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1.
Med Clin North Am ; 105(2): 263-272, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33589101

RESUMO

Although statins are generally safe and well tolerated, some patients experience muscle complaints that can be attributed to their use. Those with muscle discomfort but no demonstrable muscle weakness or creatine kinase (CK) elevations may have statin-associated muscle symptoms. Individuals with elevated CK levels, with or without muscle discomfort or weakness, may have statin-associated myotoxicity. Rare patients have statin-associated autoimmune myopathy, a disease characterized by proximal muscle weakness, elevated CK levels, and autoantibodies recognizing hydroxy-methyl-glutaryl coenzyme A reductase. In this review, the author provides the clinician with a practical approach to diagnosing and managing patients with each of these statin side effects.


Assuntos
Inibidores de Hidroximetilglutaril-CoA Redutases , Hiperlipidemias/tratamento farmacológico , Miotoxicidade , Autoimunidade/efeitos dos fármacos , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/efeitos adversos , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Hiperlipidemias/sangue , Lipoproteínas LDL/análise , Miotoxicidade/etiologia , Miotoxicidade/imunologia , Miotoxicidade/fisiopatologia , Miotoxicidade/terapia
2.
Nat Commun ; 12(1): 76, 2021 01 04.
Artigo em Inglês | MEDLINE | ID: mdl-33397953

RESUMO

Full development of IL-17 producing CD4+ T helper cells (TH17 cells) requires the transcriptional activity of both orphan nuclear receptors RORα and RORγt. However, RORα is considered functionally redundant to RORγt; therefore, the function and therapeutic value of RORα in TH17 cells is unclear. Here, using mouse models of autoimmune and chronic inflammation, we show that expression of RORα is required for TH17 cell pathogenicity. T-cell-specific deletion of RORα reduces the development of experimental autoimmune encephalomyelitis (EAE) and colitis. Reduced inflammation is associated with decreased TH17 cell development, lower expression of tissue-homing chemokine receptors and integrins, and increased frequencies of Foxp3+ T regulatory cells. Importantly, inhibition of RORα with a selective small molecule antagonist mostly phenocopies our genetic data, showing potent suppression of the in vivo development of both chronic/progressive and relapsing/remitting EAE, but with no effect on overall thymic cellularity. Furthermore, use of the RORα antagonist effectively inhibits human TH17 cell differentiation and memory cytokine secretion. Together, these data suggest that RORα functions independent of RORγt in programming TH17 pathogenicity and identifies RORα as a safer and more selective therapeutic target for the treatment of TH17-mediated autoimmunity.


Assuntos
Inflamação/imunologia , Membro 1 do Grupo F da Subfamília 1 de Receptores Nucleares/antagonistas & inibidores , Células Th17/imunologia , Animais , Autoimunidade/efeitos dos fármacos , Peso Corporal/efeitos dos fármacos , Doença Crônica , Colo/patologia , Modelos Animais de Doenças , Encefalomielite Autoimune Experimental , Células HEK293 , Humanos , Inflamação/genética , Camundongos Endogâmicos C57BL , Membro 1 do Grupo F da Subfamília 1 de Receptores Nucleares/genética , Tamanho do Órgão/efeitos dos fármacos , Índice de Gravidade de Doença , Bibliotecas de Moléculas Pequenas/química , Bibliotecas de Moléculas Pequenas/farmacologia , Sulfonamidas/química , Sulfonamidas/farmacologia , Tiofenos/química , Tiofenos/farmacologia
3.
Phytomedicine ; 80: 153381, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33086170

RESUMO

BACKGROUND: Hyperactivation of B cells by activators has been demonstrated to play a central role in the pathogenesis of Sjögren's syndrome (SS). In this study, we found that artesunate (ART) can attenuate BAFF-induced B cell hyperactivation and SS-like symptoms in NOD/Ltj mice. PURPOSE: To determine the efficacy of ART in attenuating SS-like symptoms in vivo and explore the underlying mechanism in vitro. STUDY DESIGN: ART was intragastrically injected into SS-like NOD/Ltj mice. The cytokine hsBAFF was used to activate Raji and Daudi B cells to mimic B cell hyperactivation in vitro. METHODS: The efficacy of ART in inhibiting SS progression was studied in NOD/Ltj mice. Salivary flow rate, the number of lymphocytic infiltration foci, the level of autoantibodies and the extent of B cell infiltration were measured in the indicated groups. CCK-8 assays, flow cytometry-based EdU staining and Annexin V/PI staining were also used to detect the effect of ART on the survival and proliferation mechanism in BAFF-induced Raji and Daudi cells. Further studies determined that TRAF6 degradation is a potential mechanism by which ART determines B cell fate. RESULTS: Treatment with ART inhibited lymphocytic foci formation, B cell infiltration and autoantibody secretion in SS-like NOD/Ltj mice. In vitro assay results indicated that ART effectively inhibited BAFF-induced viability, survival and proliferation of neoplastic B cells. Mechanistically, ART targeted BAFF-activated NFκB by regulating the proteasome-mediated degradation of TRAF6 in Raji and Daudi cells. CONCLUSION: ART ameliorated murine SS-like symptoms and regulated TRAF6-NFκB signaling, thus determining survival and proliferation of B cells.


Assuntos
Artesunato/farmacologia , Fator Ativador de Células B/farmacologia , Linfócitos B/efeitos dos fármacos , Fatores Imunológicos/farmacologia , Síndrome de Sjogren/imunologia , Animais , Autoanticorpos/metabolismo , Autoimunidade/efeitos dos fármacos , Fator Ativador de Células B/metabolismo , Linfócitos B/imunologia , Linfócitos B/metabolismo , Linfócitos B/patologia , Linhagem Celular Tumoral , Modelos Animais de Doenças , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Linfócitos/efeitos dos fármacos , Camundongos Endogâmicos ICR , Camundongos Endogâmicos NOD , NF-kappa B/metabolismo , Glândulas Salivares/efeitos dos fármacos , Glândulas Salivares/metabolismo , Transdução de Sinais/efeitos dos fármacos , Síndrome de Sjogren/tratamento farmacológico , Síndrome de Sjogren/patologia
4.
Biomed Pharmacother ; 134: 111157, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33370631

RESUMO

Autoimmune diseases (AUDs) are a multifactorial disease, among which rheumatoid arthritis, systemic lupus erythematosus and multiple sclerosis are more prevalent. Several anti-inflammatory, biologics, and AUD-modifying drugs are found effective against them, but their repeated use are associated with various adverse effects. In this review article, we have focused on the regulation of inflammatory molecules, molecular signaling pathways, immune cells, and epigenetics by natural product thymoquinone on AUDs. Studies indicate that thymoquinone can regulate inflammatory molecules including interferons, interleukins, tumor necrosis factor-α (TNF-α), oxidative stress, regulatory T cells, and various signaling pathways such as nuclear factor kappa beta (NF-κß), janus kinase/signal transduction and activator of transcription (JAK-STAT), mitogen-activated protein kinase (MAPK) at the molecular level and epigenetic alteration. As these molecules and signaling pathways with defective immune function play an important role in AUD development, controlling these molecules and deregulated molecular mechanism is a significant feature of AUD therapeutics. Interestingly thymoquinone is reported to possess all these potential. This article reviewed the deregulated mechanism of AUDs, and the action of thymoquinone on inflammatory molecules, immune cells, signaling pathways, and epigenetic machinery. Thymoquinone can be regarded as a potential drug candidate for AUD treatment.


Assuntos
Anti-Inflamatórios/uso terapêutico , Doenças Autoimunes/tratamento farmacológico , Autoimunidade/efeitos dos fármacos , Benzoquinonas/uso terapêutico , Sistema Imunitário/efeitos dos fármacos , Fatores Imunológicos/uso terapêutico , Animais , Anti-Inflamatórios/efeitos adversos , Doenças Autoimunes/imunologia , Doenças Autoimunes/metabolismo , Doenças Autoimunes/fisiopatologia , Benzoquinonas/efeitos adversos , Epigênese Genética/efeitos dos fármacos , Humanos , Sistema Imunitário/imunologia , Sistema Imunitário/metabolismo , Sistema Imunitário/fisiopatologia , Fatores Imunológicos/efeitos adversos , Mediadores da Inflamação/metabolismo , Transdução de Sinais
5.
Nature ; 582(7810): 89-94, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32483373

RESUMO

A hexanucleotide-repeat expansion in C9ORF72 is the most common genetic variant that contributes to amyotrophic lateral sclerosis and frontotemporal dementia1,2. The C9ORF72 mutation acts through gain- and loss-of-function mechanisms to induce pathways that are implicated in neural degeneration3-9. The expansion is transcribed into a long repetitive RNA, which negatively sequesters RNA-binding proteins5 before its non-canonical translation into neural-toxic dipeptide proteins3,4. The failure of RNA polymerase to read through the mutation also reduces the abundance of the endogenous C9ORF72 gene product, which functions in endolysosomal pathways and suppresses systemic and neural inflammation6-9. Notably, the effects of the repeat expansion act with incomplete penetrance in families with a high prevalence of amyotrophic lateral sclerosis or frontotemporal dementia, indicating that either genetic or environmental factors modify the risk of disease for each individual. Identifying disease modifiers is of considerable translational interest, as it could suggest strategies to diminish the risk of developing amyotrophic lateral sclerosis or frontotemporal dementia, or to slow progression. Here we report that an environment with reduced abundance of immune-stimulating bacteria10,11 protects C9orf72-mutant mice from premature mortality and significantly ameliorates their underlying systemic inflammation and autoimmunity. Consistent with C9orf72 functioning to prevent microbiota from inducing a pathological inflammatory response, we found that reducing the microbial burden in mutant mice with broad spectrum antibiotics-as well as transplanting gut microflora from a protective environment-attenuated inflammatory phenotypes, even after their onset. Our studies provide further evidence that the microbial composition of our gut has an important role in brain health and can interact in surprising ways with well-known genetic risk factors for disorders of the nervous system.


Assuntos
Proteína C9orf72/genética , Microbioma Gastrointestinal/fisiologia , Gliose/microbiologia , Gliose/patologia , Inflamação/genética , Inflamação/microbiologia , Medula Espinal/patologia , Esclerose Amiotrófica Lateral/genética , Esclerose Amiotrófica Lateral/patologia , Animais , Antibacterianos/farmacologia , Autoimunidade/efeitos dos fármacos , Autoimunidade/genética , Autoimunidade/imunologia , Movimento Celular/efeitos dos fármacos , Citocinas/imunologia , Transplante de Microbiota Fecal , Feminino , Demência Frontotemporal/genética , Demência Frontotemporal/patologia , Microbioma Gastrointestinal/efeitos dos fármacos , Microbioma Gastrointestinal/imunologia , Gliose/genética , Gliose/prevenção & controle , Inflamação/patologia , Inflamação/prevenção & controle , Mutação com Perda de Função/genética , Masculino , Camundongos , Microglia/imunologia , Microglia/microbiologia , Microglia/patologia , Medula Espinal/imunologia , Medula Espinal/microbiologia , Taxa de Sobrevida
6.
Nat Commun ; 11(1): 1998, 2020 04 24.
Artigo em Inglês | MEDLINE | ID: mdl-32332730

RESUMO

Alcohol consumption is a consistent protective factor for the development of autoimmune diseases such as rheumatoid arthritis (RA). The underlying mechanism for this tolerance-inducing effect of alcohol, however, is unknown. Here we show that alcohol and its metabolite acetate alter the functional state of T follicular helper (TFH) cells in vitro and in vivo, thereby exerting immune regulatory and tolerance-inducing properties. Alcohol-exposed mice have reduced Bcl6 and PD-1 expression as well as IL-21 production by TFH cells, preventing proper spatial organization of TFH cells to form TFH:B cell conjugates in germinal centers. This effect is associated with impaired autoantibody formation, and mitigates experimental autoimmune arthritis. By contrast, T cell independent immune responses and passive models of arthritis are not affected by alcohol exposure. These data clarify the immune regulatory and tolerance-inducing effect of alcohol consumption.


Assuntos
Consumo de Bebidas Alcoólicas/imunologia , Artrite Experimental/imunologia , Artrite Reumatoide/imunologia , Etanol/farmacologia , Linfócitos T Auxiliares-Indutores/efeitos dos fármacos , Ácido Acético/metabolismo , Ácido Acético/farmacologia , Animais , Artrite Experimental/prevenção & controle , Artrite Reumatoide/prevenção & controle , Autoanticorpos/imunologia , Autoimunidade/efeitos dos fármacos , Linfócitos B/efeitos dos fármacos , Linfócitos B/imunologia , Colágeno/administração & dosagem , Colágeno/imunologia , Etanol/metabolismo , Feminino , Humanos , Camundongos , Fatores de Proteção , Tolerância a Antígenos Próprios/efeitos dos fármacos , Linfócitos T Auxiliares-Indutores/imunologia
7.
Cancer Immunol Immunother ; 69(9): 1737-1749, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32333082

RESUMO

Combination immunotherapy targeting the PD-1 and CTLA-4 checkpoint inhibitor pathways provides substantial clinical benefit in patients with advanced-stage cancer but at the risk of dose-limiting inflammatory and autoimmune toxicity. The delicate balance that exists between unleashing tumor killing and promoting systemic autoimmune toxicity represents a major clinical challenge. We hypothesized that targeting anti-CTLA-4 so that it perfuses tumor-draining lymph nodes would provide a significant therapeutic advantage and developed an injectable hydrogel with controlled antibody release characteristics for this purpose. Injection of hydrogel-encapsulated anti-CTLA-4 at a peri-tumor location (MC-38 tumor model) produced dose-dependent antitumor responses and survival that exceeded those by anti-CTLA-4 alone (p < 0.05). Responses to 100 µg of targeted anti-CTLA-4 also equaled or exceeded those observed with a series of systemic injections delivering 600 µg (p < 0.05). While preserving antitumor activity, this approach resulted in serum anti-CTLA-4 exposure (area under the curve) that averaged only 1/16th of that measured with systemic therapy. Consistent with the marked differences in systemic exposure, systemic anti-CTLA-4 stimulated the onset of autoimmune thyroiditis in iodide-exposed NOD.H-2h4 mice, as measured by anti-thyroglobulin antibody titer, while hydrogel-encapsulated anti-CTLA-4 had a minimal effect (p ≤ 0.01). At the same time, this targeted low-dose anti-CTLA-4 approach synergized well with systemic anti-PD-1 to control tumor growth and resulted in a high frequency of complete responders that were immune to tumor re-challenge at a distant site. We conclude that targeted and controlled delivery of low-dose anti-CTLA-4 has the potential to improve the benefit-risk ratio associated with combination checkpoint inhibitor therapy.


Assuntos
Antineoplásicos/farmacologia , Antígeno CTLA-4/imunologia , Preparações de Ação Retardada/farmacologia , Imunidade/efeitos dos fármacos , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Animais , Autoimunidade/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Terapia Combinada/métodos , Sinergismo Farmacológico , Feminino , Imunoterapia/métodos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos NOD
8.
Best Pract Res Clin Endocrinol Metab ; 34(1): 101411, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-32278687

RESUMO

Immunotherapy has transformed the treatment of cancer by restoring the power of the immune system against tumor cells. Disruption of the innate immune inhibition has introduced a large and growing spectrum of immune-related adverse effects (irAEs), with the endocrine system being a prominent target to autoimmune damage. What makes the endocrine system a prominent target when facing an unleashed immune system? Why are the endocrine irAEs mostly irreversible and unresponsive to glucocorticoid therapy? Is it possible to identify those prone to develop irAEs? The presents review describes the unique characteristics of the endocrine system and its crosstalk with the immune system. In a broader perspective, the iatrogenic side effects of immunotherapy provide a unique opportunity to explore the genetic, humoral and cytotoxic immune confounders.


Assuntos
Antineoplásicos Imunológicos/efeitos adversos , Autoimunidade/efeitos dos fármacos , Doenças do Sistema Endócrino/induzido quimicamente , Imunoterapia/efeitos adversos , Inibidores de Proteínas Quinases/efeitos adversos , Antineoplásicos Imunológicos/uso terapêutico , Autoimunidade/fisiologia , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Suscetibilidade a Doenças/etiologia , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/etiologia , Doenças do Sistema Endócrino/etiologia , Doenças do Sistema Endócrino/imunologia , Humanos , Fatores Imunológicos/efeitos adversos , Fatores Imunológicos/uso terapêutico , Imunoterapia/métodos , Neoplasias/tratamento farmacológico , Neoplasias/imunologia , Inibidores de Proteínas Quinases/uso terapêutico
9.
Best Pract Res Clin Endocrinol Metab ; 34(1): 101412, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-32265102

RESUMO

An adjuvant is an immunological or pharmacological substance or group of substances that can be added to a given agent to enhance its effect in terms of efficacy, effectiveness and potency. Different mechanisms have been hypothesized underlying the action of the adjuvant, including boosting immune (innate and adaptive) response: this generally results in sparing the necessary amount of the agent and can potentially reduce the frequency of the needed number of therapeutic interventions. Adjuvants can be commonly found in vaccines, immunization products, mineral oils, cosmetics, silicone breast implants and other therapeutic/medical devices, being usually safe and effective. However, in a fraction of genetically susceptible and predisposed subjects, the administration of adjuvants may lead to the insurgence of serious side-effects, called "autoimmune/inflammatory syndrome by adjuvants" (ASIA) or Shoenfeld's syndrome. The present review is aimed at focusing on the "endocrine pebbles" of the mosaic of autoimmunity and of the ASIA syndrome, collecting together 54 cases of sub-acute thyroiditis, 2 cases of Hashimoto's thyroiditis, 11 cases of primary ovarian failure/primary ovarian insufficiency, 13 cases of autoimmune diabetes type 1, and 1 case of autoimmune adrenal gland insufficiency occurred after exposure to adjuvants.


Assuntos
Adjuvantes Imunológicos/efeitos adversos , Doenças Autoimunes/induzido quimicamente , Autoimunidade/efeitos dos fármacos , Doenças do Sistema Endócrino/induzido quimicamente , Doenças Autoimunes/genética , Autoimunidade/genética , Diabetes Mellitus Tipo 1/induzido quimicamente , Diabetes Mellitus Tipo 1/genética , Diabetes Mellitus Tipo 1/imunologia , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/genética , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/imunologia , Doenças do Sistema Endócrino/genética , Doenças do Sistema Endócrino/imunologia , Predisposição Genética para Doença , Humanos , Fatores de Risco , Síndrome
10.
Nat Rev Rheumatol ; 16(5): 282-292, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32157196

RESUMO

In the past three decades, extraordinary advances have been made in the understanding of the pathogenesis of, and treatment options for, inflammatory arthritides, including rheumatoid arthritis and spondyloarthritis. The use of methotrexate and subsequently biologic therapies (such as TNF inhibitors, among others) and oral small molecules have substantially improved clinical outcomes for many patients with inflammatory arthritis; for others, however, these agents do not substantially improve their symptoms. The emerging field of pharmacomicrobiomics, which investigates the effect of variations within the human gut microbiome on drugs, has already provided important insights into these therapeutics. Pharmacomicrobiomic studies have demonstrated that human gut microorganisms and their enzymatic products can affect the bioavailability, clinical efficacy and toxicity of a wide array of drugs through direct and indirect mechanisms. This discipline promises to facilitate the advent of microbiome-based precision medicine approaches in inflammatory arthritis, including strategies for predicting response to treatment and for modulating the microbiome to improve response to therapy or reduce drug toxicity.


Assuntos
Artrite Reumatoide/microbiologia , Microbioma Gastrointestinal/efeitos dos fármacos , Medicina de Precisão/métodos , Espondilartrite/microbiologia , Animais , Antirreumáticos/metabolismo , Antirreumáticos/farmacocinética , Antirreumáticos/uso terapêutico , Artrite Reumatoide/tratamento farmacológico , Artrite Reumatoide/patologia , Autoimunidade/efeitos dos fármacos , Disponibilidade Biológica , Microbioma Gastrointestinal/genética , Humanos , Metotrexato/metabolismo , Metotrexato/farmacocinética , Metotrexato/uso terapêutico , Camundongos , Espondilartrite/tratamento farmacológico , Espondilartrite/patologia , Inibidores do Fator de Necrose Tumoral/metabolismo , Inibidores do Fator de Necrose Tumoral/farmacocinética , Inibidores do Fator de Necrose Tumoral/uso terapêutico
11.
Sci Rep ; 10(1): 3766, 2020 02 28.
Artigo em Inglês | MEDLINE | ID: mdl-32111885

RESUMO

Th17 cells are critical drivers of autoimmune diseases and immunopathology. There is an unmet need to develop therapies targeting pathogenic Th17 cells for the treatment of autoimmune disorders. Here, we report that anxiolytic FGIN-1-27 inhibits differentiation and pathogenicity of Th17 cells in vitro and in vivo using the experimental autoimmune encephalomyelitis (EAE) model of Th17 cell-driven pathology. Remarkably, we found that the effects of FGIN-1-27 were independent of translocator protein (TSPO), the reported target for this small molecule, and instead were driven by a metabolic switch in Th17 cells that led to the induction of the amino acid starvation response and altered cellular fatty acid composition. Our findings suggest that the small molecule FGIN-1-27 can be re-purposed to relieve autoimmunity by metabolic reprogramming of pathogenic Th17 cells.


Assuntos
Ansiolíticos/farmacologia , Autoimunidade/efeitos dos fármacos , Técnicas de Reprogramação Celular , Encefalomielite Autoimune Experimental , Ácidos Indolacéticos/farmacologia , Células Th17/imunologia , Animais , Encefalomielite Autoimune Experimental/imunologia , Encefalomielite Autoimune Experimental/patologia , Encefalomielite Autoimune Experimental/terapia , Camundongos , Camundongos Transgênicos , Receptores de GABA/imunologia , Células Th17/patologia
12.
Autoimmun Rev ; 19(4): 102493, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32062034

RESUMO

Chronic graft-versus-host disease (cGVHD) remains the main complication of allogeneic hematopoietic stem cell transplantation, limiting its chances for a successful outcome. The over-activity of CD4+ effector T cells and the excessive production of pro-inflammatory cytokines are followed by the development of immune-mediated inflammation and fibrosis of multiple organs. This is the reason for adopting T cell targeting therapies such as cyclosporine A, tacrolimus and mycophenolate mofetil. However, 40% of treated cGVHD patients remain unresponsive, which results in increased morbidity and mortality. Given the complexity of cGVHD pathogenesis, the involvement of B cells as an important player also needs to be explored. Function of aberrant B cells and secretion of relevant cytokines such as B cell activating factor (BAFF) have been found to correlate with cGVHD severity and have therefore become therapeutic targets. Better understanding of the role of B cells and their efficient targeting could improve the outcome of cGVHD.


Assuntos
Autoimunidade/efeitos dos fármacos , Autoimunidade/imunologia , Linfócitos B/efeitos dos fármacos , Linfócitos B/imunologia , Doença Enxerto-Hospedeiro/tratamento farmacológico , Doença Enxerto-Hospedeiro/imunologia , Doença Crônica/tratamento farmacológico , Transplante de Células-Tronco Hematopoéticas , Humanos
13.
Best Pract Res Clin Endocrinol Metab ; 34(1): 101377, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-32081544

RESUMO

Many papers evaluated the effect of the environmental, or occupational endocrine disruptors (ED), on the thyroid gland, that can lead to thyroid autoimmunity. A higher prevalence of autoimmune thyroid diseases (AITD) was observed in people living in polluted areas near to petrochemical plants, and in petrochemical workers, but also in area contaminated with organochlorine pesticides, or with polychlorinated biphenyls, or near aluminum foundries. The exposure to Hg in chloralkali workers, or in swordfish consumers has been also found to increase AITD prevalence. Vanadium has been shown to increase the inflammatory response of thyrocytes. A beneficial effect of omega-3 fatty acids, and of myo-inositol and selenomethionine have been shown to counteract the appearance of AITD in subjects exposed to environmental or occupational ED. More large studies are needed to investigate the potential roles of ED in the induction of AITD, and of agents or habits that are able to prevent them.


Assuntos
Autoimunidade/efeitos dos fármacos , Disruptores Endócrinos/farmacologia , Glândula Tireoide/efeitos dos fármacos , Glândula Tireoide/imunologia , Tireoidite Autoimune/etiologia , Disruptores Endócrinos/toxicidade , Exposição Ambiental/efeitos adversos , Exposição Ambiental/prevenção & controle , Ácidos Graxos Ômega-3/uso terapêutico , Humanos , Inositol/uso terapêutico , Exposição Ocupacional/efeitos adversos , Exposição Ocupacional/prevenção & controle , Fatores de Risco , Selenometionina/uso terapêutico , Tireoidite Autoimune/epidemiologia , Tireoidite Autoimune/prevenção & controle , Vanádio/farmacologia
14.
Int Immunopharmacol ; 80: 106221, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32007707

RESUMO

CD28 and CTLA-4 are both important stimulatory receptors for the regulation of T cell activation. Because receptors share common ligands, B7.1 and B7.2, the expression and biological function of CTLA-4 is important for the negative regulation of T cell responses. Therefore, elimination of CTLA-4 can result in the breakdown of immune tolerance and the development of several diseases such as autoimmunity. Inhibitory signals of CTLA-4 suppress T cell responses and protect against autoimmune diseases in many ways. In this review, we summarize the structure, expression and signaling pathway of CTLA-4. We also highlight how CTLA-4 defends against potentially self-reactive T cells. Finally, we discuss how the CTLA-4 regulates a number of autoimmune diseases that indicate manipulation of this inhibitory molecule is a promise as a strategy for the immunotherapy of autoimmune diseases.


Assuntos
Doenças Autoimunes/tratamento farmacológico , Antígeno CTLA-4/metabolismo , Imunossupressores/farmacologia , Transdução de Sinais/efeitos dos fármacos , Linfócitos T/imunologia , Abatacepte/farmacologia , Abatacepte/uso terapêutico , Animais , Doenças Autoimunes/genética , Doenças Autoimunes/imunologia , Doenças Autoimunes/patologia , Autoimunidade/efeitos dos fármacos , Autoimunidade/genética , Antígeno CTLA-4/agonistas , Antígeno CTLA-4/genética , Antígeno CTLA-4/imunologia , Ensaios Clínicos como Assunto , Modelos Animais de Doenças , Humanos , Tolerância Imunológica/efeitos dos fármacos , Tolerância Imunológica/genética , Imunoconjugados/farmacologia , Imunoconjugados/uso terapêutico , Imunossupressores/uso terapêutico , Ativação Linfocitária/efeitos dos fármacos , Transdução de Sinais/imunologia , Linfócitos T/metabolismo , Resultado do Tratamento
15.
Int Immunopharmacol ; 80: 106239, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32007709

RESUMO

Previous research has recently indicated that TLR7 is able to induce CD4+T cell anergy, which is the opposite of the role it plays in innate immune cells. Therefore, TLR7 ligands may be used as a manner in which to induce CD4+T cells "tolerance" in autoimmune diseases. T follicular helper (Tfh) cells were demonstrated to be a subset of CD4+T cells that help B cells produce antibodies. The abnormal activity of Tfh cells, though, is their function as a primary pathogenic factor in systemic lupus erythematosus (SLE). However, the role of TLR7 in Tfh cells is not clear. Our study was aimed at determining the influence of TLR7 on Tfh cells in a murine model of SLE (MRL/lpr mice). We were surprised to find that the frequency of Tfh cells and germinal center (GC) B cells was significantly reduced after treatment with the TLR7 agonist imiquimod. Imiquimod also significantly reduced the expression of inducible costimulatory molecule (ICOS) and programmed death 1(PD-1) in Tfh cells and decreased IL-21 secretion. Moreover, imiquimod significantly reduced the mRNA expression of several transcription factors, including Bcl-6, c-Maf, Batf3, Nfatc2 and Stat3, and enhanced the expression of Prdm1 and Stat5b in CD4+T cells. Imiquimod also ameliorated the progression of SLE in MRL/lpr mice by inhibiting anti-dsDNA antibodies and antinuclear antibody (ANA) secretion in the serum. Our findings indicated that TLR7 inhibited the development of Tfh cells both in vivo and ex vivo, which depended on many transcription factors aside from Bcl-6. Our results demonstrated that a TLR7 agonist has the potential to be used to inhibit Tfh cell responses during SLE.


Assuntos
Diferenciação Celular/efeitos dos fármacos , Imiquimode/farmacologia , Lúpus Eritematoso Sistêmico/tratamento farmacológico , Glicoproteínas de Membrana/agonistas , Linfócitos T Auxiliares-Indutores/efeitos dos fármacos , Receptor 7 Toll-Like/agonistas , Animais , Anticorpos Antinucleares/sangue , Anticorpos Antinucleares/imunologia , Anticorpos Antinucleares/metabolismo , Autoimunidade/efeitos dos fármacos , Diferenciação Celular/imunologia , Modelos Animais de Doenças , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Regulação da Expressão Gênica/imunologia , Humanos , Imiquimode/uso terapêutico , Lúpus Eritematoso Sistêmico/sangue , Lúpus Eritematoso Sistêmico/imunologia , Lúpus Eritematoso Sistêmico/patologia , Glicoproteínas de Membrana/metabolismo , Camundongos , Camundongos Endogâmicos MRL lpr , Fator 1 de Ligação ao Domínio I Regulador Positivo/metabolismo , Proteínas Proto-Oncogênicas c-bcl-6/metabolismo , Fatores de Transcrição STAT/metabolismo , Linfócitos T Auxiliares-Indutores/imunologia , Receptor 7 Toll-Like/metabolismo
16.
Int J Nanomedicine ; 15: 1215-1228, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32110018

RESUMO

Background: Helper T cell activity is dysregulated in a number of diseases including those associated with rheumatic autoimmunity. Treatment options are limited and usually consist of systemic immune suppression, resulting in undesirable consequences from compromised immunity. Hedgehog (Hh) signaling has been implicated in the activation of T cells and the formation of the immune synapse, but remains understudied in the context of autoimmunity. Modulation of Hh signaling has the potential to enable controlled immunosuppression but a potential therapy has not yet been developed to leverage this opportunity. Methods: In this work, we developed biodegradable nanoparticles to enable targeted delivery of eggmanone (Egm), a specific Hh inhibitor, to CD4+ T cell subsets. We utilized two FDA-approved polymers, poly(lactic-co-glycolic acid) and polyethylene glycol, to generate hydrolytically degradable nanoparticles. Furthermore, we employed maleimide-thiol mediated conjugation chemistry to decorate nanoparticles with anti-CD4 F(ab') antibody fragments to enable targeted delivery of Egm. Results: Our novel delivery system achieved a highly specific association with the majority of CD4+ T cells present among a complex cell population. Additionally, we have demonstrated antigen-specific inhibition of CD4+ T cell responses mediated by nanoparticle-formulated Egm. Conclusion: This work is the first characterization of Egm's immunomodulatory potential. Importantly, this study also suggests the potential benefit of a biodegradable delivery vehicle that is rationally designed for preferential interaction with a specific immune cell subtype for targeted modulation of Hh signaling.


Assuntos
Autoimunidade/efeitos dos fármacos , Sistemas de Liberação de Medicamentos/métodos , Fatores Imunológicos/administração & dosagem , Nanopartículas/administração & dosagem , Pirimidinonas/administração & dosagem , Linfócitos T/efeitos dos fármacos , Tiofenos/administração & dosagem , Animais , Linfócitos T CD4-Positivos/efeitos dos fármacos , Linfócitos T CD4-Positivos/imunologia , Citocinas/metabolismo , Feminino , Proteínas Hedgehog/antagonistas & inibidores , Proteínas Hedgehog/metabolismo , Fragmentos de Imunoglobulinas/química , Camundongos Endogâmicos C57BL , Nanopartículas/química , Copolímero de Ácido Poliláctico e Ácido Poliglicólico , Doenças Reumáticas/imunologia , Linfócitos T/imunologia , Linfócitos T Auxiliares-Indutores/efeitos dos fármacos , Linfócitos T Auxiliares-Indutores/imunologia
17.
J Immunol ; 204(4): 810-818, 2020 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-31907283

RESUMO

T cells chronically stimulated with the same peptide tend to express exhaustion markers such as PD-1 or LAG-3. Deficiencies in the PD-1 and LAG-3 pathways have been linked to the development of autoimmune diseases. IMP761 is a LAG-3-specific humanized agonist Ab with immunosuppressive properties both in vitro and in vivo in an Ag-specific delayed-type hypersensitivity (DTH) model in the cynomolgus macaque (Macaca fascicularis). IMP761 inhibits TCR-mediated NFAT activation and Ag-induced human T cell proliferation and activation. In the DTH model, assessment of T cell infiltration and gene expression profile at the DTH biopsy site corresponds to immunosuppression of an Ag-induced T cell response. IMP761 is the first LAG-3-specific agonist product candidate, acting upstream on activated T cells, the root cause of self-Ag-specific T cell-induced autoimmune diseases.


Assuntos
Anticorpos Monoclonais Humanizados/farmacologia , Antígenos CD/efeitos dos fármacos , Doenças Autoimunes/imunologia , Imunossupressores/farmacologia , Linfócitos T/efeitos dos fármacos , Animais , Antígenos CD/imunologia , Autoimunidade/efeitos dos fármacos , Autoimunidade/imunologia , Proliferação de Células/efeitos dos fármacos , Humanos , Hipersensibilidade Tardia/imunologia , Ativação Linfocitária/efeitos dos fármacos , Macaca fascicularis , Masculino , Linfócitos T/imunologia
18.
Immunol Lett ; 217: 25-30, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31726186

RESUMO

In a previous work we demonstrated that inhibition of mouse indoleamine 2,3-dioxygenase (IDO) by methyltryptophan (MT) exacerbated the pathological actions of mouse hepatitis virus (MHV-A59) infection, suggesting that tryptophan (TRP) catabolism was involved in viral effects. Since there is a second enzyme that dioxygenates TRP, tryptophan-2, 3-dioxygenase (TDO), which is mainly located in liver, we decided to study its role in our model of MHV-infection. Results showed that in vivo TDO inhibition by LM10, a derivative of 3-(2-(pyridyl) ethenyl) indole, resulted in a decrease of anti- MHV Ab titers induced by the virus infection. Besides, a reduction of some alarmin release, i.e, uric acid and high-mobility group box1 protein (HMGB1), was observed. Accordingly, since alarmin liberation was related to the expression of autoantibodies (autoAb) to fumarylacetoacetate hydrolase (FAH), these autoAb also diminished. Moreover, PCR results indicated that TDO inhibition did not abolish viral replication. Furthermore, histological liver examination did not reveal strong pathologies, whereas mouse survival was hundred percent in control as well as in MHV-infected mice treated with LM10. Data presented in this work indicate that in spite of the various TDO actions already described, specific TDO blockage could also restrain some MHV actions, mainly suppressing autoimmune reactions. Such results should prompt further experiments with various viruses to confirm the possible use of a TDO inhibitor such as LM-10 to treat either viral infections or even autoimmune diseases triggered by a viral infection.


Assuntos
Doenças Autoimunes/enzimologia , Autoimunidade/efeitos dos fármacos , Infecções por Coronavirus/enzimologia , Infecções por Coronavirus/imunologia , Fígado/enzimologia , Vírus da Hepatite Murina/imunologia , Triptofano Oxigenase/antagonistas & inibidores , Triptofano Oxigenase/metabolismo , Alarminas/metabolismo , Animais , Autoanticorpos/efeitos dos fármacos , Autoanticorpos/imunologia , Doenças Autoimunes/tratamento farmacológico , Doenças Autoimunes/imunologia , Doenças Autoimunes/virologia , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/virologia , Feminino , Proteína HMGB1/sangue , Proteína HMGB1/metabolismo , Hidrolases/imunologia , Indóis/uso terapêutico , Fígado/efeitos dos fármacos , Fígado/imunologia , Fígado/patologia , Camundongos , Camundongos Endogâmicos BALB C , Vírus da Hepatite Murina/efeitos dos fármacos , Vírus da Hepatite Murina/crescimento & desenvolvimento , Triptofano/metabolismo , Triptofano Oxigenase/genética , Ácido Úrico/sangue , Ácido Úrico/metabolismo , Replicação Viral/efeitos dos fármacos , Replicação Viral/imunologia
20.
Front Immunol ; 11: 631743, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33569065

RESUMO

The concept of trained immunity has recently emerged as a mechanism contributing to several immune mediated inflammatory conditions. Trained immunity is defined by the immunological memory developed in innate immune cells after a primary non-specific stimulus that, in turn, promotes a heightened inflammatory response upon a secondary challenge. The most characteristic changes associated to this process involve the rewiring of cell metabolism and epigenetic reprogramming. Under physiological conditions, the role of trained immune cells ensures a prompt response. This action is limited by effective resolution of inflammation and tissue repair in order to restore homeostasis. However, unrestrained activation of innate immune cells contributes to the development of chronic inflammation and tissue destruction through the secretion of inflammatory cytokines, proteases and growth factors. Therefore, interventions aimed at reversing the changes induced by trained immunity provide potential therapeutic approaches to treat inflammatory and autoimmune diseases like rheumatoid arthritis (RA). We review cellular approaches that target metabolism and the epigenetic reprogramming of dendritic cells, macrophages, natural killer cells, and other trained cells in the context of autoimmune inflammatory diseases.


Assuntos
Anti-Inflamatórios/uso terapêutico , Doenças Autoimunes/tratamento farmacológico , Autoimunidade/efeitos dos fármacos , Produtos Biológicos/uso terapêutico , Sistema Imunitário/efeitos dos fármacos , Inflamação/tratamento farmacológico , Animais , Doenças Autoimunes/genética , Doenças Autoimunes/imunologia , Doenças Autoimunes/metabolismo , /imunologia , Metabolismo Energético/efeitos dos fármacos , Epigênese Genética/efeitos dos fármacos , Humanos , Sistema Imunitário/imunologia , Sistema Imunitário/metabolismo , Imunidade Inata/efeitos dos fármacos , Memória Imunológica/efeitos dos fármacos , Inflamação/genética , Inflamação/imunologia , Inflamação/metabolismo , Transdução de Sinais
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