of regulatory T cells (Treg) cells. Further studies are needed to better understand the real impact of dysbiosis on the course of pSS and to conceive preventive or therapeutic strategies to counteract microbiome-driven inflammation.
Assuntos
Disbiose/microbiologia , Fatores de Transcrição Forkhead/imunologia , Microbioma Gastrointestinal/imunologia , Intestinos/microbiologia , Síndrome de Sjogren/microbiologia , Actinobacteria/classificação , Actinobacteria/genética , Actinobacteria/isolamento & purificação , Adolescente , Adulto , Idoso , Bacteroides/classificação , Bacteroides/genética , Bacteroides/isolamento & purificação , Índice de Massa Corporal , Estudos de Casos e Controles , Disbiose/genética , Disbiose/imunologia , Disbiose/patologia , Fezes/microbiologia , Feminino , Firmicutes/classificação , Firmicutes/genética , Firmicutes/isolamento & purificação , Fatores de Transcrição Forkhead/genética , Variação Genética , Humanos , Inflamação , Interleucina-10/genética , Interleucina-10/imunologia , Intestinos/imunologia , Pessoa de Meia-Idade , Permeabilidade , Proteobactérias/classificação , Proteobactérias/genética , Proteobactérias/isolamento & purificação , RNA Ribossômico 16S/genética , Síndrome de Sjogren/genética , Síndrome de Sjogren/imunologia , Síndrome de Sjogren/patologia , Linfócitos T Reguladores/microbiologiaRESUMO
Despite standardized postoperative care, some lung transplant patients suffer multiple episodes of acute and chronic rejection while others avoid graft problems for reasons that are poorly understood. Using an established model of C57BL/10 to C57BL/6 minor antigen mismatched single lung transplantation, we now demonstrate that the recipient microbiota contributes to variability in the alloimmune response. Specifically, mice from the Envigo facility in Frederick, Maryland contain nearly double the number of CD4+ Foxp3+ regulatory T cells (Tregs ) than mice from the Jackson facility in Bar Harbor, Maine or the Envigo facility in Indianapolis, Indiana (18 vs 9 vs 7%). Lung graft recipients from the Maryland facility thus do not develop acute or chronic rejection. Treatment with broad-spectrum antibiotics decreases Tregs and increases both acute and chronic graft rejection in otherwise tolerant strains of mice. Constitutive depletion of regulatory T cells, using Foxp3-driven expression of diphtheria toxin receptor, leads to the development of chronic rejection and supports the role of Tregs in both acute and chronic alloimmunity. Taken together, our data demonstrate that the microbiota of certain individuals may contribute to tolerance through Treg -dependent mechanisms and challenges the practice of indiscriminate broad-spectrum antibiotic use in the perioperative period.
Assuntos
Linfócitos T CD4-Positivos/imunologia , Comércio/normas , Fatores de Transcrição Forkhead/fisiologia , Rejeição de Enxerto/prevenção & controle , Pneumopatias/imunologia , Transplante de Pulmão/efeitos adversos , Microbiota , Linfócitos T Reguladores/imunologia , Aloenxertos , Animais , Linfócitos T CD4-Positivos/microbiologia , Rejeição de Enxerto/etiologia , Rejeição de Enxerto/metabolismo , Sobrevivência de Enxerto/imunologia , Pneumopatias/microbiologia , Pneumopatias/cirurgia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Linfócitos T Reguladores/microbiologia , TransplantadosRESUMO
BACKGROUND & AIMS: Faecalibacterium prausnitzii, a member of the Clostridium IV group of the Firmicutes phylum that is abundant in the intestinal microbiota, has anti-inflammatory effects. The relative level of F prausnitzii is decreased in fecal samples from patients with inflammatory bowel diseases (IBDs) compared with healthy individuals. Reduced F prausnitzii was correlated with relapse of Crohn's disease after surgery. We identified, in human colonic mucosa and blood, a population of T regulatory type 1-like T regulatory (TREG) cells that express CD4 and CD8α (DP8α T cells) and are specific for F prausnitzii. We aimed to determine whether they are altered in patients with IBD. METHODS: We isolated DP8α T cells from human colon lamina propria and blood samples and used flow cytometry to detect markers of cells that are of colon origin. We quantified DP8α cells that express colon-specific markers in blood samples from 106 patients with IBD, 12 patients with infectious colitis, and 35 healthy donors (controls). We identified cells that respond to F prausnitzii. Cells were stimulated with anti-CD3, and their production of interleukin 10 was measured by enzyme-linked immunosorbent assay. We compared the frequency and reactivity of cells from patients vs controls using the 2-sided Student t test or 1-way analysis of variance. RESULTS: Circulating DP8α T cells that proliferate in response to F prausnitzii express the C-C motif chemokine receptor 6 (CCR6) and C-X-C motif chemokine receptor 6 (CXCR6). These cells also have features of TREG cells, including production of IL-10 and inhibition of T-cell proliferation via CD39 activity. The proportion of circulating CCR6+/CXCR6+ DP8α T cells was significantly reduced (P < .0001) within the total population of CD3+ T cells from patients with IBD compared with patients with infectious colitis or controls. A threshold of <7.875 CCR6+/CXCR6+ DP8α T cells/10,000 CD3+ cells discriminated patients with IBD from those with infectious colitis with 100% specificity and 72.2% sensitivity. CONCLUSIONS: We identified a population of gut-derived TREG cells that are reduced in blood samples from patients with IBD compared with patients with infectious colitis or controls. These cells should be studied further to determine the mechanisms of this reduction and how it might contribute to the pathogenesis of IBD and their prognostic or diagnostic value.
Assuntos
Linfócitos T CD8-Positivos/metabolismo , Colo/metabolismo , Doenças Inflamatórias Intestinais/sangue , Mucosa Intestinal/metabolismo , Receptores CCR6/sangue , Receptores CXCR6/sangue , Linfócitos T Reguladores/metabolismo , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/microbiologia , Estudos de Casos e Controles , Proliferação de Células , Células Cultivadas , Colo/imunologia , Colo/microbiologia , Colo/patologia , Faecalibacterium prausnitzii/imunologia , Humanos , Doenças Inflamatórias Intestinais/imunologia , Doenças Inflamatórias Intestinais/microbiologia , Doenças Inflamatórias Intestinais/patologia , Mucosa Intestinal/imunologia , Mucosa Intestinal/microbiologia , Mucosa Intestinal/patologia , Ativação Linfocitária , Fenótipo , Receptores CCR6/imunologia , Receptores CXCR6/imunologia , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/microbiologiaRESUMO
Protective immunity against Mycobacterium tuberculosis is poorly understood. The role of interleukin (IL)-4, the archetypal T-helper type 2 (Th2) cytokine, in the immunopathogenesis of human tuberculosis remains unclear.Blood and/or bronchoalveolar lavage fluid (BAL) were obtained from participants with pulmonary tuberculosis (TB) (n=23) and presumed latent TB infection (LTBI) (n=22). Messenger RNA expression levels of interferon (IFN)-γ, IL-4 and its splice variant IL-4δ2 were determined by real-time PCR. The effect of human recombinant (hr)IL-4 on mycobacterial survival/containment (CFU·mL-1) was evaluated in M. tuberculosis-infected macrophages co-cultured with mycobacterial antigen-primed effector T-cells. Regulatory T-cell (Treg) and Th1 cytokine levels were evaluated using flow cytometry.In blood, but not BAL, IL-4 mRNA levels (p=0.02) and the IL-4/IFN-γ ratio (p=0.01) was higher in TB versus LTBI. hrIL-4 reduced mycobacterial containment in infected macrophages (p<0.008) in a dose-dependent manner and was associated with an increase in Tregs (p<0.001), but decreased CD4+Th1 cytokine levels (CD4+IFN-γ+ p<0.001; CD4+TNFα+ p=0.01). Blocking IL-4 significantly neutralised mycobacterial containment (p=0.03), CD4+IFNγ+ levels (p=0.03) and Treg expression (p=0.03).IL-4 can subvert mycobacterial containment in human macrophages, probably via perturbations in Treg and Th1-linked pathways. These data may have implications for the design of effective TB vaccines and host-directed therapies.
Assuntos
Interleucina-4/farmacologia , Tuberculose Latente/microbiologia , Macrófagos/citologia , Mycobacterium tuberculosis/imunologia , Antígenos de Bactérias/imunologia , Líquido da Lavagem Broncoalveolar , Linfócitos T CD4-Positivos/citologia , Linfócitos T CD4-Positivos/imunologia , Células Cultivadas , Técnicas de Cocultura , Citocinas/imunologia , Humanos , Imunoterapia , Inflamação , Interferon gama/metabolismo , Tuberculose Latente/metabolismo , Macrófagos/microbiologia , RNA Mensageiro/metabolismo , Proteínas Recombinantes/farmacologia , Linfócitos T Reguladores/citologia , Linfócitos T Reguladores/microbiologia , Células Th1/citologia , Células Th1/microbiologia , Células Th2/citologia , Células Th2/microbiologia , Tuberculose Pulmonar/imunologiaRESUMO
Pemphigus vulgaris (PV) is an autoimmune disease characterized by the production of IgG autoantibodies owing to an imbalance in the Th1/Th2 and Th17/Tregs cell pathways. The role of gut microbiota in the development of immune system and autoimmune diseases has been unraveled in the last two decades. However, data pertaining to gut microbiota of PV patients is largely lacking. We aimed to compare the gut microbiota of PV patients and healthy controls and assessed potential correlation with circulating cytokines of Th1/Th2/Th17 cell. Faecal bacterial diversity was analysed in 18 PV patients and 14 age- and gender-matched healthy individuals using hypervariable tag sequencing of the V3-V4 region of the 16S rRNA gene. Plasma levels of 20 inflammatory cytokines were assessed using the Luminex screening system. As a result, we identified 10 differentially abundant taxa between patients and controls. At the genera level, Lachnospiracea_incertae_sedis and Coprococcus decreased, while Granulicatella, Flavonifractor enriched in PV. Plasma levels of C5a, interleukin (IL)-2R, IL-6, IL-8, IL-7, IL-1ß, IL17A, IL-5 and IL-21 were significantly increased in PV Flavonifractor exhibited a positive correlation with C5a, IL-6, IL-8, IL-7, IL-1ß, IL17A and IL-21. Lachnospiracea_incertae_sedis and Coprococcus showed a negative correlation with IL-17A. Our results are consistent with the hypothesis that PV patients have gut microbial dysbiosis which might contribute to the immune disorder and the development of PV.
Assuntos
Doenças Autoimunes/imunologia , Citocinas/imunologia , Microbioma Gastrointestinal/imunologia , Inflamação/imunologia , Pênfigo/imunologia , Plasma/imunologia , Adulto , Autoanticorpos/imunologia , Doenças Autoimunes/microbiologia , Fezes/microbiologia , Feminino , Humanos , Inflamação/microbiologia , Masculino , Pessoa de Meia-Idade , Pênfigo/microbiologia , Plasma/microbiologia , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/microbiologia , Células Th1/imunologia , Células Th1/microbiologia , Células Th17/imunologia , Células Th17/microbiologia , Células Th2/imunologia , Células Th2/microbiologiaRESUMO
BACKGROUND: The role of bacterial biofilm in hidradenitis suppurativa (HS) is highly debated. Less biofilm is found in clinically unaffected axillary perilesional skin of HS patients compared with healthy controls. OBJECTIVE: To study the correlation between biofilm and the phenotypical characterization of the preclinical inflammatory infiltrate. MATERIALS AND METHODS: An exploratory comparative study of punch biopsies from unaffected axillary HS skin compared to similarly biopsies from healthy controls underwent standard staining procedures for CD4, CD8, CD25, FoxP3 and IL17. Standard-sized inflammatory histological hotspots were identified manually. Slides were scanned into Leica Biosystems' Digital Image Hub. Number of stained cells per slide and hotspot was found using an algorithm. RESULTS: 12.5% of HS had biofilm compared to 85% of controls. For full slides, HS patients had more CD4+ cells than controls; HS patients with biofilm had higher CD4+ cell number than controls with or without biofilm and HS patients without biofilm. For hotspots, HS patients with biofilm had higher number of CD4+FoxP3+ cells than HS patients without biofilm and controls with biofilm. CONCLUSION: The association between biofilm and the number of regulatory T cells in HS patients supports the concept of dysbiosis as a factor in the preclinical HS lesions.