RESUMO
The morbidity and mortality of autoimmune diseases (Ads) have been increasing worldwide, and the identification of novel therapeutic strategies for prevention and treatment is urgently needed. Sirtuin 1 (SIRT1), a member of the class III family of nicotinamide adenine dinucleotide (NAD+)-dependent histone deacetylases, has been reported to participate in the progression of several diseases. SIRT1 also regulates inflammation, oxidative stress, mitochondrial function, immune responses, cellular differentiation, proliferation and metabolism, and its altered functions are likely involved in Ads. Several inhibitors and activators have been shown to affect the development of Ads. SIRT1 may represent a novel therapeutic target in these diseases, and small molecules or natural products that modulate the functions of SIRT1 are potential therapeutic agents. In the present review, we summarize current studies of the biological functions of SIRT1 and its role in the pathogenesis and treatment of Ads.
Assuntos
Doenças Autoimunes/tratamento farmacológico , Autoimunidade/efeitos dos fármacos , Ativadores de Enzimas/uso terapêutico , Inibidores de Histona Desacetilases/uso terapêutico , Sirtuína 1/antagonistas & inibidores , Imunidade Adaptativa/efeitos dos fármacos , Animais , Doenças Autoimunes/enzimologia , Doenças Autoimunes/imunologia , Ativação Enzimática , Ativadores de Enzimas/efeitos adversos , Inibidores de Histona Desacetilases/efeitos adversos , Humanos , Imunidade Inata/efeitos dos fármacos , Terapia de Alvo Molecular , Transdução de Sinais , Sirtuína 1/metabolismoRESUMO
Tyrosine kinase 2 (Tyk2) is a member of the Janus family of protein tyrosine kinases (Jaks). Tyk2 associates with interferon (IFN)-α, IFN-ß, interleukin (IL)-6, IL-10, IL-12, and IL-23 receptors and mediates their downstream signaling pathways. Based on our data using Tyk2-deficient mice and cells, Tyk2 plays crucial roles in the differentiation, maintenance, and function of T helper 1 (Th1) and Th17 cells, and its dysregulation may promote autoimmune and/or inflammatory diseases. IFN-α-induced growth inhibition of B lymphocyte progenitors is dependent on Tyk2-mediated signals to regulate death-associated protein (Daxx) nuclear localization and Daxx-promyelocytic leukemia protein interactions. Tyk2-deficient mice show impaired constitutive production of type I IFNs by macrophages under steady-state conditions. When heat-killed Cutibacterium acnes is injected intraperitoneally, Tyk2-deficient mice show less granuloma formation through enhanced prostaglandin E2 and protein kinase A activities, leading to high IL-10 production by macrophages. Thus, Tyk2 is widely involved in the immune and inflammatory response at multiple events; therefore, Tyk2 is likely to be a suitable target for treating patients with autoimmune and/or chronic inflammatory diseases. Clinical trials of Tyk2 inhibitors have shown higher response rates and improved tolerability in the treatment of patients with psoriasis and inflammatory bowel diseases. Taken together, Tyk2 inhibition has great potential for clinical application in the management of a variety of diseases.
Assuntos
Doenças Autoimunes/tratamento farmacológico , Inflamação/tratamento farmacológico , TYK2 Quinase/antagonistas & inibidores , Animais , Doenças Autoimunes/enzimologia , Doença Crônica , Humanos , Inflamação/enzimologiaRESUMO
The ubiquitin-proteasome pathway is responsible for the turnover of different cellular proteins, such as transport proteins, presentation of antigens to the immune system, control of the cell cycle, and activities that promote cancer. The enzymes which remove ubiquitin, deubiquitylating enzymes (DUBs), play a critical role in central and peripheral immune tolerance to prevent the development of autoimmune diseases and thus present a potential therapeutic target for the treatment of autoimmune diseases. DUBs function by removing ubiquitin(s) from target protein and block ubiquitin chain elongation. The addition and removal of ubiquitin molecules have a significant impact on immune responses. DUBs and E3 ligases both specifically cleave target protein and modulate protein activity and expression. The balance between ubiquitylation and deubiquitylation modulates protein levels and also protein interactions. Dysregulation of the ubiquitin-proteasome pathway results in the development of various autoimmune diseases such as inflammatory bowel diseases (IBD), psoriasis, multiple sclerosis (MS), systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA). This review summarizes the current understanding of ubiquitination in autoimmune diseases and focuses on various DUBs responsible for the progression of autoimmune diseases.
Assuntos
Doenças Autoimunes/fisiopatologia , Enzimas Desubiquitinantes/metabolismo , Terapia de Alvo Molecular , Animais , Doenças Autoimunes/enzimologia , Doenças Autoimunes/terapia , Progressão da Doença , Humanos , Ubiquitina/metabolismo , Ubiquitina-Proteína Ligases/metabolismo , Ubiquitinação/fisiologiaRESUMO
Bruton's tyrosine kinase (BTK) is a TEC kinase with a multifaceted role in B-cell biology and function, highlighted by its position as a critical component of the B-cell receptor signalling pathway. Due to its role as a therapeutic target in several haematological malignancies including chronic lymphocytic leukaemia, BTK has been gaining tremendous momentum in recent years. Within the immune system, BTK plays a part in numerous pathways and cells beyond B cells (i.e. T cells, macrophages). Not surprisingly, BTK has been elucidated to be a driving factor not only in lymphoproliferative disorders but also in autoimmune diseases and response to infection. To extort this role, BTK inhibitors such as ibrutinib have been developed to target BTK in other diseases. However, due to rising levels of resistance, the urgency to develop new inhibitors with alternative modes of targeting BTK is high. To meet this demand, an expanding list of BTK inhibitors is currently being trialled. In this review, we synopsize recent discoveries regarding BTK and its role within different immune cells and pathways. Additionally, we discuss the broad significance and relevance of BTK for various diseases ranging from haematology and rheumatology to the COVID-19 pandemic. Overall, BTK signalling and its targetable nature have emerged as immensely important for a wide range of clinical applications. The development of novel, more specific and less toxic BTK inhibitors could be revolutionary for a significant number of diseases with yet unmet treatment needs.
Assuntos
Tirosina Quinase da Agamaglobulinemia/metabolismo , Linfócitos B/enzimologia , Sistema Imunitário/enzimologia , Tirosina Quinase da Agamaglobulinemia/antagonistas & inibidores , Animais , Doenças Autoimunes/tratamento farmacológico , Doenças Autoimunes/enzimologia , Doenças Autoimunes/imunologia , Linfócitos B/efeitos dos fármacos , Linfócitos B/imunologia , COVID-19/enzimologia , COVID-19/imunologia , Humanos , Sistema Imunitário/efeitos dos fármacos , Sistema Imunitário/imunologia , Transtornos Linfoproliferativos/tratamento farmacológico , Transtornos Linfoproliferativos/enzimologia , Transtornos Linfoproliferativos/imunologia , Terapia de Alvo Molecular , Inibidores de Proteínas Quinases/uso terapêutico , Receptores de Antígenos de Linfócitos B/metabolismo , Receptores de Quimiocinas/metabolismo , Transdução de Sinais , Receptores Toll-Like/metabolismo , Tratamento Farmacológico da COVID-19RESUMO
Bruton's tyrosine kinase (BTK) plays a crucial role in B-cell receptor and Fc receptor signaling pathways. BTK is also involved in the regulation of Toll-like receptors and chemokine receptors. Given the central role of BTK in immunity, BTK inhibition represents a promising therapeutic approach for the treatment of inflammatory and autoimmune diseases. Great efforts have been made in developing BTK inhibitors for potential clinical applications in inflammatory and autoimmune diseases. This review covers the recent development of BTK inhibitors at preclinical and clinical stages in treating these diseases. Individual examples of three types of inhibitors, namely covalent irreversible inhibitors, covalent reversible inhibitors, and non-covalent reversible inhibitors, are discussed with a focus on their structure, bioactivity and selectivity. Contrary to expectations, reversible BTK inhibitors have not yielded a significant breakthrough so far. The development of covalent, irreversible BTK inhibitors has progressed more rapidly. Many candidates entered different stages of clinical trials; tolebrutinib and evobrutinib are undergoing phase 3 clinical evaluation. Rilzabrutinib, a covalent reversible BTK inhibitor, is now in phase 3 clinical trials and also offers a promising future. An analysis of the protein-inhibitor interactions based on published co-crystal structures provides useful clues for the rational design of safe and effective small-molecule BTK inhibitors.
Assuntos
Tirosina Quinase da Agamaglobulinemia/antagonistas & inibidores , Doenças Autoimunes/tratamento farmacológico , Doenças Autoimunes/enzimologia , Inflamação/tratamento farmacológico , Inflamação/enzimologia , Inibidores de Proteínas Quinases/uso terapêutico , Tirosina Quinase da Agamaglobulinemia/química , Tirosina Quinase da Agamaglobulinemia/metabolismo , Sítios de Ligação , Desenvolvimento de Medicamentos , HumanosRESUMO
INTRODUCTION: Aberrant citrullination and excessive peptidylarginine deiminase (PAD) activity are detected in numerous challenging autoimmune diseases such as rheumatoid arthritis, inflammatory bowel diseases, systemic lupus erythematosus, multiple sclerosis, and type 1 diabetes. Because excessive PAD activity is a common denominator in these diseases, PADs are interesting potential therapeutic targets for future therapies. AREAS COVERED: This review summarizes the advances made in the design of PAD inhibitors, their utilization and therapeutic potential in preclinical mouse models of autoimmunity. Relevant literature encompasses studies from 1994 to 2021 that are available on PubMed.gov. EXPERT OPINION: Pan-PAD inhibition is a promising therapeutic strategy for autoimmune diseases. Drugs achieving pan-PAD inhibition were capable of ameliorating, reversing, and preventing clinical symptoms in preclinical mouse models. However, the implications for PADs in key biological processes potentially present a high risk for clinical complications and could hamper the translation of PAD inhibitors to the clinic. We envisage that PAD isozyme-specific inhibitors will improve the understanding the role of PAD isozymes in disease pathology, reduce the risk of side-effects and enhance prospects for future clinical translation.
Assuntos
Doenças Autoimunes/tratamento farmacológico , Terapia de Alvo Molecular , Desiminases de Arginina em Proteínas/antagonistas & inibidores , Animais , Doenças Autoimunes/enzimologia , Doenças Autoimunes/fisiopatologia , Autoimunidade , Citrulinação/efeitos dos fármacos , Modelos Animais de Doenças , Desenho de Fármacos , Humanos , Isoenzimas , Camundongos , Desiminases de Arginina em Proteínas/metabolismoRESUMO
Protein Kinase C theta (PKCθ) is a serine/threonine kinase that belongs to the novel PKC subfamily. In normal tissue, its expression is restricted to skeletal muscle cells, platelets and T lymphocytes in which PKCθ controls several essential cellular processes such as survival, proliferation and differentiation. Particularly, PKCθ has been extensively studied for its role in the immune system where its translocation to the immunological synapse plays a critical role in T cell activation. Beyond its physiological role in immune responses, increasing evidence implicates PKCθ in the pathology of various diseases, especially autoimmune disorders and cancers. In this review, we discuss the implication of PKCθ in various types of cancers and the PKCθ-mediated signaling events controlling cancer initiation and progression. In these types of cancers, the high PKCθ expression leads to aberrant cell proliferation, migration and invasion resulting in malignant phenotype. The recent development and application of PKCθ inhibitors in the context of autoimmune diseases could benefit the emergence of treatment for cancers in which PKCθ has been implicated.
Assuntos
Doenças Autoimunes/genética , Regulação Neoplásica da Expressão Gênica , Neoplasias/genética , Proteína Quinase C-theta/genética , Subunidades Proteicas/genética , Transdução de Sinais/genética , Animais , Doenças Autoimunes/enzimologia , Doenças Autoimunes/imunologia , Doenças Autoimunes/patologia , Movimento Celular , Proliferação de Células , Humanos , NF-kappa B/genética , NF-kappa B/metabolismo , Invasividade Neoplásica , Metástase Neoplásica , Neoplasias/enzimologia , Neoplasias/imunologia , Neoplasias/patologia , Ligação Proteica , Domínios e Motivos de Interação entre Proteínas , Proteína Quinase C-theta/química , Proteína Quinase C-theta/imunologia , Subunidades Proteicas/química , Subunidades Proteicas/imunologia , Células Th17/imunologia , Células Th17/patologia , Células Th2/imunologia , Células Th2/patologiaRESUMO
The introduction of the CTLA-4 recombinant fusion protein has demonstrated therapeutic effects by selectively modulating T-cell activation in rheumatoid arthritis. Here we show, using a forward genetic approach, that a mutation in the SH3gl1 gene encoding the endocytic protein Endophilin A2 is associated with the development of arthritis in rodents. Defective expression of SH3gl1 affects T cell effector functions and alters the activation threshold of autoreactive T cells, thereby leading to complete protection from chronic autoimmune inflammatory disease in both mice and rats. We further show that SH3GL1 regulates human T cell signaling and T cell receptor internalization, and its expression is upregulated in rheumatoid arthritis patients. Collectively our data identify SH3GL1 as a key regulator of T cell activation, and as a potential target for treatment of autoimmune diseases.
Assuntos
Aciltransferases/deficiência , Artrite Reumatoide/enzimologia , Artrite Reumatoide/imunologia , Doenças Autoimunes/enzimologia , Doenças Autoimunes/imunologia , Ativação Linfocitária/imunologia , Linfócitos T/imunologia , Aciltransferases/genética , Aciltransferases/metabolismo , Animais , Artrite Reumatoide/prevenção & controle , Autoimunidade , Endocitose , Feminino , Humanos , Células Jurkat , Linfonodos/metabolismo , Linfonodos/patologia , Masculino , Camundongos , Mutação/genética , Ratos , Receptores de Antígenos de Linfócitos T/metabolismo , Transdução de Sinais , Regulação para Cima/genéticaRESUMO
Pemphigoid diseases refer to a group of severe autoimmune skin blistering diseases characterized by subepidermal blistering and loss of dermal-epidermal adhesion induced by autoantibody and immune cell infiltrate at the dermal-epidermal junction and upper dermis. Here, we explore the role of the immune cell-secreted serine protease, granzyme B, in pemphigoid disease pathogenesis using three independent murine models. In all models, granzyme B knockout or topical pharmacological inhibition significantly reduces total blistering area compared to controls. In vivo and in vitro studies show that granzyme B contributes to blistering by degrading key anchoring proteins in the dermal-epidermal junction that are necessary for dermal-epidermal adhesion. Further, granzyme B mediates IL-8/macrophage inflammatory protein-2 secretion, lesional neutrophil infiltration, and lesional neutrophil elastase activity. Clinically, granzyme B is elevated and abundant in human pemphigoid disease blister fluids and lesional skin. Collectively, granzyme B is a potential therapeutic target in pemphigoid diseases.
Assuntos
Doenças Autoimunes/enzimologia , Doenças Autoimunes/patologia , Granzimas/antagonistas & inibidores , Granzimas/metabolismo , Animais , Autoantígenos/metabolismo , Vesícula , Quimiocina CXCL2/metabolismo , Fatores Quimiotáticos/farmacologia , Modelos Animais de Doenças , Epidermólise Bolhosa/enzimologia , Epidermólise Bolhosa/patologia , Humanos , Inflamação/patologia , Integrina alfa6/metabolismo , Interleucina-8/metabolismo , Infiltração de Neutrófilos/efeitos dos fármacos , Colágenos não Fibrilares/metabolismo , Penfigoide Bolhoso/enzimologia , Penfigoide Bolhoso/patologia , Índice de Gravidade de Doença , Colágeno Tipo XVIIRESUMO
BACKGROUND: Concurrent extrahepatic autoimmune disorders (CEHAID) are frequently observed in autoimmune hepatitis (AIH). It is not clear whether there is any prognostic significance of CEHAID on AIH. The aim of this study was to examine the prognostic impact of CEHAID and the correlation with the disease severity of AIH. METHODS: This study included 65 hospitalized subjects who fulfilled the accepted criteria for AIH during an 8-year period (2009-2016). All records were manually screened for presence of associated autoimmune diseases. Disease severity of AIH was assessed by liver laboratory tests including the ratio of aspartate aminotransferase to alanine aminotransferase (AST/ALT) and liver histology. RESULTS: Among the enrolled patients, 52 (80%) were female (median age 61 years, IQR 45-75). Fifty-six (86.2%) were classified as type-1 AIH. In 26 (40%) patients at least one additional extrahepatic autoimmune disease was diagnosed. Thirty-four subjects were referred to our hospital because of acute presentation of AIH (supposed by an acute elevation of hepatic enzymes) for subsequent liver biopsy resulting in initial diagnosis of AIH. This group was stratified into 3 subgroups: (A) AIH alone (n = 14); (B) overlap with primary biliary cirrhosis (PBC) / primary sclerosing cholangitis (PSC) (n = 11); and (C) with CEHAID (n = 9). AST/ALT ratio was the lowest in subgroup C (median 0.64, IQR 0.51-0.94; P = 0.023), compared to subgroup A (median 0.91, IQR 0.66-1.10) and subgroup B (median 1.10, IQR 0.89-1.36). Patients with AIH alone showed a trend to the highest grade of fibrosis (mean 2.3; 95% CI: 1.5-3.0) with no statistical significance compared to subjects with CEHAID (lowest grade of fibrosis; mean 1.5; 95% CI: 0.2-2.8; P = 0.380) whereas the ongoing inflammation was comparable. CONCLUSIONS: AST/ALT ratio and extent of fibrosis were lower in subjects with AIH and CEHAID, compared to subjects with only AIH. Therefore, the occurrence of CEHAID might be a predictor for lower disease severity of newly diagnosed acute onset AIH, possibly caused by an earlier diagnosis or different modes of damage.
Assuntos
Doenças Autoimunes/diagnóstico , Hepatite Autoimune/diagnóstico , Fígado/patologia , Transaminases/sangue , Idoso , Doenças Autoimunes/complicações , Doenças Autoimunes/enzimologia , Biomarcadores/sangue , Biópsia , Feminino , Seguimentos , Hepatite Autoimune/complicações , Hepatite Autoimune/enzimologia , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos , Índice de Gravidade de Doença , Fatores de TempoRESUMO
Previous studies have shown that CD73 is pivotal in the conversion of pro-inflammatory adenosine triphosphate into anti-inflammatory adenosine and that immune cells of the same type that express different levels of CD73 are functionally distinct. In this study we show that adenosine enhances the Th17 promoting effect of dendritic cells (DCs), and DCs expressing CD73 critically augment Th17 responses. Bone marrow dendritic cells (BMDCs) do not constantly express CD73; however, a significant portion of the BMDCs expressed CD73 after exposure to Toll-like receptor ligand, leading to stronger Th17 responses by converting adenosine monophosphate to adenosine. We show that the CD73+ BMDCs play a critical role in cascading Th17 responses, and CD73+ BMDCs are functionally augmented after treatment with Toll-like receptor ligand. Splenic antigen presenting cells (DCs) of CD73-/- mouse have a poor Th17-stimulating effect, even after exposure to lipopolysaccharide (LPS) or γδ T cells, indicating that induction of CD73+ DCs is critically involved in augmented Th17 responses. We conclude that CD73+ DCs critically trigger cascading Th17 responses, and the activated Th17 cells that express CD73 further augment Th17 responses, leading to cascading exacerbation. Hence, disabling the CD73 function of DCs should block this cascading response and mitigate Th17 responses.
Assuntos
5'-Nucleotidase/metabolismo , Doenças Autoimunes/enzimologia , Células Dendríticas/enzimologia , Células Th17/metabolismo , Úvea/enzimologia , Uveíte/enzimologia , 5'-Nucleotidase/genética , Adenosina/metabolismo , Monofosfato de Adenosina/farmacologia , Animais , Doenças Autoimunes/genética , Doenças Autoimunes/imunologia , Doenças Autoimunes/patologia , Comunicação Celular , Células Cultivadas , Técnicas de Cocultura , Citocinas/metabolismo , Células Dendríticas/efeitos dos fármacos , Células Dendríticas/imunologia , Modelos Animais de Doenças , Feminino , Proteínas Ligadas por GPI/genética , Proteínas Ligadas por GPI/metabolismo , Genes Codificadores da Cadeia delta de Receptores de Linfócitos T , Lipopolissacarídeos/farmacologia , Ativação Linfocitária , Camundongos Endogâmicos C57BL , Camundongos Knockout , Transdução de Sinais , Células Th17/imunologia , Úvea/imunologia , Úvea/patologia , Uveíte/genética , Uveíte/imunologia , Uveíte/patologiaRESUMO
The c-Jun-N-terminal kinase (JNK) is a critical mediator involved in various physiological processes, such as immune responses, and the pathogenesis of various diseases, including autoimmune disorders. JNK is one of the crucial downstream signaling molecules of various immune triggers, mainly proinflammatory cytokines, in autoimmune arthritic conditions, mainly including rheumatoid arthritis, ankylosing spondylitis, and psoriatic arthritis. The activation of JNK is regulated in a complex manner by upstream kinases and phosphatases. Noticeably, different subtypes of JNKs behave differentially in immune responses. Furthermore, aside from biologics targeting proinflammatory cytokines, small-molecule inhibitors targeting signaling molecules such as Janus kinases can act as very powerful therapeutics in autoimmune arthritis patients unresponsiveness to conventional synthetic antirheumatic drugs. Nevertheless, despite these encouraging therapies, a population of patients with an inadequate therapeutic response to all currently available medications still remains. These findings identify the critical signaling molecule JNK as an attractive target for investigation of the immunopathogenesis of autoimmune disorders and for consideration as a potential therapeutic target for patients with autoimmune arthritis to achieve better disease control. This review provides a useful overview of the roles of JNK, how JNK is regulated in immunopathogenic responses, and the potential of therapeutically targeting JNK in patients with autoimmune arthritis.
Assuntos
Artrite Reumatoide/tratamento farmacológico , Artrite Reumatoide/enzimologia , Doenças Autoimunes/tratamento farmacológico , Doenças Autoimunes/enzimologia , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Terapia de Alvo Molecular , Animais , Artrite Reumatoide/imunologia , Doenças Autoimunes/imunologia , Citocinas/metabolismo , Ativação Enzimática , HumanosRESUMO
Eukaryotic proteomes are enormously sophisticated through versatile post-translational modifications (PTMs) of proteins. A large variety of code generated via PTMs of proteins by ubiquitin (ubiquitination) and ubiquitin-like proteins (Ubls), such as interferon (IFN)-stimulated gene 15 (ISG15), small ubiquitin-related modifier (SUMO) and neural precursor cell expressed, developmentally downregulated 8 (NEDD8), not only provides distinct signals but also orchestrates a plethora of biological processes, thereby underscoring the necessity for sophisticated and fine-tuned mechanisms of code regulation. Deubiquitinases (DUBs) play a pivotal role in the disassembly of the complex code and removal of the signal. Ubiquitin-specific protease 18 (USP18), originally referred to as UBP43, is a major DUB that reverses the PTM of target proteins by ISG15 (ISGylation). Intriguingly, USP18 is a multifaceted protein that not only removes ISG15 or ubiquitin from conjugated proteins in a deconjugating activity-dependent manner but also acts as a negative modulator of type I IFN signaling, irrespective of its catalytic activity. The function of USP18 has become gradually clear, but not yet been completely addressed. In this review, we summarize recent advances in our understanding of the multifaceted roles of USP18. We also highlight new insights into how USP18 is implicated not only in physiology but also in pathogenesis of various human diseases, involving infectious diseases, neurological disorders, and cancers. Eventually, we integrate a discussion of the potential of therapeutic interventions for targeting USP18 for disease treatment.
Assuntos
Doenças Autoimunes/metabolismo , Doenças Transmissíveis/metabolismo , Citocinas/metabolismo , Enzimas Desubiquitinantes/metabolismo , Interferons/metabolismo , Neoplasias/metabolismo , Doenças do Sistema Nervoso/metabolismo , Ubiquitina Tiolesterase/metabolismo , Sequência de Aminoácidos , Animais , Doenças Autoimunes/enzimologia , Doenças Transmissíveis/enzimologia , Doenças Transmissíveis/microbiologia , Doenças Transmissíveis/virologia , Citocinas/genética , Humanos , Neoplasias/enzimologia , Doenças do Sistema Nervoso/enzimologia , Processamento de Proteína Pós-Traducional , Transdução de Sinais/genética , Ubiquitina Tiolesterase/química , Ubiquitina Tiolesterase/genética , Ubiquitinação/genética , Ubiquitinas/genética , Ubiquitinas/metabolismoRESUMO
Tyrosine kinase 2 (TYK2) is a member of the JAK kinase family that regulates signal transduction downstream of receptors for the IL-23/IL-12 pathways and type I interferon family, where it pairs with JAK2 or JAK1, respectively. On the basis of human genetic and emerging clinical data, a selective TYK2 inhibitor provides an opportunity to treat autoimmune diseases delivering a potentially differentiated clinical profile compared to currently approved JAK inhibitors. The discovery of an ATP-competitive pyrazolopyrazinyl series of TYK2 inhibitors was accomplished through computational and structurally enabled design starting from a known kinase hinge binding motif. With understanding of PK/PD relationships, a target profile balancing TYK2 potency and selectivity over off-target JAK2 was established. Lead optimization involved modulating potency, selectivity, and ADME properties which led to the identification of the clinical candidate PF-06826647 (22).
Assuntos
Doenças Autoimunes/enzimologia , Descoberta de Drogas/métodos , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , TYK2 Quinase/antagonistas & inibidores , Animais , Doenças Autoimunes/tratamento farmacológico , Humanos , Camundongos , Camundongos Transgênicos , Microssomos Hepáticos/efeitos dos fármacos , Microssomos Hepáticos/enzimologia , Inibidores de Proteínas Quinases/uso terapêutico , Estrutura Secundária de Proteína , TYK2 Quinase/química , TYK2 Quinase/metabolismoRESUMO
Atherosclerosis and its clinical complications constitute the major healthcare problems of the world population. Due to the central role of endothelium throughout the atherosclerotic disease process, endothelial dysfunction is regarded as a common mechanism for various cardiovascular (CV) disorders. It is well established that patients with rheumatic autoimmune diseases are characterized by significantly increased prevalence of cardiovascular morbidity and mortality compared with the general population. The current European guidelines on cardiovascular disease (CVD) prevention in clinical practice recommend to use a 1,5-factor multiplier for CV risk in rheumatoid arthritis as well as in other autoimmune inflammatory diseases. However, mechanisms of accelerated atherosclerosis in these diseases, especially in the absence of traditional risk factors, still remain unclear. Oxidative stress plays the major role in the endothelial dysfunction and recently is strongly attributed to endothelial NO synthase dysfunction (eNOS uncoupling). Converted to a superoxide-producing enzyme, uncoupled eNOS not only leads to reduction of the nitric oxide (NO) generation but also potentiates the preexisting oxidative stress, which contributes significantly to atherogenesis. However, to date, there are no systemic analyses on the role of eNOS uncoupling in the excess CV mortality linked with autoimmune rheumatic diseases. The current review paper addresses this issue.
Assuntos
Doenças Autoimunes/metabolismo , Óxido Nítrico Sintase Tipo III/metabolismo , Óxido Nítrico/metabolismo , Doenças Reumáticas/metabolismo , Animais , Doenças Autoimunes/enzimologia , Doenças Autoimunes/imunologia , Humanos , Redes e Vias Metabólicas , Doenças Reumáticas/enzimologia , Doenças Reumáticas/imunologia , Transdução de SinaisRESUMO
Generating inhibitors for A Disintegrin And Metalloproteinase 10 (ADAM10), a zinc-dependent protease, was heavily invested in by the pharmaceutical industry starting over 20 years ago. There has been much enthusiasm in basic research for these inhibitors, with a multitude of studies generating significant data, yet the clinical trials have not replicated the same results. ADAM10 is ubiquitously expressed and cleaves many important substrates such as Notch, PD-L1, EGFR/HER ligands, ICOS-L, TACI, and the "stress related molecules" MIC-A, MIC-B and ULBPs. This review goes through the most recent pre-clinical data with inhibitors as well as clinical data supporting the use of ADAM10 inhibitor use in cancer and autoimmunity. It additionally addresses how ADAM10 inhibitor therapy can be improved and if inhibitor therapy can be paired with other drug treatments to maximize effectiveness in various disease states. Finally, it examines the ADAM10 substrates that are important to each disease state and if any of these substrates or ADAM10 itself is a potential biomarker for disease.
Assuntos
Proteína ADAM10/antagonistas & inibidores , Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Doenças Autoimunes/tratamento farmacológico , Proteínas de Membrana/antagonistas & inibidores , Terapia de Alvo Molecular , Proteínas de Neoplasias/antagonistas & inibidores , Neoplasias/tratamento farmacológico , Inibidores de Proteases/uso terapêutico , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Doenças Autoimunes/enzimologia , Doenças Autoimunes/imunologia , Diferenciação Celular/efeitos dos fármacos , Diferenciação Celular/fisiologia , Ensaios Clínicos como Assunto , Dipeptídeos/farmacologia , Dipeptídeos/uso terapêutico , Avaliação Pré-Clínica de Medicamentos , Humanos , Ácidos Hidroxâmicos/farmacologia , Ácidos Hidroxâmicos/uso terapêutico , Estudos Multicêntricos como Assunto , Neoplasias/enzimologia , Neoplasias/imunologia , Inibidores de Proteases/farmacologia , Receptores Notch/fisiologia , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/fisiologia , Especificidade por SubstratoRESUMO
Biallelic mutations in ACP5, encoding tartrate-resistant acid phosphatase (TRACP), have recently been identified to cause the inherited immuno-osseous disorder, spondyloenchondrodysplasia (SPENCD). This study was undertaken to characterize the eight reported missense mutations in ACP5 associated with SPENCD on TRACP expression. ACP5 mutant genes were synthesized, transfected into human embryonic kidney (HEK-293) cells and stably expressing cell lines were established. TRACP expression was assessed by cytochemical and immuno-cytochemical staining with a panel of monoclonal antibodies. Analysis of wild (WT) type and eight mutant stable cell lines indicated that all mutants lacked stainable enzyme activity. All ACP5 mutant constructs were translated into intact proteins by HEK-293 cells. The mutant TRACP proteins displayed variable immune reactivity patterns, and all drastically reduced enzymatic activity, revealing that there is no gross inhibition of TRACP biosynthesis by the mutations. But they likely interfere with folding thereby impairing enzyme function. TRACP exists as two isoforms. TRACP 5a is a less active monomeric enzyme (35kD), with the intact loop peptide and TRACP 5b is proteolytically cleaved highly active enzyme encompassing two subunits (23 kD and 16 kD) held together by disulfide bonds. None of the mutant proteins were proteolytically processed into isoform 5b intracellularly, and only three mutants were secreted in significant amounts into the culture medium as intact isoform 5a-like proteins. Analysis of antibody reactivity patterns revealed that T89I and M264K mutant proteins retained some native conformation, whereas all others were in "denatured" or "unfolded" forms. Western blot analysis with intracellular and secreted TRACP proteins also revealed similar observations indicating that mutant T89I is amply secreted as inactive protein. All mutant proteins were attacked by Endo-H sensitive glycans and none could be activated by proteolytic cleavage in vitro. In conclusion, determining the structure-function relationship of the SPENCD mutations in TRACP will expand our understanding of basic mechanisms underlying immune responsiveness and its involvement in dysregulated bone metabolism.
Assuntos
Doenças Autoimunes/patologia , Proteínas Mutantes/metabolismo , Mutação de Sentido Incorreto , Osteocondrodisplasias/patologia , Fosfatase Ácida Resistente a Tartarato/metabolismo , Substituição de Aminoácidos , Doenças Autoimunes/enzimologia , Doenças Autoimunes/genética , Glicosilação , Humanos , Proteínas Mutantes/química , Proteínas Mutantes/genética , Osteocondrodisplasias/enzimologia , Osteocondrodisplasias/genética , Proteólise , Fosfatase Ácida Resistente a Tartarato/química , Fosfatase Ácida Resistente a Tartarato/genéticaRESUMO
Innate immune signaling plays an important role in inflammation, and dysregulation of signaling components within this pathway has been focused as a critical mediator in initiation, progression of inflammatory autoimmune diseases. Toll-like receptors (TLRs) are the most upstream pattern recognition receptors in the immune cells, detecting pathogen associated molecular patterns, initiating signal transduction, by which interleukin-1 receptor-associated kinase (IRAK) family mediates activating signal from TLRs and interleukin-1 receptor. The family comprises of four members, IRAK1, IRAK2, IRAK-M, IRAK4. The family members have a role in either positive or negative regulation of innate immunity, adaptive immunity and inflammation. Accumulated evidence proves that IRAK performs significantly in the pathogenesis of inflammatory autoimmune disorders. On the one hand, both patients and animal modes reported abnormal expression of the family members. On the other hand, functional study in vivo and in vitro demonstrated that the members are implicated in the development of the diseases. Interestingly, IRAK inhibition has potential therapeutic benefits. In this review, we focus on the family, review the physiological roles in different immune cells, and summarize emerging data for highlighting the importance of them in inflammatory autoimmunity.
Assuntos
Doenças Autoimunes/enzimologia , Inflamação/imunologia , Quinases Associadas a Receptores de Interleucina-1/imunologia , Transdução de Sinais , Animais , Humanos , Receptores de Interleucina-1/metabolismo , Receptores Toll-Like/metabolismoRESUMO
Mammalian STE20-like protein kinases (MST), including MST1, MST2, MST3, and MST4, belong to the germinal center kinase (GCK) family. Kinase MST1/2 is an important component of the Hippo pathway in regulating cell proliferation, tissue homeostasis, and organ development. Recent studies have shown that Hippo kinase MST1/2 plays a crucial role in immune-associated diseases, which has attracted extensive attention of researchers. This review summarizes recent research on Hippo kinases MST1/2 in regulating the function of immune cells in innate and adaptive immune systems, and also includes its regulatory role and significance in cancer, infection, and autoimmune diseases.
Assuntos
Doenças Autoimunes/imunologia , Infecções/imunologia , Neoplasias/imunologia , Proteínas Serina-Treonina Quinases/metabolismo , Doenças Autoimunes/enzimologia , Doenças Autoimunes/patologia , Proliferação de Células , Via de Sinalização Hippo , Homeostase , Humanos , Infecções/enzimologia , Infecções/patologia , Peptídeos e Proteínas de Sinalização Intracelular , Neoplasias/enzimologia , Neoplasias/patologia , Serina-Treonina Quinase 3RESUMO
The small guanosine triphosphatase Rho and its target Rho kinase are involved in a heterogeneous spectrum of cellular activities, many of which are integral to cytoskeletal organization. Furthermore, the Rho kinases result in NF kappa beta activation and hence the induction of various pro-inflammatory cytokines including TNF-alpha, IL-1B and IL-6. ROCK2 is a downstream protein, whose expression is indicative of Rho Kinase activation. Given the diverse effects of Rho-kinase, including a potentially critical role in augmenting inflammation, ROCK2 expression was examined in biopsies of select autoimmune connective tissue diseases as compared to control diagnoses. Select cases of lupus erythematosus, dermatomyositis, autoimmune sclerodermoid disorders and Kohlmeier-Degos disease (a distinctive vasculopathy that occurs in the other aforesaid conditions but also as a forme fruste microvascular and arteriopathic syndrome) were studied. Control biopsies included normal skin and cutaneous inflammatory conditions unrelated to collagen vascular disease/autoimmune disease. We found ROCK2 expression significantly increased in biopsies of lupus erythematosus, dermatomyositis, scleroderma and Kohlmeier-Degos disease. A pattern emerged of consistent marked ROCK2 upregulation in endothelium and variable expression in inflammatory cells and epithelium. While expression was undetectable in normal skin, it was found in inflamed skin unrelated to specific autoimmune disease. The staining pattern could approach that seen in study group cases but was less pronounced and preferentially upregulated in the endothelium, with a lesser extent of staining in the epidermis and inflammatory cells. Rho kinase is a driving factor in diverse cutaneous diseases especially autoimmune disease and Kohlmeier-Degos disease. This significantly upregulated pathway defines a potential target for biologic therapy.