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1.
Immunity ; 54(3): 514-525.e6, 2021 03 09.
Artigo em Inglês | MEDLINE | ID: mdl-33657395

RESUMO

MicroRNAs are important regulators of immune responses. Here, we show miR-221 and miR-222 modulate the intestinal Th17 cell response. Expression of miR-221 and miR-222 was induced by proinflammatory cytokines and repressed by the cytokine TGF-ß. Molecular targets of miR-221 and miR-222 included Maf and Il23r, and loss of miR-221 and miR-222 expression shifted the transcriptomic spectrum of intestinal Th17 cells to a proinflammatory signature. Although the loss of miR-221 and miR-222 was tolerated for maintaining intestinal Th17 cell homeostasis in healthy mice, Th17 cells lacking miR-221 and miR-222 expanded more efficiently in response to IL-23. Both global and T cell-specific deletion of miR-221 and miR-222 rendered mice prone to mucosal barrier damage. Collectively, these findings demonstrate that miR-221 and miR-222 are an integral part of intestinal Th17 cell response that are induced after IL-23 stimulation to constrain the magnitude of proinflammatory response.


Assuntos
Inflamação/imunologia , Interleucina-23/metabolismo , Mucosa Intestinal/imunologia , MicroRNAs/genética , Células Th17/imunologia , Animais , Retroalimentação Fisiológica , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteínas Proto-Oncogênicas c-maf/metabolismo , Receptores de Interleucina/metabolismo , Transdução de Sinais , Fator de Crescimento Transformador beta/metabolismo
2.
Cell ; 151(5): 981-93, 2012 Nov 21.
Artigo em Inglês | MEDLINE | ID: mdl-23178119

RESUMO

Signaling pathways are intimately involved in cellular differentiation, allowing cells to respond to their environment by regulating gene expression. Although enhancers are recognized as key elements that regulate selective gene expression, the interplay between signaling pathways and actively used enhancer elements is not clear. Here, we use CD4(+) T cells as a model of differentiation, mapping the activity of cell-type-specific enhancer elements in T helper 1 (Th1) and Th2 cells. Our data establish that STAT proteins have a major impact on the activation of lineage-specific enhancers and the suppression of enhancers associated with alternative cell fates. Transcriptome analysis further supports a functional role for enhancers regulated by STATs. Importantly, expression of lineage-defining master regulators in STAT-deficient cells fails to fully recover the chromatin signature of STAT-dependent enhancers. Thus, these findings point to a critical role of STATs as environmental sensors in dynamically molding the specialized enhancer architecture of differentiating cells.


Assuntos
Linfócitos T CD4-Positivos/citologia , Diferenciação Celular , Elementos Facilitadores Genéticos , Fatores de Transcrição STAT/metabolismo , Células Th1/citologia , Células Th2/citologia , Animais , Linfócitos T CD4-Positivos/metabolismo , Citocinas/metabolismo , Fator de Transcrição GATA3/metabolismo , Genes Essenciais , Camundongos , Camundongos Endogâmicos C57BL , Fatores de Transcrição STAT/genética , Proteínas com Domínio T/metabolismo , Fatores de Transcrição de p300-CBP/metabolismo
3.
Int Immunol ; 36(8): 413-424, 2024 Jul 13.
Artigo em Inglês | MEDLINE | ID: mdl-38576231

RESUMO

Autoimmune diseases often arise from conditions where the immune system is compromised. While lymphopenia-induced proliferation (LIP) is crucial for immune system development and maturation, it is also caused by environmental insults, such as infection, and becomes a risk factor for autoimmunity in adults. We used Dsg3H1 TCR transgenic mice, whose T cells are designed to recognize desmogrein-3, a skin antigen, to explore the impact of lymphopenia on post-thymic tolerance. Dsg3H1 mice are known to delete the most highly autoreactive T cells in the thymus, and develop only subtle immune-mediated pathology in the steady state. However, we found that transient lymphopenia induced by total body irradiation (TBI) or cyclophosphamide (CY) results in massive dermatitis in Dsg3H1 mice. The symptoms included expansion and development of self-reactive T cells, their differentiation into CD44high IL-17-producing helper T cells, and severe neutrophilic inflammation. Repopulation of FOXP3+ T regulatory cells after lymphopenia normally occurred, suggesting escape of skin-reactive conventional T cells from control by regulatory T cells. Furthermore, we found that a depletion of the intestinal microbiota by antibiotics prevents CY-induced dermatitis, indicating roles of the commensal intestinal microbiota in LIP and Th17 development in vivo. The current data suggested that post-thymic tolerance of Dsg3H1 mice is established on a fragile balance in the lymphoreplete immune environment and broken by the interplay between lymphopenia and intestinal microbiota. The dynamic phenotypes observed in Dsg3H1 mice prompt a re-evaluation of opportunistic lymphopenia together with the microbiota as pivotal environmental factors, impacting individuals with genetic predispositions for autoimmune diseases.


Assuntos
Microbioma Gastrointestinal , Tolerância Imunológica , Linfopenia , Camundongos Transgênicos , Animais , Camundongos , Microbioma Gastrointestinal/imunologia , Linfopenia/imunologia , Tolerância Imunológica/imunologia , Pele/imunologia , Pele/microbiologia , Pele/patologia , Receptores de Antígenos de Linfócitos T/imunologia , Receptores de Antígenos de Linfócitos T/metabolismo , Timo/imunologia , Camundongos Endogâmicos C57BL
4.
Nat Immunol ; 13(6): 587-95, 2012 Apr 29.
Artigo em Inglês | MEDLINE | ID: mdl-22544395

RESUMO

Distinct CD4(+) T cell subsets are critical for host defense and immunoregulation. Although these subsets can act as terminally differentiated lineages, they have been increasingly noted to demonstrated plasticity. MicroRNAs are factors that control T cell stability and plasticity. Here we report that naturally occurring regulatory T cells (T(reg) cells) had high expression of the microRNA miR-10a and that miR-10a was induced by retinoic acid and transforming growth factor-ß (TGF-ß) in inducible T(reg) cells. By simultaneously targeting the transcriptional repressor Bcl-6 and the corepressor Ncor2, miR-10a attenuated the phenotypic conversion of inducible T(reg) cells into follicular helper T cells. We also found that miR-10a limited differentiation into the T(H)17 subset of helper T cells and therefore represents a factor that can fine-tune the plasticity and fate of helper T cells.


Assuntos
MicroRNAs/biossíntese , Proteínas Proto-Oncogênicas c-bcl-6/metabolismo , Linfócitos T Auxiliares-Indutores/efeitos dos fármacos , Linfócitos T Reguladores/efeitos dos fármacos , Fator de Crescimento Transformador beta/farmacologia , Tretinoína/farmacologia , Animais , Diferenciação Celular/imunologia , Regulação para Baixo/imunologia , Citometria de Fluxo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , MicroRNAs/genética , MicroRNAs/imunologia , Correpressor 2 de Receptor Nuclear/imunologia , Fenótipo , Proteínas Proto-Oncogênicas c-bcl-6/imunologia , RNA Mensageiro/biossíntese , RNA Mensageiro/química , RNA Mensageiro/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Proteínas com Domínio T/imunologia , Linfócitos T Auxiliares-Indutores/imunologia , Linfócitos T Auxiliares-Indutores/fisiologia , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/fisiologia , Transcrição Gênica
5.
Br J Dermatol ; 2024 Aug 14.
Artigo em Inglês | MEDLINE | ID: mdl-39141587

RESUMO

Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) represent a severe spectrum of rare mucocutaneous reactions, primarily drug-induced and characterized by significant morbidity and mortality. These conditions manifest through extensive skin detachment, distinguishing them from other generalized skin eruptions. The rarity and severity of SJS/TEN underscore the importance of accurate diagnostic criteria and effective treatments, which are currently lacking consensus. This review proposes new diagnostic criteria to improve specificity and global applicability. Recent advancements in understanding the immunopathogenesis of SJS/TEN are explored, emphasizing the role of drug-specific T cell responses and HLA polymorphisms in disease onset. The review also addresses current therapeutic approaches, including controversies surrounding the use of immunosuppressive agents and the emerging role of TNF-α inhibitors. Novel therapeutic strategies targeting specific pathogenic mechanisms, such as necroptosis and specific immune cell pathways, are discussed. Furthermore, the development of new drugs based on these insights, including targeted monoclonal antibodies and inhibitors, are examined. The review concludes by advocating for more robust and coordinated efforts across multidisciplinary medical fields to develop effective treatments and diagnostic tools for SJS/TEN, with the aim of improving patient outcomes and understanding of the disease and its mechanisms.

6.
J Immunol ; 208(3): 582-593, 2022 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-34996836

RESUMO

Pemphigus vulgaris is an autoimmune blistering disease caused by IgG targeting desmoglein 3 (Dsg3), an adhesion molecule of keratinocytes. Anti-Dsg3 IgG production is prevented in healthy individuals, but it is unclear how Dsg3-specific B cells are regulated. To clarify the immunological condition regulating Dsg3-specific B cells, a pathogenic anti-Dsg3 Ig (AK23) knock-in mouse was generated. AK23 knock-in B cells developed normally without undergoing deletion or acquiring an anergic phenotype in vivo. The knock-in B cells showed Ca2+ influx upon IgM cross-linking and differentiated into AK23-IgG+ B cells after LPS and IL-4 stimulation in vitro that induced a pemphigus phenotype after adoptive transfer into Rag2 -/- mice. However, the knock-in mouse itself produced AK23-IgM but little IgG without blisters in vivo. Dsg3 immunization and skin inflammation caused AK23-IgG production and a pemphigus phenotype in vivo. Furthermore, Fcgr2b deficiency or haploinsufficiency spontaneously induced AK23-IgG production and a pemphigus phenotype with poor survival rates in AK23 knock-in mice. To assess Fcgr2b involvement in Ig class-switch efficiency, postswitch transcripts of B cells were quantified and significantly higher in Fcgr2b -/- and Fcgr2b +/- mice than wild-type mice in a gene dose-dependent manner. Finally, RNA sequencing revealed reduced expression of FCGR2B and FcγRIIB-related genes in patient B cells. These results indicated that Dsg3-specific B cells do not spontaneously perform pathogenic class switching in vivo, and pemphigus phenotype induction was prevented under normal conditions. Attenuated FcγRIIB signaling is also one of the drivers for pathogenic class switching and is consistent with immunological features identified from clinical samples. This study unveiled a characteristic immune state silencing autoreactive B cells in mice.


Assuntos
Desmogleína 3/genética , Switching de Imunoglobulina/imunologia , Imunoglobulina G/imunologia , Imunoglobulina M/imunologia , Pênfigo/genética , Receptores de IgG/genética , Adulto , Idoso , Animais , Autoimunidade/imunologia , Linfócitos B/imunologia , Desmogleína 3/imunologia , Feminino , Técnicas de Introdução de Genes , Humanos , Imunoglobulina G/genética , Imunoglobulina M/genética , Queratinócitos/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Pessoa de Meia-Idade , Pênfigo/imunologia , Pênfigo/patologia , Receptores de IgG/metabolismo
7.
Proc Natl Acad Sci U S A ; 118(49)2021 12 07.
Artigo em Inglês | MEDLINE | ID: mdl-34848535

RESUMO

Antigen-specific peripheral tolerance is crucial to prevent the development of organ-specific autoimmunity. However, its function decoupled from thymic tolerance remains unclear. We used desmoglein 3 (Dsg3), a pemphigus antigen expressed in keratinocytes, to analyze peripheral tolerance under physiological antigen-expression conditions. Dsg3-deficient thymi were transplanted into athymic mice to create a unique condition in which Dsg3 was expressed only in peripheral tissue but not in the thymus. When bone marrow transfer was conducted from high-avidity Dsg3-specific T cell receptor-transgenic mice to thymus-transplanted mice, Dsg3-specific CD4+ T cells developed in the transplanted thymus but subsequently disappeared in the periphery. Additionally, when Dsg3-specific T cells developed in Dsg3-/- mice were adoptively transferred into Dsg3-sufficient recipients, the T cells disappeared in an antigen-specific manner without inducing autoimmune dermatitis. However, Dsg3-specific T cells overcame this disappearance and thus induced autoimmune dermatitis in Treg-ablated recipients but not in Foxp3-mutant recipients with dysfunctional Tregs. The molecules involved in disappearance were sought by screening the transcriptomes of wild-type and Foxp3-mutant Tregs. OX40 of Tregs was suggested to be responsible. Consistently, when OX40 expression of Tregs was constrained, Dsg3-specific T cells did not disappear. Furthermore, Tregs obtained OX40L from dendritic cells in an OX40-dependent manner in vitro and then suppressed OX40L expression in dendritic cells and Birc5 expression in Dsg3-specific T cells in vivo. Lastly, CRISPR/Cas9-mediated knockout of OX40 signaling in Dsg3-specific T cells restored their disappearance in Treg-ablated recipients. Thus, Treg-mediated peripheral deletion of autoreactive T cells operates as an OX40-dependent regulatory mechanism to avoid undesired autoimmunity besides thymic tolerance.


Assuntos
Proteínas de Ligação a DNA/metabolismo , Desmogleína 3/metabolismo , Pênfigo/imunologia , Abatacepte/farmacologia , Transferência Adotiva , Animais , Técnicas de Cocultura , Proteínas de Ligação a DNA/genética , Desmogleína 3/genética , Antagonistas de Estrogênios/farmacologia , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Regulação da Expressão Gênica/imunologia , Inibidores de Checkpoint Imunológico/farmacologia , Masculino , Camundongos , Camundongos Knockout , Linfócitos T Reguladores , Tamoxifeno/farmacologia
8.
Microbiol Immunol ; 67(6): 293-302, 2023 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-37067224

RESUMO

Human herpesvirus 8 (HHV8; also known as Kaposi's sarcoma-associated herpesvirus [KSHV]) utilizes the viral E3 ubiquitin ligase family members K3 and K5 for immune evasion. Both K3 and K5 mediate the ubiquitination of host MHC class I (MHC-I) molecules, which play a key role in antigen presentation to cytotoxic T lymphocytes (CTLs). Because ubiquitinated MHC-I is immediately down-regulated from the cell surface, HHV8-infected cells can escape surveillance by CTLs. K3 and K5 have similar domain structures and topologies. They contain an N-terminal RINGv ubiquitin ligase domain, two transmembrane helices, and an intrinsically disordered cytoplasmic tail at the C-terminus. The cytoplasmic tail contains a membrane-proximal "conserved region" involved in ligase activity. On the other hand, the role of the membrane-distal region of the cytoplasmic tail, termed the "C-tail" in this study, remains unclear. Here, we demonstrate that the C-tail contributes to the protein expression of both K3 and K5. The C-tail-truncated K3 and K5 mutants were rapidly reduced in cells. The recombinant C-tail proteins bind to acidic lipids via a basic charge cluster located near the C-terminus of the C-tails. Similar to the C-tail-truncated mutants, the basic charge cluster-substituting mutants showed decreased protein expression of K3 and K5. These findings suggest that the basic charge cluster near the C-terminus of the cytoplasmic tail contributes to the molecular stability of K3 and K5.


Assuntos
Herpesvirus Humano 8 , Ubiquitina-Proteína Ligases , Humanos , Ubiquitina-Proteína Ligases/genética , Ubiquitina-Proteína Ligases/metabolismo , Herpesvirus Humano 8/genética , Herpesvirus Humano 8/metabolismo , Antígenos de Histocompatibilidade Classe I/metabolismo , Ubiquitina/metabolismo
9.
Immun Ageing ; 20(1): 26, 2023 Jun 12.
Artigo em Inglês | MEDLINE | ID: mdl-37308897

RESUMO

Various autoimmune responses increase with age, but the underlying mechanism is not clear. In this study, we used CD4+ T cells expressing a transgenic T cell receptor specific for desmoglein 3 (Dsg3), which is the target antigen of the autoimmune bullous disease pemphigus vulgaris, to examine how peripheral immunological tolerance against pathogenic autoreactive CD4+ T cells changes with age. Dsg3-specific T cells were deleted within 14 days after adoptive transfer into young mice (8 weeks old), while they escaped deletion when transferred into older mice over 42 weeks old. Dsg3-specific T cells produced higher levels of the proinflammatory cytokine IFN-γ in aged mice than in young mice. In addition, the expression levels of both OX40 and Birc5, which are important for cell survival in T cell clonal proliferation, were higher in aged than in young mice. The dysfunction in suppressing proinflammatory cytokine secretion and Birc5 upregulation in Dsg3-specific autoreactive T cells may reflect an aspect of the preliminary steps in autoimmune disease development in the aged population. Understanding this mechanism may lead to better risk evaluation of autoimmune disease development and to onset prevention.

10.
Int J Mol Sci ; 23(8)2022 Apr 18.
Artigo em Inglês | MEDLINE | ID: mdl-35457276

RESUMO

Niemann-Pick disease type C (NPC) is an autosomal recessive disease caused by a functional deficiency of cholesterol-transporting proteins in lysosomes, and exhibits various clinical symptoms. Since mitochondrial dysfunction in NPC has recently been reported, cholesterol catabolism to steroid hormones may consequently be impaired. In this study, we developed a comprehensive steroid hormone analysis method using liquid chromatography/tandem mass spectrometry (LC-MS/MS) and applied it to analyze changes in steroid hormone concentrations in NPC model cells. We investigated the analytical conditions for simultaneous LC-MS/MS analysis, which could be readily separated from each other and showed good reproducibility. The NPC phenotype was verified as an NPC model with mitochondrial abnormalities using filipin staining and organelle morphology observations. Steroid hormones in the cell suspension and cell culture medium were also analyzed. Steroid hormone analysis indicated that the levels of six steroid hormones were significantly decreased in the NPC model cell and culture medium compared to those in the wild-type cell and culture medium. These results indicate that some steroid hormones change during NPC pathophysiology and this change is accompanied by mitochondrial abnormalities.


Assuntos
Doença de Niemann-Pick Tipo C , Biomarcadores , Colesterol , Cromatografia Líquida/métodos , Hormônios , Humanos , Doença de Niemann-Pick Tipo C/metabolismo , Reprodutibilidade dos Testes , Esteroides , Espectrometria de Massas em Tandem/métodos
11.
Molecules ; 27(16)2022 Aug 18.
Artigo em Inglês | MEDLINE | ID: mdl-36014520

RESUMO

Despite the importance of the insight about the oxidation mechanisms (i.e., radical and singlet oxygen (1O2) oxidation) in extra virgin olive oil (EVOO), the elucidation has been difficult due to its various triacylglycerol molecular species and complex matrix. This study tried to evaluate the mechanisms responsible for EVOO oxidation in our daily use by quantitative determination of triacylglycerol hydroperoxide (TGOOH) isomers using LC-MS/MS. The standards of dioleoyl-(hydroperoxy octadecadienoyl)-triacylglycerol and dioleoyl-(hydroperoxy octadecamonoenoyl)-triacylglycerol, which are the predominant TGOOHs contained in EVOO, were prepared. Subsequently, fresh, thermal-, and photo-oxidized EVOO were analyzed. The obtained results mostly agreed with the previously reported characteristics of the radical and 1O2 oxidation of linoleic acid and oleic acid. This suggests that the methods described in this paper should be valuable in understanding how different factors that determine the quality of EVOO (e.g., olive species, cultivation area, cultivation timing, and extraction methods) contribute to its oxidative stability.


Assuntos
Peróxido de Hidrogênio , Espectrometria de Massas em Tandem , Cromatografia Líquida , Azeite de Oliva/análise , Triglicerídeos
12.
Allergol Int ; 71(1): 125-130, 2022 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-34393037

RESUMO

BACKGROUND: Natto (fermented soybeans)-induced hypersensitivity is characterized by delayed symptom onset that hampers diagnosis. We aimed to clarify the clinical utility of the basophil activation test (BAT) in the diagnosis of natto-induced hypersensitivity. METHODS: Five patients with a history of anaphylaxis and chronic urticaria suspected of natto-induced hypersensitivity and seven with chronic spontaneous urticaria clinically unrelated to natto were enrolled in the patient and control groups, respectively. The BAT was performed with two incubation times, 15 min and 1 h, in combination with various concentrations of natto-mucilage extract. RESULTS: In controls, CD203c levels in basophils remained low in the 15-min incubation but were significantly increased in the 1-h incubation. In the patient group, in the 15-min condition, basophil CD203c was significantly upregulated by natto mucilage but not by soybean vs controls (P = 0.001). Low concentrations of natto mucilage were sufficient to upregulate basophil CD203c in the anaphylaxis cases, but high concentrations were required to induce the same effect in the urticaria cases. Finally, the dose-dependent pattern of the BAT results differed significantly between the anaphylaxis and urticaria cases (P = 0.006). Thus, a strong background reaction was observed in the BAT with 1 h incubation; 15 min of incubation was sufficient to identify patients with natto-induced hypersensitivity and may distinguish the clinical phenotype of natto-induced hypersensitivity, i.e., anaphylaxis or urticaria. CONCLUSIONS: The BAT with a 15-min incubation period is useful in diagnosing natto-induced hypersensitivity.


Assuntos
Teste de Degranulação de Basófilos/métodos , Hipersensibilidade Alimentar/diagnóstico , Estudos de Casos e Controles , Feminino , Humanos , Masculino , Diester Fosfórico Hidrolases/sangue , Pirofosfatases/sangue , Alimentos de Soja/efeitos adversos , Urticária/complicações
13.
Am J Physiol Lung Cell Mol Physiol ; 321(5): L872-L884, 2021 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-34523355

RESUMO

The influenza virus infection poses a serious health threat worldwide. Myeloid cells play pivotal roles in regulating innate and adaptive immune defense. A disintegrin and metalloproteinase (ADAM) family of proteins contributes to various immune responses; however, the role of a disintegrin and metalloproteinase domain-containing protein 10 (ADAM10) in influenza virus infection remains largely unknown. Herein, we investigated its role, focusing on myeloid cells, during influenza virus infection in mice. ADAM10 gene (Adam10)flox/flox/Lyz2-Cre (Adam10ΔLyz2) and control Adam10flox/flox mice were intranasally infected with 200 plaque-forming units of influenza virus A/H1N1/PR8/34. Adam10ΔLyz2 mice exhibited a significantly higher mortality rate, stronger lung inflammation, and a higher virus titer in the lungs than control mice. Macrophages and inflammatory cytokines, such as TNF-α, IL-1ß, and CCL2, were increased in bronchoalveolar lavage fluid from Adam10ΔLyz2 mice following infection. CD11b+Ly6G-F4/80+ myeloid cells, which had an inflammatory monocyte/macrophage-like phenotype, were significantly increased in the lungs of Adam10ΔLyz2 mice. Adoptive transfer experiments suggested that these cells likely contributed to the poorer prognosis in Adam10ΔLyz2 mice. Seven days after infection, CD11b+Ly6G-F4/80+ lung cells exhibited significantly higher arginase-1 expression levels in Adam10ΔLyz2 mice than in control mice, whereas an arginase-1 inhibitor improved the prognosis of Adam10ΔLyz2 mice. Enhanced granulocyte-macrophage colony-stimulating factor (GM-CSF)/GM-CSF receptor signaling likely contributed to this process. Collectively, these results indicate that myeloid ADAM10 protects against influenza virus pneumonia and may be a promising therapeutic target.


Assuntos
Proteína ADAM10/metabolismo , Secretases da Proteína Precursora do Amiloide/metabolismo , Arginase/biossíntese , Vírus da Influenza A Subtipo H1N1/metabolismo , Macrófagos/imunologia , Proteínas de Membrana/metabolismo , Células Mieloides/imunologia , Infecções por Orthomyxoviridae/patologia , Proteína ADAM10/genética , Transferência Adotiva/métodos , Secretases da Proteína Precursora do Amiloide/genética , Animais , Arginase/antagonistas & inibidores , Líquido da Lavagem Broncoalveolar/química , Líquido da Lavagem Broncoalveolar/citologia , Citocinas/análise , Imunidade Inata/imunologia , Macrófagos/transplante , Proteínas de Membrana/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Células Mieloides/transplante , Infecções por Orthomyxoviridae/mortalidade , Infecções por Orthomyxoviridae/prevenção & controle , Prognóstico , Receptores de Fator Estimulador das Colônias de Granulócitos e Macrófagos/metabolismo
14.
Immunity ; 36(6): 1017-30, 2012 Jun 29.
Artigo em Inglês | MEDLINE | ID: mdl-22726954

RESUMO

Interleukin-27 (IL-27) is a key immunosuppressive cytokine that counters T helper 17 (Th17) cell-mediated pathology. To identify mechanisms by which IL-27 might exert its immunosuppressive effect, we analyzed genes in T cells rapidly induced by IL-27. We found that IL-27 priming of naive T cells upregulated expression of programmed death ligand 1 (PD-L1) in a signal transducer and activator of transcription 1 (STAT1)-dependent manner. When cocultured with naive CD4(+) T cells, IL-27-primed T cells inhibited the differentiation of Th17 cells in trans through a PD-1-PD-L1 interaction. In vivo, coadministration of naive TCR transgenic T cells (2D2 T cells) with IL-27-primed T cells expressing PD-L1 inhibited the development of Th17 cells and protected from severe autoimmune encephalomyelitis. Thus, these data identify a suppressive activity of IL-27, by which CD4(+) T cells can restrict differentiation of Th17 cells in trans.


Assuntos
Antígeno B7-H1/fisiologia , Interleucina-17/biossíntese , Interleucinas/farmacologia , Células Th17/efeitos dos fármacos , Animais , Antígeno B7-H1/biossíntese , Antígeno B7-H1/deficiência , Antígeno B7-H1/genética , Efeito Espectador , Linfócitos T CD4-Positivos/imunologia , Diferenciação Celular , Encefalomielite Autoimune Experimental/etiologia , Encefalomielite Autoimune Experimental/imunologia , Encefalomielite Autoimune Experimental/patologia , Encefalomielite Autoimune Experimental/prevenção & controle , Fatores de Transcrição Forkhead/deficiência , Regulação da Expressão Gênica/imunologia , Interferon gama/biossíntese , Interferon gama/genética , Interleucina-17/genética , Interleucina-17/fisiologia , Interleucina-1beta/farmacologia , Interleucina-23/farmacologia , Interleucina-6/farmacologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Antígenos de Histocompatibilidade Menor , Proteínas da Mielina/imunologia , Proteínas da Mielina/toxicidade , Glicoproteína Mielina-Oligodendrócito , Receptores de Citocinas/deficiência , Subpopulações de Linfócitos T/citologia , Subpopulações de Linfócitos T/imunologia , Células Th17/citologia , Células Th17/metabolismo , Células Th17/transplante , Fator de Crescimento Transformador beta/farmacologia
15.
J Allergy Clin Immunol ; 146(5): 1070-1079.e8, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32311391

RESUMO

BACKGROUND: Pemphigus vulgaris (PV) is an autoimmune bullous disease mediated by autoantibodies against desmoglein 3 (DSG3). Inducible costimulator (ICOS) is a costimulatory receptor expressed on T cells and influences the activity of T follicular helper (TFH) cells in various autoimmune diseases, but the roles of ICOS and TFH cells in PV remain unclear. OBJECTIVE: We examined the immunological characteristics, antigen specificity, and pathogenicity of CD4+ T-cell subpopulations, as well as the therapeutic effect of anti-ICOS blocking antibodies in PV. METHODS: A mouse model of PV was established by adoptive transfer of immune cells from the skin-draining lymph nodes or spleens of DSG3-expressing skin-grafted Dsg3-/- mice into Rag1-/- mice. The TFH cells and CD4+ T cells in PBMCs from PV patients were examined by flow cytometry. RESULTS: Among CD4+ T cells from the mouse model, ICOS-positive TFH cells were associated with B-cell differentiation and were required for disease induction. Using an MHC class II tetramer, DSG3-specific ICOS+ TFH cells were found to be associated with anti-DSG3 antibody production and expanded in the absence of B cells. In human PV, the frequency of ICOS+CXCR5+PD-1+ memory CD4+ T cells correlated with the autoantibody level. Treatment with anti-ICOS blocking antibodies targeting ICOS+ TFH cells decreased the anti-DSG3 antibody level and delayed disease progression in vivo. CONCLUSIONS: Mouse Dsg3-specific ICOS+ TFH cells and human ICOS+CXCR5+PD-1+ TH cells are associated with the anti-DSG3 antibody response in PV. ICOS expressed on CXCR5+PD-1+ TH cells may be a therapeutic target for PV.


Assuntos
Anti-Inflamatórios/uso terapêutico , Anticorpos Bloqueadores/uso terapêutico , Desmogleína 3/metabolismo , Centro Germinativo/imunologia , Proteína Coestimuladora de Linfócitos T Induzíveis/metabolismo , Pênfigo/terapia , Células Th1/metabolismo , Animais , Autoanticorpos/metabolismo , Desmogleína 3/genética , Modelos Animais de Doenças , Progressão da Doença , Citometria de Fluxo , Humanos , Memória Imunológica , Proteína Coestimuladora de Linfócitos T Induzíveis/imunologia , Camundongos , Camundongos Knockout , Pênfigo/imunologia , Receptor de Morte Celular Programada 1/metabolismo , Receptores CXCR5/metabolismo , Células Th1/imunologia
16.
Allergol Int ; 70(3): 335-342, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-33618992

RESUMO

BACKGROUND: Evidence for the risk and incidence of anticonvulsant-induced Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) in Japan is scarce. METHODS: We conducted a matched case-control study using a large-scale Japanese claims database. SJS/TEN cases were identified using a claims-based algorithm developed in a previous study (sensitivity 76.9%, specificity 99.0%). Conditional logistic regression with Firth's bias correction to address an issue of rare events was used to estimate odds ratios (ORs) for SJS/TEN for each anticonvulsant use (90 days before the index date) versus non-use. 90-day cumulative incidence of SJS/TEN per 100,000 new users was calculated for 33 anticonvulsants. Causality between anticonvulsant use and SJS/TEN in each exposed case was assessed using the algorithm of drug causality for epidermal necrolysis (ALDEN) score. RESULTS: From 5,114,492 subjects, we selected 71 SJS/TEN cases and 284 controls. We observed significantly increased ORs for SJS/TEN among new users of carbamazepine (OR 68.00) and lamotrigine (OR 36.00) with ALDEN scores of "probable" or higher. Cumulative incidence of SJS/TEN was 93.83 for carbamazepine and 84.33 for lamotrigine. One case newly exposed to phenytoin which developed SJS/TEN was rated "unlikely" in ALDEN causality, resulting in cumulative incidence of 66.27. Cumulative incidence of SJS/TEN was 25.23 for levetiracetam, 7.52 for clonazepam, and 1.23 for diazepam, but their ALDEN scores were "very unlikely". CONCLUSIONS: This study is the first to document the differential risk of SJS/TEN for anticonvulsants in a real-world setting in Japan. Exposure to carbamazepine and lamotrigine was associated with an increased risk of SJS/TEN.


Assuntos
Anticonvulsivantes/efeitos adversos , Carbamazepina/efeitos adversos , Lamotrigina/efeitos adversos , Síndrome de Stevens-Johnson/epidemiologia , Adulto , Estudos de Casos e Controles , Clonazepam/efeitos adversos , Estudos de Coortes , Diazepam/efeitos adversos , Feminino , Humanos , Incidência , Japão/epidemiologia , Levetiracetam/efeitos adversos , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Razão de Chances , Fenitoína/efeitos adversos , Fatores de Risco , Síndrome de Stevens-Johnson/etiologia
17.
Int Immunol ; 31(7): 431-437, 2019 07 13.
Artigo em Inglês | MEDLINE | ID: mdl-30887049

RESUMO

Autoimmune diseases are devastating conditions in which the immune system is directed against the host, leading to life-threatening destruction of organs. Although autoantigens are ill-defined in most autoimmune diseases, this is not the case in the skin. Autoimmune bullous diseases have been extensively studied with detailed characterization of autoantigens, the epitopes that are targeted, and the mechanisms of action that mediate autoimmune tissue destruction. Pemphigus is an autoimmune bullous disease caused by circulating IgG that targets two desmosomal proteins, desmoglein 1 and 3, which are crucial for cell-cell adhesion of keratinocytes. Binding of auto-antibodies to desmogleins impairs keratinocyte adhesion, leading to severe blistering disease. Mouse models that recapitulate the human disease have been instrumental in elucidating the detailed pathophysiology. Taking advantage of the fact that desmogleins are specifically targeted in pemphigus, studying humoral and cellular autoimmunity against these autoantigens provides us with an opportunity to understand not only the effector mechanisms of B and T cells in mediating pathology but also how autoreactive lymphocytes are regulated during development in the thymus and post-development in the periphery. This review introduces pemphigus and its subtypes as prototypic autoimmune diseases from which recent basic and translational developments should provide insight into how autoimmunity develops.


Assuntos
Autoimunidade/imunologia , Tolerância Imunológica/imunologia , Pênfigo/classificação , Pênfigo/imunologia , Animais , Humanos
18.
Immunity ; 35(6): 919-31, 2011 Dec 23.
Artigo em Inglês | MEDLINE | ID: mdl-22195747

RESUMO

Follicular helper T (Tfh) cells comprise an important subset of helper T cells; however, their relationship with other helper lineages is incompletely understood. Herein, we showed interleukin-12 acting via the transcription factor STAT4 induced both Il21 and Bcl6 genes, generating cells with features of both Tfh and Th1 cells. However, STAT4 also induced the transcription factor T-bet. With ChIP-seq, we defined the genome-wide targets of T-bet and found that it repressed Bcl6 and other markers of Tfh cells, thereby attenuating the nascent Tfh cell-like phenotype in the late phase of Th1 cell specification. Tfh-like cells were rapidly generated after Toxoplasma gondii infection in mice, but T-bet constrained Tfh cell expansion and consequent germinal center formation and antibody production. Our data argue that Tfh and Th1 cells share a transitional stage through the signal mediated by STAT4, which promotes both phenotypes. However, T-bet represses Tfh cell functionalities, promoting full Th1 cell differentiation.


Assuntos
Diferenciação Celular , Células Th1/citologia , Células Th1/imunologia , Animais , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/metabolismo , Linfócitos T CD4-Positivos/parasitologia , Proteínas de Ligação a DNA/genética , Regulação da Expressão Gênica/efeitos dos fármacos , Imunofenotipagem , Interferon gama/metabolismo , Interleucina-12/farmacologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Proteínas Proto-Oncogênicas c-bcl-6 , Fator de Transcrição STAT4/metabolismo , Proteínas com Domínio T/metabolismo , Linfócitos T Auxiliares-Indutores/citologia , Linfócitos T Auxiliares-Indutores/imunologia , Linfócitos T Auxiliares-Indutores/metabolismo , Células Th1/metabolismo , Toxoplasma
19.
Immunity ; 32(5): 605-15, 2010 May 28.
Artigo em Inglês | MEDLINE | ID: mdl-20493732

RESUMO

STAT3, an essential transcription factor with pleiotropic functions, plays critical roles in the pathogenesis of autoimmunity. Despite recent data linking STAT3 with inflammatory bowel disease, exactly how it contributes to chronic intestinal inflammation is not known. Using a T cell transfer model of colitis, we found that STAT3 expression in T cells was essential for the induction of both colitis and systemic inflammation. STAT3 was critical in modulating the balance of T helper 17 (Th17) and regulatory T (Treg) cells, as well as in promoting CD4(+) T cell proliferation. We used chromatin immunoprecipitation and massive parallel sequencing (ChIP-Seq) to define the genome-wide targets of STAT3 in CD4(+) T cells. We found that STAT3 bound to multiple genes involved in Th17 cell differentiation, cell activation, proliferation, and survival, regulating both expression and epigenetic modifications. Thus, STAT3 orchestrates multiple critical aspects of T cell function in inflammation and homeostasis.


Assuntos
Colite/imunologia , Colite/fisiopatologia , Homeostase/imunologia , Fator de Transcrição STAT3/imunologia , Linfócitos T/imunologia , Animais , Linfócitos T CD4-Positivos/imunologia , Diferenciação Celular , Proliferação de Células , Células Cultivadas , Modelos Animais de Doenças , Interleucina-17/imunologia , Subpopulações de Linfócitos/imunologia , Camundongos , Camundongos Knockout , Linfócitos T/citologia , Linfócitos T Reguladores/imunologia
20.
Immunity ; 32(6): 840-51, 2010 Jun 25.
Artigo em Inglês | MEDLINE | ID: mdl-20620946

RESUMO

Signal transducer and activator of transcription 4 (STAT4) and STAT6 are key factors in the specification of helper T cells; however, their direct roles in driving differentiation are not well understood. Using chromatin immunoprecipitation and massive parallel sequencing, we quantitated the full complement of STAT-bound genes, concurrently assessing global STAT-dependent epigenetic modifications and gene transcription by using cells from cognate STAT-deficient mice. STAT4 and STAT6 each bound over 4000 genes with distinct binding motifs. Both played critical roles in maintaining chromatin configuration and transcription of a core subset of genes through the combination of different epigenetic patterns. Globally, STAT4 had a more dominant role in promoting active epigenetic marks, whereas STAT6 had a more prominent role in antagonizing repressive marks. Clusters of genes negatively regulated by STATs were also identified, highlighting previously unappreciated repressive roles of STATs. Therefore, STAT4 and STAT6 play wide regulatory roles in T helper cell specification.


Assuntos
Diferenciação Celular/imunologia , Regulação da Expressão Gênica/imunologia , Fator de Transcrição STAT4/imunologia , Fator de Transcrição STAT6/imunologia , Linfócitos T Auxiliares-Indutores/citologia , Animais , Imunoprecipitação da Cromatina , Epigênese Genética , Expressão Gênica , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Análise de Sequência com Séries de Oligonucleotídeos , Fator de Transcrição STAT4/genética , Fator de Transcrição STAT6/genética , Linfócitos T Auxiliares-Indutores/imunologia , Linfócitos T Auxiliares-Indutores/metabolismo , Transcrição Gênica
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