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1.
Int J Mol Sci ; 24(2)2023 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-36674855

RESUMO

ANCA-associated vasculitis (AAV) is intricately linked with infections. Toll-like receptors (TLR) provide a potential link between infection and anti-myeloperoxidase (MPO) autoimmunity. TLR9 ligation has been shown to promote anti-MPO autoimmunity and glomerular vasculitis in murine MPO-AAV. This study investigates dendritic cell TLR9 ligation in murine experimental anti-MPO glomerulonephritis. We analyzed autoimmune responses to MPO following transfer of TLR9 stimulated, MPO pulsed dendritic cells and kidney injury following a sub-nephritogenic dose of sheep anti-mouse glomerular basement membrane globulin. TLR9 ligation enhanced dendritic cell activation upregulating CD40 and CD80 expression, promoting systemic anti-MPO autoimmunity and T cell recall responses and exacerbating kidney injury. CD40 upregulation by TLR9 was critical for the induction of nephritogenic autoimmunity. The presence of DEC205, which transports the TLR9 ligand to TLR9 located in the endosome, also promoted kidney injury. This confirms TLR9 mediated dendritic cell activation as a mechanism of anti-MPO autoimmunity in AAV and further defines the link between infection and the generation of MPO specific autoimmune inflammation.


Assuntos
Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos , Glomerulonefrite , Receptor Toll-Like 9 , Animais , Camundongos , Autoimunidade , Células Dendríticas , Glomerulonefrite/metabolismo , Peroxidase/metabolismo , Ovinos , Receptor Toll-Like 9/metabolismo
2.
Clín. investig. ginecol. obstet. (Ed. impr.) ; 50(1): 100798-100798, Ene-Mar. 2023. ilus
Artigo em Inglês | IBECS | ID: ibc-214988

RESUMO

Introducción: El herpes gestationis (HG) es una de las principales dermatosis del embarazo que debe ser reconocida y tratada oportunamente ya que se relaciona con un empeoramiento del pronóstico fetal. Aunque se ha investigado la afectación cutánea, hay escasez de estudios morfológicos y funcionales de la placenta en esta patología. Principales síntomas o hallazgos clínicos: Erupción vesicular eritematosa a las 32+1 semanas de gestación. Diagnósticos principales: HG. Intervenciones terapéuticas y resultados: Inmunogammaglobulina en casos graves refractarios a los corticoides por vía oral con desaparición completa de las lesiones. Conclusión: Hasta donde sabemos, este es el primer caso que reporta un análisis detallado de los depósitos de IgG y C3 en la membrana basal de las vellosidades de la placenta mediante un estudio de inmunofluorescencia. Estos hallazgos podrían relacionarse con el ligero mal funcionamiento de la placenta que puede explicar los efectos neonatales adversos.(AU)


Introduction: Pemphigoid gestationis (PG) is one of the main dermatoses of pregnancy that must be recognized and treated promptly, since it is related to worsening of foetal prognosis. Although skin involvement has been investigated, there is a lack of morphological and functional studies of the placenta in this pathology. Main symptoms and/or clinical findings: Erythematous vesicular rash at 32+1 weeks of gestation. Main diagnoses: PG. Therapeutic interventions and results: Immunogammaglobulin in severe cases refractory to oral corticosteroids with complete disappearance of the lesions. Conclusion: To our knowledge, this is the first case to report a detailed analysis of IgG and C3 deposits in the basement membrane of the placental villi by means of an immunofluorescence study. These findings could be related to a slight malfunction of the placenta that may explain the adverse neonatal effects.(AU)


Assuntos
Humanos , Feminino , Gravidez , Imunofluorescência , Placenta , Penfigoide Gestacional , Autoimunidade , Corticosteroides , Ginecologia , Obstetrícia
5.
Signal Transduct Target Ther ; 8(1): 28, 2023 Jan 23.
Artigo em Inglês | MEDLINE | ID: mdl-36690610

RESUMO

Interleukin-2 (IL-2) is a pleiotropic cytokine that orchestrates bidirectional immune responses via regulatory T cells (Tregs) and effector cells, leading to paradoxical consequences. Here, we report a strategy that exploited genetic code expansion-guided incorporation of the latent bioreactive artificial amino acid fluorosulfate-L-tyrosine (FSY) into IL-2 for proximity-enabled covalent binding to IL-2Rα to selectively promote Treg activation. We found that FSY-bearing IL-2 variants, such as L72-FSY, covalently bound to IL-2Rα via sulfur-fluoride exchange when in proximity, resulting in persistent recycling of IL-2 and selectively promoting the expansion of Tregs but not effector cells. Further assessment of L72-FSY-expanded Tregs demonstrated that L72-FSY maintained Tregs in a central memory phenotype without driving terminal differentiation, as demonstrated by simultaneously attenuated expression of lymphocyte activation gene-3 (LAG-3) and enhanced expression of programmed cell death protein-1 (PD-1). Subcutaneous administration of L72-FSY in murine models of pristane-induced lupus and graft-versus-host disease (GvHD) resulted in enhanced and sustained therapeutic efficacy compared with wild-type IL-2 treatment. The efficacy of L72-FSY was further improved by N-terminal PEGylation, which increased its circulatory retention for preferential and sustained effects. This proximity-enabled covalent binding strategy may accelerate the development of pleiotropic cytokines as a new class of immunomodulatory therapies.


Assuntos
Interleucina-2 , Linfócitos T Reguladores , Camundongos , Animais , Subunidade alfa de Receptor de Interleucina-2 , Autoimunidade
6.
Artigo em Inglês | MEDLINE | ID: mdl-36657993

RESUMO

BACKGROUND AND OBJECTIVES: Anti-CD20 monoclonal antibody (mAb) B-cell depletion is a remarkably successful multiple sclerosis (MS) treatment. Chimeric antigen receptor (CAR)-T cells, which target antigens in a non-major histocompatibility complex (MHC)-restricted manner, can penetrate tissues more thoroughly than mAbs. However, a previous study indicated that anti-CD19 CAR-T cells can paradoxically exacerbate experimental autoimmune encephalomyelitis (EAE) disease. We tested anti-CD19 CAR-T cells in a B-cell-dependent EAE model that is responsive to anti-CD20 B-cell depletion similar to the clinical benefit of anti-CD20 mAb treatment in MS. METHODS: Anti-CD19 CAR-T cells or control cells that overexpressed green fluorescent protein were transferred into C57BL/6 mice pretreated with cyclophosphamide (Cy). Mice were immunized with recombinant human (rh) myelin oligodendrocyte protein (MOG), which causes EAE in a B-cell-dependent manner. Mice were evaluated for B-cell depletion, clinical and histologic signs of EAE, and immune modulation. RESULTS: Clinical scores and lymphocyte infiltration were reduced in mice treated with either anti-CD19 CAR-T cells with Cy or control cells with Cy, but not with Cy alone. B-cell depletion was observed in peripheral lymphoid tissue and in the CNS of mice treated with anti-CD19 CAR-T cells with Cy pretreatment. Th1 or Th17 populations did not differ in anti-CD19 CAR-T cell, control cell-treated animals, or Cy alone. DISCUSSION: In contrast to previous data showing that anti-CD19 CAR-T cell treatment exacerbated EAE, we observed that anti-CD19 CAR-T cells ameliorated EAE. In addition, anti-CD19 CAR-T cells thoroughly depleted B cells in peripheral tissues and in the CNS. However, the clinical benefit occurred independently of antigen specificity or B-cell depletion.


Assuntos
Encefalomielite Autoimune Experimental , Imunoterapia Adotiva , Animais , Humanos , Camundongos , Anticorpos Monoclonais , Antígenos CD19 , Autoimunidade , Sistema Nervoso Central , Encefalomielite Autoimune Experimental/tratamento farmacológico , Camundongos Endogâmicos C57BL , Esclerose Múltipla/tratamento farmacológico , Glicoproteína Mielina-Oligodendrócito , Linfócitos T , Linfócitos B
7.
Cells ; 12(2)2023 Jan 14.
Artigo em Inglês | MEDLINE | ID: mdl-36672249

RESUMO

Antigen presentation by major histocompatibility complex class II (MHC-II) molecules is crucial for eliciting an efficient immune response by CD4+ T cells and maintaining self-antigen tolerance. Some MHC-II alleles are known to be positively or negatively associated with the risk of the development of different autoimmune diseases (ADs), including those characterized by the emergence of autoreactive T cells. Apparently, the MHC-II presentation of self-antigens contributes to the autoimmune T cell response, initiated through a breakdown of central tolerance to self-antigens in the thymus. The appearance of autoreactive T cell might be the result of (i) the unusual interaction between T cell receptors (TCRs) and self-antigens presented on MHC-II; (ii) the posttranslational modifications (PTMs) of self-antigens; (iii) direct loading of the self-antigen to classical MHC-II without additional nonclassical MHC assistance; (iv) the proinflammatory environment effect on MHC-II expression and antigen presentation; and (v) molecular mimicry between foreign and self-antigens. The peculiarities of the processes involved in the MHC-II-mediated presentation may have crucial importance in the elucidation of the mechanisms of triggering and developing ADs as well as for clarification on the protective effect of MHC-II alleles that are negatively associated with ADs.


Assuntos
Doenças Autoimunes , Autoimunidade , Humanos , Linfócitos T CD4-Positivos , Antígenos de Histocompatibilidade Classe II/metabolismo , Apresentação de Antígeno , Autoantígenos/metabolismo
8.
Int J Mol Sci ; 24(2)2023 Jan 12.
Artigo em Inglês | MEDLINE | ID: mdl-36675037

RESUMO

Regulatory T cells (Tregs) play an important role in maintaining immune tolerance and homeostasis by modulating how the immune system is activated. Several studies have documented the critical role of Tregs in suppressing the functions of effector T cells and antigen-presenting cells. Under certain conditions, Tregs can lose their suppressive capability, leading to a compromised immune system. For example, mutations in the Treg transcription factor, Forkhead box P3 (FOXP3), can drive the development of autoimmune diseases in multiple organs within the body. Furthermore, mutations leading to a reduction in the numbers of Tregs or a change in their function facilitate autoimmunity, whereas an overabundance can inhibit anti-tumor and anti-pathogen immunity. This review discusses the characteristics of Tregs and their mechanism of action in select autoimmune skin diseases, transplantation, and skin cancer. We also examine the potential of Tregs-based cellular therapies in autoimmunity.


Assuntos
Doenças Autoimunes , Dermatopatias , Neoplasias Cutâneas , Humanos , Linfócitos T Reguladores , Doenças Autoimunes/etiologia , Doenças Autoimunes/terapia , Autoimunidade , Neoplasias Cutâneas/etiologia , Neoplasias Cutâneas/terapia , Dermatopatias/etiologia , Dermatopatias/terapia , Fatores de Transcrição Forkhead
9.
J Immunol ; 210(2): 126-133, 2023 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-36596219

RESUMO

DNA topoisomerases (TOPs) are complex enzymatic machines with extraordinary capacity to maintain DNA topology during torsion-intensive steps of replication and transcription. Recently, TOPs have gained significant attention for their tissue-specific function, and the vital role of TOPs in immune homeostasis and dysfunction is beginning to emerge. TOPs have been implicated in various immunological disorders such as autoimmunity, B cell immunodeficiencies, and sepsis, underscoring their importance in immune regulation. However, much remains unknown about immunological underpinnings of TOPs, and a deeper understanding of the role of TOPs in the immune system will be critical for yielding significant insights into the etiology of immunological disorders. In this review, we first discuss the recent literature highlighting the contribution of TOPs in the development of immune cells, and we further provide an overview of their importance in immune cell responses.


Assuntos
DNA , Síndromes de Imunodeficiência , Humanos , Autoimunidade
10.
Cell Res ; 33(2): 97-115, 2023 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-36599968

RESUMO

Autoimmunity and autoinflammation arise from aberrant immunological and inflammatory responses toward self-components, contributing to various autoimmune diseases and autoinflammatory diseases. RNA-binding proteins (RBPs) are essential for immune cell development and function, mainly via exerting post-transcriptional regulation of RNA metabolism and function. Functional dysregulation of RBPs and abnormities in RNA metabolism are closely associated with multiple autoimmune or autoinflammatory disorders. Distinct RBPs play critical roles in aberrant autoreactive inflammatory responses via orchestrating a complex regulatory network consisting of DNAs, RNAs and proteins within immune cells. In-depth characterizations of RBP-RNA interactomes during autoimmunity and autoinflammation will lead to a better understanding of autoimmune pathogenesis and facilitate the development of effective therapeutic strategies. In this review, we summarize and discuss the functions of RBP-RNA interactions in controlling aberrant autoimmune inflammation and their potential as biomarkers and therapeutic targets.


Assuntos
Doenças Autoimunes , Autoimunidade , Humanos , RNA , Regulação da Expressão Gênica , Inflamação
11.
J Exp Med ; 220(2)2023 Feb 06.
Artigo em Inglês | MEDLINE | ID: mdl-36520516

RESUMO

In this issue of JEM, Tanaka et al. (2022. J. Exp. Med.https://doi.org/10.1084/jem.20220386) advance our understanding of how genetic mutants that decrease T cell recognition of antigen, a critical event for immune activation to invading microbes and virus, paradoxically results in autoimmunity.


Assuntos
Autoimunidade , Linfócitos T , Transdução de Sinais
12.
Brief Bioinform ; 24(1)2023 Jan 19.
Artigo em Inglês | MEDLINE | ID: mdl-36513375

RESUMO

Type 1 diabetes (T1D) outcome prediction plays a vital role in identifying novel risk factors, ensuring early patient care and designing cohort studies. TEDDY is a longitudinal cohort study that collects a vast amount of multi-omics and clinical data from its participants to explore the progression and markers of T1D. However, missing data in the omics profiles make the outcome prediction a difficult task. TEDDY collected time series gene expression for less than 6% of enrolled participants. Additionally, for the participants whose gene expressions are collected, 79% time steps are missing. This study introduces an advanced bioinformatics framework for gene expression imputation and islet autoimmunity (IA) prediction. The imputation model generates synthetic data for participants with partially or entirely missing gene expression. The prediction model integrates the synthetic gene expression with other risk factors to achieve better predictive performance. Comprehensive experiments on TEDDY datasets show that: (1) Our pipeline can effectively integrate synthetic gene expression with family history, HLA genotype and SNPs to better predict IA status at 2 years (sensitivity 0.622, AUC 0.715) compared with the individual datasets and state-of-the-art results in the literature (AUC 0.682). (2) The synthetic gene expression contains predictive signals as strong as the true gene expression, reducing reliance on expensive and long-term longitudinal data collection. (3) Time series gene expression is crucial to the proposed improvement and shows significantly better predictive ability than cross-sectional gene expression. (4) Our pipeline is robust to limited data availability. Availability: Code is available at https://github.com/compbiolabucf/TEDDY.


Assuntos
Diabetes Mellitus Tipo 1 , Ilhotas Pancreáticas , Humanos , Diabetes Mellitus Tipo 1/genética , Autoimunidade/genética , Estudos Longitudinais , Fatores de Tempo , Estudos Transversais , Predisposição Genética para Doença , Expressão Gênica
13.
J Therm Biol ; 111: 103425, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36585089

RESUMO

BACKGROUND: Autoimmune disorders encompass a diverse subset of diseases whose common symptoms include, among others, fever. Fever of unknown origins, once an infectious or tumor agent have been ruled out as possible causes, may originate with an autoimmune disease. OBJECTIVE: To determine the role of febrile temperatures on the stability of antigens pertinent to autoimmunity, and on the immune complexes they form with commercial therapeutic monoclonal antibodies. METHODS: Using molecular dynamics simulations, the binding between four antigens belonging to a set of autoimmune diseases and their individual monoclonal antibodies was investigated under different febrile temperatures. RESULTS: It was determined that at febrile temperatures, monoclonal antibodies used in the therapy of autoimmune diseases bind with higher binding free energy to pertinent antigens, once the autoimmune condition has been established and treatment is warranted. CONCLUSION: Performing molecular dynamics simulations at fever temperatures may be important for delineating the role antibodies may play in other diseases, including in cancers and infections.


Assuntos
Complexo Antígeno-Anticorpo , Doenças Autoimunes , Humanos , Temperatura , Autoimunidade , Antígenos , Febre , Anticorpos Monoclonais
16.
J Dermatol ; 50(2): 112-123, 2023 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-36539957

RESUMO

Pemphigus is a life-threatening autoimmune bullous disease mediated by anti-desmoglein IgG autoantibodies. Pemphigus is mainly classified into three subtypes: pemphigus vulgaris, pemphigus foliaceus, and paraneoplastic pemphigus. The pathogenicity of autoantibodies has been extensively studied. Anti-human CD20 antibody therapy targeting B cells emerged as a more effective treatment option compared to conventional therapy for patients with an intractable disease. On the other hand, autoreactive T cells are considered to be involved in the pathogenesis based on the test results of human leukocyte antigen association, autoreactive T cell detection, and cytokine profile analysis. Research on the role of T cells in pemphigus has continued to progress, including that on T follicular helper cells, which initiate molecular mechanisms involved in antibody production in B cells. Autoreactive T cell research in mice has highlighted the crucial roles of cellular autoimmunity and improved the understanding of its pathogenesis, especially in paraneoplastic pemphigus. The mouse research has helped elucidate novel regulatory mechanisms of autoreactive T cells, such as thymic tolerance to desmoglein 3 and the essential roles of regulatory T cells, Langerhans cells, and other molecules in peripheral tissues. This review focuses on the immunological aspects of autoreactive T cells in pemphigus by providing detailed information on various related topics.


Assuntos
Pênfigo , Humanos , Camundongos , Animais , Pênfigo/patologia , Autoantígenos , Autoimunidade , Desmogleína 3 , Autoanticorpos , Desmogleína 1
17.
Biomed Pharmacother ; 158: 114180, 2023 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-36586241

RESUMO

Gastric cancer (GC) remains one of the most common malignancies worldwide. Despite immune-checkpoint inhibitors (ICIs) has revolutionized cancer treatment and obtained durable clinical responses, only a fraction of GC patients benefit from it. As an important component of T cells, regulatory T cells (Tregs) play a vital role in the pathogenesis of GC, keep a core balance between immune suppression and autoimmunity, and function as predictive biomarkers for prognosis of GC patients. In this review, we discuss the role of Tregs in the pathogenesis of GC, and targeting Tregs via influencing their transcription factor, migration, co-stimulatory receptors, immune checkpoints, and cytokines. We also focus on the currently important findings of Tregs metabolism including amino acid, fatty acid, and lactic acid metabolism of GC. The emerging role of microbiome and clinical combined therapy in modulating Tregs in GC treatment is also summarized. Meanwhile, this review recapitulates a novel regulator, magnesium, is involved in mediating Tregs in GC. These research advances on Treg-related strategies provide new insights and challenges for GC progression, treatment, and prognosis. And we hope our review can stimulate further discovery and implication of mediators and pathways targeting Tregs.


Assuntos
Neoplasias Gástricas , Linfócitos T Reguladores , Humanos , Neoplasias Gástricas/tratamento farmacológico , Imunoterapia , Terapia de Imunossupressão , Autoimunidade
18.
Front Immunol ; 13: 1004644, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36466846

RESUMO

The modulation of inflammatory (auto)immune reactions by nutrients and gut bacterial metabolites is of great interest for potential preventive and therapeutic strategies. B cell-derived plasma cells are major players in inflammatory (auto)immune responses and can exhibit pro- or anti-inflammatory effects through (auto)antibody-dependent and -independent functions. Emerging evidence indicates a key role of nutrients and microbial metabolites in regulating the differentiation of plasma cells as well as their differentiation to pro- or anti-inflammatory phenotypes. These effects might be mediated indirectly by influencing other immune cells or directly through B cell-intrinsic mechanisms. Here, we provide an overview of nutrients and metabolites that influence B cell-intrinsic signaling pathways regulating B cell activation, plasma cell differentiation, and effector functions. Furthermore, we outline important inflammatory plasma cell phenotypes whose differentiation could be targeted by nutrients and microbial metabolites. Finally, we discuss possible implications for inflammatory (auto)immune conditions.


Assuntos
Autoimunidade , Plasmócitos , Diferenciação Celular , Linfócitos B , Nutrientes
20.
Front Immunol ; 13: 1055466, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36466912

RESUMO

Regulatory T cells (Tregs) are critical for tolerance in humans. The exact mechanisms by which the loss of peripheral tolerance leads to the development of autoimmunity and the specific role Tregs play in allograft tolerance are not fully understood; however, this population of T cells presents a unique opportunity in the development of targeted therapeutics. In this review, we discuss the potential roles of Foxp3+ Tregs in the development of tolerance in transplantation and autoimmunity, and the available data regarding their use as a treatment modality.


Assuntos
Autoimunidade , Transplante de Órgãos , Humanos , Linfócitos T Reguladores , Tolerância Imunológica , Transplante de Órgãos/efeitos adversos , Tolerância a Medicamentos , Fatores de Transcrição , Fatores de Transcrição Forkhead
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