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1.
Med Hypotheses ; 144: 110250, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-33254555

RESUMO

This study presents two new concepts and definitions to the medical literature. One of those is "endogenous retinoic acid theory" and the other "retinoic acid depletion syndrome". A new classification will be provided for the immune system: "retinoic acid-dependent component" and "retinoic acid non-dependent component". If this theory is verified, all the diseases where the retinoic acid metabolism is defective and retinoic acid levels are low will be identified and new approaches will be developed fortreating such diseases. When the need for retinoic acids increases, such as acute infection, high fever, severe catabolic process, or chronic antigenic stimulation, cytochrome oxidase enzymes are inhibited by drugs or internal mechanisms. Metabolism and excretion of retinoic acids stored in the liver are prevented. In this way, retinoic acid levels in the blood are raised to therapeutic levels. This is called "Endogenous Retinoic Acid Theory". Retinoic acids also manage their metabolism through feedback mechanisms. Despite compensatory mechanisms, causes such as high fever, serious catabolic process and excessively large viral genome (SARS-CoV-2), excessive use of RIG-I and Type I interferon synthesis pathway using retinoic acid causes emptying of retinoic acid stores. As a result, the RIG-I pathway becomes ineffective, Type I IFN synthesis stops, and the congenital immune system collapses. Then the immune mechanism passes to TLR3, TLR7, TLR8, TLR9, MDA5 and UPS pathways in the monocyte, macrophage, neutrophil and dendritic cells of the adaptive immune defense system that do not require retinoic acid. This leads to excessive TNFα and cytokine discharge from the pathway. With the depletion of retinoic acid stores as a result of this overuse, the immune defense mechanism switches from the congenital immune system to the adaptive immune system, where retinoic acids cannot be used. As a result of this depletion of retinoic acids, the shift of the immune system to the NFκB arm, which causes excessive cytokine release, is called "retinoic acid depletion syndrome". COVID-19 and previously defined sepsis, SIRS and ARDS are each retinoic acid depletion syndrome. We claim that retinoic acid metabolism is defective in most inflammatory diseases, particularly COVID-19 (cytokine storm) sepsis, SIRS and ARDS. Finding a solution to this mechanism will bring a new perspective and treatment approach to such diseases.


Assuntos
/imunologia , Tretinoína/metabolismo , Autoimunidade , Carotenoides/metabolismo , Proteína DEAD-box 58/imunologia , Humanos , Sistema Imunitário , Interferon Tipo I/metabolismo , Interferons/metabolismo , Fígado/metabolismo , Modelos Teóricos , Sistema Nervoso/metabolismo , Síndrome , Carga Viral , Vitamina A/farmacologia , Deficiência de Vitamina A/metabolismo , Zinco/metabolismo
2.
Nat Commun ; 11(1): 6264, 2020 12 08.
Artigo em Inglês | MEDLINE | ID: mdl-33293517

RESUMO

The molecular and cellular mechanisms mediating thymic central tolerance and prevention of autoimmunity are not fully understood. Here we show that B7-CD28 co-stimulation and B7 expression by specific antigen-presenting cell (APC) types are required for clonal deletion and for regulatory T (Treg) cell generation from endogenous tissue-restricted antigen (TRA)-specific thymocytes. While B7-CD28 interaction is required for both clonal deletion and Treg induction, these two processes differ in their CD28 signaling requirements and in their dependence on B7-expressing dendritic cells, B cells, and thymic epithelial cells. Meanwhile, defective thymic clonal deletion due to altered B7-CD28 signaling results in the accumulation of mature, peripheral TRA-specific T cells capable of mediating destructive autoimmunity. Our findings thus reveal a function of B7-CD28 co-stimulation in shaping the T cell repertoire and limiting autoimmunity through both thymic clonal deletion and Treg cell generation.


Assuntos
Antígeno B7-1/metabolismo , Antígenos CD28/metabolismo , Tolerância Central , Deleção Clonal , Linfócitos T Reguladores/imunologia , Timo/imunologia , Animais , Células Apresentadoras de Antígenos/metabolismo , Autoimunidade/fisiologia , Antígenos CD28/genética , Diferenciação Celular/imunologia , Encefalomielite Autoimune Experimental/imunologia , Citometria de Fluxo , Técnicas de Introdução de Genes , Camundongos , Camundongos Knockout , Receptores de Antígenos de Linfócitos T alfa-beta/genética , Receptores de Antígenos de Linfócitos T alfa-beta/metabolismo , Transdução de Sinais/imunologia , Linfócitos T Reguladores/metabolismo , Timócitos/fisiologia , Timo/citologia , Timo/metabolismo
3.
Nat Commun ; 11(1): 6372, 2020 12 11.
Artigo em Inglês | MEDLINE | ID: mdl-33311516

RESUMO

The thymus is a primary lymphoid organ, essential for T cell maturation and selection. There has been long-standing interest in processes underpinning thymus generation and the potential to manipulate it clinically, because alterations of thymus development or function can result in severe immunodeficiency and autoimmunity. Here, we identify epithelial-mesenchymal hybrid cells, capable of long-term expansion in vitro, and able to reconstitute an anatomic phenocopy of the native thymus, when combined with thymic interstitial cells and a natural decellularised extracellular matrix (ECM) obtained by whole thymus perfusion. This anatomical human thymus reconstruction is functional, as judged by its capacity to support mature T cell development in vivo after transplantation into humanised immunodeficient mice. These findings establish a basis for dissecting the cellular and molecular crosstalk between stroma, ECM and thymocytes, and offer practical prospects for treating congenital and acquired immunological diseases.


Assuntos
Células Estromais , Timo/imunologia , Animais , Autoimunidade , Diferenciação Celular , Células Epiteliais/imunologia , Matriz Extracelular , Feminino , Humanos , Masculino , Camundongos , Camundongos Nus , Ratos , Regeneração , Timócitos , Timo/patologia , Timo/transplante , Tecidos Suporte
4.
Nat Commun ; 11(1): 6149, 2020 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-33262343

RESUMO

Autoimmune connective tissue diseases arise in a stepwise fashion from asymptomatic preclinical autoimmunity. Type I interferons have a crucial role in the progression to established autoimmune diseases. The cellular source and regulation in disease initiation of these cytokines is not clear, but plasmacytoid dendritic cells have been thought to contribute to excessive type I interferon production. Here, we show that in preclinical autoimmunity and established systemic lupus erythematosus, plasmacytoid dendritic cells are not effector cells, have lost capacity for Toll-like-receptor-mediated cytokine production and do not induce T cell activation, independent of disease activity and the blood interferon signature. In addition, plasmacytoid dendritic cells have a transcriptional signature indicative of cellular stress and senescence accompanied by increased telomere erosion. In preclinical autoimmunity, we show a marked enrichment of an interferon signature in the skin without infiltrating immune cells, but with interferon-κ production by keratinocytes. In conclusion, non-hematopoietic cellular sources, rather than plasmacytoid dendritic cells, are responsible for interferon production prior to clinical autoimmunity.


Assuntos
Autoimunidade , Células Dendríticas/imunologia , Interferon Tipo I/imunologia , Lúpus Eritematoso Sistêmico/imunologia , Citocinas/genética , Citocinas/imunologia , Humanos , Interferon Tipo I/genética , Lúpus Eritematoso Sistêmico/genética , Ativação Linfocitária , Linfócitos T/imunologia , Receptores Toll-Like/genética , Receptores Toll-Like/imunologia
5.
PLoS One ; 15(11): e0241719, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33137121

RESUMO

INTRODUCTION: Interstitial lung disease (ILD) is a heterogeneous group of diseases characterized by varying degrees of lung inflammation and/or fibrosis. We investigated biomarkers to infer whether patients with collagen vascular diseases associated ILD (CVD-ILD) and interstitial pneumonia with autoimmune features (IPAF) benefit from immunosuppressive therapy. MATERIALS AND METHODS: We retrospectively investigated patients with CVD-ILD, IPAF, and idiopathic pulmonary fibrosis (IPF) between June 2013 and May 2017 at our department. First, we assessed differences in serum and bronchoalveolar lavage fluid (BALF) levels of cytokines between groups. Second, we assessed the associations of patient's clinical variables with serum and BALF levels of those cytokines that were different between groups. Finally, we assessed the associations of diagnosis and response to immunosuppressive therapy with serum levels of those cytokines that were different between groups. RESULTS: We included 102 patients (51 with IPF, 35 with IPAF, and 16 with CVD-ILD). Serum and BALF levels of CXCL9, CXCL10, and CXCL11 were significantly elevated in patients with IPAF or CVD-ILD compared with those in patients with IPF. BALF levels of CXCL9 and CXCL10 were correlated with the percentages of lymphocytes and macrophages in BALF. Serum levels of CXCL9 and CXCL10 were correlated with BALF levels. Serum levels of CXCL9, CXCL10, and CXCL11 were correlated C-reactive protein, percent predicted forced vital capacity, alveolar-arterial oxygen difference, and the percentages of lymphocytes and macrophages in BALF. Serum levels of CXCL9, CXCL10, and CXCL11 showed moderate accuracy to distinguish patients with CVD-ILD from those with IPAF and IPF. Pre-treatment serum levels of CXCL9 and CXCL11 showed strong positive correlations with the annual forced vital capacity changes in patients with IPAF and CVD-ILD treated with immunosuppressive drugs. CONCLUSIONS: Serum CXCL9, CXCL10, and CXCL11 are potential biomarkers for autoimmune inflammation and predictors of the immunosuppressive therapy responses in ILD with background autoimmunity.


Assuntos
Biomarcadores/sangue , Quimiocina CXCL10/sangue , Quimiocina CXCL11/sangue , Quimiocina CXCL9/sangue , Doenças Pulmonares Intersticiais/diagnóstico , Doenças Vasculares/complicações , Idoso , Autoimunidade , Biomarcadores/análise , Líquido da Lavagem Broncoalveolar/química , Líquido da Lavagem Broncoalveolar/citologia , Líquido da Lavagem Broncoalveolar/imunologia , Proteína C-Reativa/análise , Quimiocina CXCL10/análise , Quimiocina CXCL11/análise , Quimiocina CXCL9/análise , Colágeno/metabolismo , Feminino , Humanos , Fibrose Pulmonar Idiopática/diagnóstico , Doenças Pulmonares Intersticiais/etiologia , Linfócitos/citologia , Linfócitos/metabolismo , Macrófagos/citologia , Macrófagos/metabolismo , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Doenças Vasculares/patologia , Capacidade Vital
6.
Nucleic Acids Res ; 48(21): 12074-12084, 2020 12 02.
Artigo em Inglês | MEDLINE | ID: mdl-33219687

RESUMO

CRISPR-Cas systems require discriminating self from non-self DNA during adaptation and interference. Yet, multiple cases have been reported of bacteria containing self-targeting spacers (STS), i.e. CRISPR spacers targeting protospacers on the same genome. STS has been suggested to reflect potential auto-immunity as an unwanted side effect of CRISPR-Cas defense, or a regulatory mechanism for gene expression. Here we investigated the incidence, distribution, and evasion of STS in over 100 000 bacterial genomes. We found STS in all CRISPR-Cas types and in one fifth of all CRISPR-carrying bacteria. Notably, up to 40% of I-B and I-F CRISPR-Cas systems contained STS. We observed that STS-containing genomes almost always carry a prophage and that STS map to prophage regions in more than half of the cases. Despite carrying STS, genetic deterioration of CRISPR-Cas systems appears to be rare, suggesting a level of escape from the potentially deleterious effects of STS by other mechanisms such as anti-CRISPR proteins and CRISPR target mutations. We propose a scenario where it is common to acquire an STS against a prophage, and this may trigger more extensive STS buildup by primed spacer acquisition in type I systems, without detrimental autoimmunity effects as mechanisms of auto-immunity evasion create tolerance to STS-targeted prophages.


Assuntos
Bactérias/genética , Proteínas Associadas a CRISPR/genética , Sistemas CRISPR-Cas/imunologia , Repetições Palindrômicas Curtas Agrupadas e Regularmente Espaçadas/imunologia , Genoma Bacteriano , Prófagos/genética , Autoimunidade/genética , Bactérias/imunologia , Bactérias/virologia , Sequência de Bases , Proteína 9 Associada à CRISPR/genética , Proteína 9 Associada à CRISPR/imunologia , Proteínas Associadas a CRISPR/imunologia , Mapeamento Cromossômico/estatística & dados numéricos , Software
7.
Artigo em Japonês | MEDLINE | ID: mdl-33148926

RESUMO

Immunity, which denotes the protection of multicellular organisms against various bacterial and viral infections, is an essential protective mechanism for living organisms. Allergy is a reaction to a foreign substance existing in the environment that is basically not a component of the self. Additionally, autoimmune diseases are associated with the dysfunction in the recognition of self and non-self, and are pathological conditions caused by immune cells attacking their own tissues and cells. In this paper, we outline the current status of immunity with respect to the environment from the epidemiological perspective with regard to the following: (1) evolution and immunity, (2) allergy, (3) autoantibodies, (4) autoimmune diseases, (5) relationships of immunity with the environment, allergy, autoantibodies, and autoimmune diseases, and (6) celiac disease.


Assuntos
Doenças Autoimunes/imunologia , Autoimunidade , Hipersensibilidade/imunologia , Adolescente , Adulto , Idoso , Autoanticorpos , Doenças Autoimunes/epidemiologia , Evolução Biológica , Doença Celíaca/imunologia , Criança , Pré-Escolar , Meio Ambiente , Feminino , Humanos , Hipersensibilidade/epidemiologia , Lactente , Masculino , Pessoa de Meia-Idade , Adulto Jovem
8.
Isr Med Assoc J ; 11(22): 717-719, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-33249794

RESUMO

BACKGROUND: Innate and adaptive immune response dysregulations are equally involved in the induction of autoimmunity. Toll-like receptors play a leading role in the activation of innate immune cells, thus priming auto-reactive T cells. Th17 cells and related cytokines are widely involved in many immune-mediated diseases such as rheumatoid arthritis. Thus, the recent introduction of anti-IL-17 therapies should be further evaluated. Janus kinase inhibitors and Fc receptor-targeting drugs are some of the new therapeutic strategies that are being implemented when old classical therapies lack sufficient beneficial outcomes.


Assuntos
Doenças Autoimunes/tratamento farmacológico , Autoimunidade/imunologia , Imunidade Inata/imunologia , Imunidade Adaptativa/imunologia , Animais , Artrite Reumatoide/tratamento farmacológico , Artrite Reumatoide/imunologia , Doenças Autoimunes/imunologia , Doenças Autoimunes/fisiopatologia , Citocinas/imunologia , Humanos , Interleucina-17/imunologia , Inibidores de Janus Quinases/farmacologia , Receptores Fc/efeitos dos fármacos , Receptores Fc/imunologia , Receptores Toll-Like/imunologia
9.
Scand J Immunol ; 92(6): e12984, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33037649

RESUMO

Human herpesvirus 6A (HHV-6A) and 6B (HHV-6B) are two closely related viruses that can infect cells of the central nervous system (CNS). The similarities between these viruses have made it difficult to separate them on serological level. The broad term HHV-6 remains when referring to studies where the two species were not distinguished, and as such, the seroprevalence is over 90% in the adult population. HHV-6B has been detected in up to 100% of infants with the primary infection roseola infantum, but less is known about the primary infection of HHV-6A. Both viruses are neurotropic and have capacity to establish lifelong latency in cells of the central nervous system, with potential to reactivate and cause complications later in life. HHV-6A infection has been associated with an increased risk of multiple sclerosis (MS), whereas HHV-6B is indicated to be involved in pathogenesis of epilepsy. These two associations show how neurological diseases might be caused by viral infections, but as suggested here, through completely different molecular mechanisms, in an autoimmune disease, such as MS, by triggering an overreaction of the immune system and in epilepsy by hampering internal cellular functions when the immune system fails to eliminate the virus. Understanding the viral mechanisms of primary infection and reactivation and their spectrum of associated symptoms will aid our ability to diagnose, treat and prevent these severe and chronic diseases. This review explores the role of HHV-6A and HHV-6B specifically in MS and epilepsy, the evidence to date and the future directions of this field.


Assuntos
Sistema Nervoso Central/virologia , Epilepsia/virologia , Exantema Súbito/virologia , Herpesvirus Humano 6/fisiologia , Esclerose Múltipla/virologia , Animais , Autoimunidade , Epigênese Genética , Epilepsia/imunologia , Exantema Súbito/imunologia , Humanos , Esclerose Múltipla/imunologia , Risco
11.
Med Hypotheses ; 145: 110345, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33080459

RESUMO

With the progression of the COVID-19 pandemic, there have been different reports about the development of autoimmune diseases once the infection is controlled. After entering the respiratory epithelial cells, SARS-CoV-2-the virus that causes the disease-triggers a severe inflammatory state in some patients known as "cytokine storm" and the development of thrombotic phenomena-both conditions being associated with high mortality. Patients additionally present severe lymphopenia and, in some cases, complement consumption and autoantibody development. There is a normalization of lymphocytes once the infection is controlled. After this, autoimmune conditions of unknown etiology may occur. A hypothesis for the development of post-COVID-19 autoimmunity is proposed based on the consequences of both a transient immunosuppression (both of innate and acquired immunity) in which self-tolerance is lost and an inappropriate form of immune reconstitution that amplifies the process.


Assuntos
Autoimunidade/imunologia , /imunologia , Imunidade Adaptativa , Autoanticorpos/química , Autoantígenos , Citocinas/imunologia , Progressão da Doença , Suscetibilidade a Doenças , Humanos , Reconstituição Imune , Tolerância Imunológica , Imunidade Inata , Imunossupressão , Inflamação , Linfócitos/imunologia , Modelos Teóricos , Pandemias
12.
Med Hypotheses ; 145: 110343, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33086161

RESUMO

ABO blood groups is a cheap and affordable test that can be immediately retrieved from COVID-19 patients at the diagnosis. There is increasing evidence that non-O blood groups have both higher susceptibility and higher severity of COVID-19 infections. The reason behind such relationship seems elusive. Regarding susceptibility, Non-O individuals have Anti-A antibodies which can prevent viral entry across ACE-2 receptors, moreover, Non-O individuals are at higher risk of autoimmunity, hypercoagulable state, and dysbiosis resulting in an augmented tendency for vascular inflammatory sequelae of COVID-19. We can conclude, on the diagnostic level, that ABO blood groups can be potentially used for risk stratification of affected COVID-19 patients, to anticipate the deterioration of patients at higher risk for complications. On a therapeutic level, plasma from normal O blood group individuals might potentially replace the use of convalescent serum for the treatment of COVID-19.


Assuntos
Sistema ABO de Grupos Sanguíneos , /sangue , Medição de Risco/métodos , Anticorpos/química , Autoimunidade , /terapia , Progressão da Doença , Feminino , Furina/metabolismo , Microbioma Gastrointestinal , Humanos , Imunização Passiva , Masculino , Pandemias , Trombose
13.
Proc Natl Acad Sci U S A ; 117(44): 27516-27527, 2020 11 03.
Artigo em Inglês | MEDLINE | ID: mdl-33077601

RESUMO

Multiple sclerosis (MS) is an autoimmune disease of the central nervous system. The etiology of MS is multifactorial, with disease risk determined by genetics and environmental factors. An emerging risk factor for immune-mediated diseases is an imbalance in the gut microbiome. However, the identity of gut microbes associated with disease risk, their mechanisms of action, and the interactions with host genetics remain obscure. To address these questions, we utilized the principal autoimmune model of MS, experimental autoimmune encephalomyelitis (EAE), together with a genetically diverse mouse model representing 29 unique host genotypes, interrogated by microbiome sequencing and targeted microbiome manipulation. We identified specific gut bacteria and their metabolic functions associated with EAE susceptibility, implicating short-chain fatty acid metabolism as a key element conserved across multiple host genotypes. In parallel, we used a reductionist approach focused on two of the most disparate phenotypes identified in our screen. Manipulation of the gut microbiome by transplantation and cohousing demonstrated that transfer of these microbiomes into genetically identical hosts was sufficient to modulate EAE susceptibility and systemic metabolite profiles. Parallel bioinformatic approaches identified Lactobacillus reuteri as a commensal species unexpectedly associated with exacerbation of EAE in a genetically susceptible host, which was functionally confirmed by bacterial isolation and commensal colonization studies. These results reveal complex interactions between host genetics and gut microbiota modulating susceptibility to CNS autoimmunity, providing insights into microbiome-directed strategies aimed at lowering the risk for autoimmune disease and underscoring the need to consider host genetics and baseline gut microbiome composition.


Assuntos
Encefalomielite Autoimune Experimental/genética , Microbioma Gastrointestinal/imunologia , Predisposição Genética para Doença , Interações entre Hospedeiro e Microrganismos/imunologia , Esclerose Múltipla/genética , Animais , Autoimunidade/genética , Modelos Animais de Doenças , Encefalomielite Autoimune Experimental/imunologia , Encefalomielite Autoimune Experimental/microbiologia , Feminino , Variação Genética , Interações entre Hospedeiro e Microrganismos/genética , Humanos , Lactobacillus reuteri/imunologia , Masculino , Camundongos , Esclerose Múltipla/imunologia , Esclerose Múltipla/microbiologia
14.
Rinsho Shinkeigaku ; 60(11): 778-785, 2020 Nov 27.
Artigo em Japonês | MEDLINE | ID: mdl-33115994

RESUMO

A 29 year-old, right-handed woman was admitted to our hospital due to her headache with fever elevation lasting for two months followed by a prolonged loss of awareness with an involuntary movement in her left hand and mouth. This movement appeared very frequently, and the duration was very short, so called "faciobrachial dystonic seizures (FBDS)". Some of FBDS were followed by prolonged loss of awareness. Brain MRI fluid attenuated inversion recovery (FLAIR) image revealed high intensity lesion in the left mesial temporal lobe. Arterial spin labeling (ASL) image indicated hyper perfusion in this lesion and also the lateral temporal region. No ictal electroencephalography (EEG) change was observed before the onset of FBDS. FBDS was often followed by focal impaired awareness seizure (FIAS) in which ictal EEG showed rhythmic alpha activity arising from left mid-temporal region. This EEG seizure pattern was clearly visible in the time-frequency analysis. Given these clinical findings, along with an evidence of serum anti-leucine-rich glioma-inactivated 1 (LGI1) antibody positive, she was diagnosed with anti-LGI1 encephalitis. Immunotherapy (methylpredonisolone and intravenous immunoglobulin) with a multiple anti-epileptic drugs therapy (lacosamide, perampanel, and lamotrigine) was highly responsible to her symptoms. Although the high intensity lesion in FLAIR image still remained after the treatment, findings of ASL and EEG showed clear correlation to her cognitive function and seizures, respectively. Temporal change in ASL imaging suggested that the hyper perfusion in ASL during the acute stage could be provided by inflammation of the encephalitis its self and also the seizures activities (FBDS and FIAS). The pathophysiological indication of anti-LGI1 encephalitis was limited in terms of the therapeutic strategy, however, our findings collectively suggested that the combination analysis of EEG activity and cerebral blood flow dynamics (ASL) could be the potential candidate.


Assuntos
Autoanticorpos , Autoimunidade , Circulação Cerebrovascular , Eletroencefalografia , Peptídeos e Proteínas de Sinalização Intracelular/imunologia , Encefalite Límbica/diagnóstico , Encefalite Límbica/imunologia , Adulto , Feminino , Humanos , Imunoglobulinas Intravenosas/administração & dosagem , Encefalite Límbica/fisiopatologia , Encefalite Límbica/terapia , Imagem por Ressonância Magnética , Metilprednisolona/administração & dosagem , Pulsoterapia , Marcadores de Spin , Resultado do Tratamento
15.
Nat Commun ; 11(1): 5204, 2020 10 15.
Artigo em Inglês | MEDLINE | ID: mdl-33060576

RESUMO

Toll-like receptor 7 (TLR7) recognizes both microbial and endogenous RNAs and nucleosides. Aberrant activation of TLR7 has been implicated in several autoimmune diseases including systemic lupus erythematosus (SLE). Here, by modifying potent TLR7 agonists, we develop a series of TLR7-specific antagonists as promising therapeutic agents for SLE. These compounds protect mice against lethal autoimmunity. Combining crystallography and cryo-electron microscopy, we identify the open conformation of the receptor and reveal the structural equilibrium between open and closed conformations that underlies TLR7 antagonism, as well as the detailed mechanism by which TLR7-specific antagonists bind to their binding pocket in TLR7. Our work provides small-molecule TLR7-specific antagonists and suggests the TLR7-targeting strategy for treating autoimmune diseases.


Assuntos
Glicoproteínas de Membrana/antagonistas & inibidores , Glicoproteínas de Membrana/química , Receptor 7 Toll-Like/antagonistas & inibidores , Receptor 7 Toll-Like/química , Animais , Doenças Autoimunes , Autoimunidade , Sítios de Ligação , Microscopia Crioeletrônica , Feminino , Ligantes , Lúpus Eritematoso Sistêmico , Camundongos , Camundongos Endogâmicos NZB , Modelos Moleculares , Conformação Proteica , Taxa de Sobrevida
16.
Nat Commun ; 11(1): 5190, 2020 10 15.
Artigo em Inglês | MEDLINE | ID: mdl-33060601

RESUMO

Both higher plants and mammals rely on nucleotide-binding leucine-rich repeat (NLR) immune receptors to detect pathogens and initiate immunity. Upon effector recognition, plant NLRs oligomerize for defense activation, the mechanism of which is poorly understood. We previously showed that disruption of the E3 ligase, Senescence-Associated E3 Ubiquitin Ligase 1 (SAUL1) leads to the activation of the NLR SOC3. Here, we report the identification of suppressor of saul1 2 (susa2) and susa3 from the saul1-1 suppressor screen. Pairwise interaction analysis suggests that both SUSA proteins interact with components of an SCFSUSA2 E3 ligase complex as well as CHS1 or TN2, truncated NLRs that pair with SOC3. susa2-2 only suppresses the autoimmunity mediated by either CHS1 or TN2, suggesting its specific involvement in SOC3-mediated immunity. In summary, our study indicates links between plant NLRs and an SCF complex that may enable ubiquitination and degradation of unknown downstream components to activate defense.


Assuntos
Proteínas de Arabidopsis/metabolismo , Autoimunidade/fisiologia , Proteínas F-Box/metabolismo , Proteínas NLR/metabolismo , Imunidade Vegetal/fisiologia , Receptores Imunológicos/metabolismo , Arabidopsis/metabolismo , Ubiquitina-Proteína Ligases/metabolismo , Ubiquitinação
17.
Eur J Endocrinol ; 183(6): 571-580, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33055303

RESUMO

Objective: Iodide transport across thyrocytes constitutes a critical step for thyroid hormone biosynthesis, mediated mainly by the basolateral sodium-iodide-symporter (NIS (SLC5A5)) and the apical anion exchanger pendrin (PDS (SLC26A4)). Both transmembrane proteins have been described as autoantigens in thyroid disease, yet the reports on autoantibody (aAb) prevalence and diagnostic usefulness are conflicting. Reasons for the inconclusive findings may be small study groups and principle differences in the technologies used. Design: We decided to re-evaluate this important issue by establishing novel non-radioactive tests using full-length antigens and comparable protocols, and analyzing a large cohort of thyroid patients (n = 323) and control samples (n = 400). Methods: NIS and PDS were recombinantly expressed as fusion protein with firefly luciferase (Luc). Stably transfected HEK293 cells were used as reproducible source of the autoantigens. Results: Recombinant NIS-Luc showed iodide transport activity, indicating successful expression and correct processing. Commercial antibodies yielded dose-dependent responses in the newly established assays. Reproducibility of assay signals from patient sera was verified with respect to linearity, stability and absence of matrix effects. Prevalence of PDS-aAb was similar in thyroid patients and controls (7.7% vs 5.0%). NIS-aAb were more prevalent in patients than controls (7.7% vs 1.8%), especially in Graves' Disease (12.3%). Neither NIS-aAb nor PDS-aAb concentrations were related to TPO-aAb or TSH-receptor-aAb concentrations, or to serum zinc or selenium status. Conclusions: Our data highlight a potential relevance of autoimmunity against NIS for thyroid disease, whereas an assessment of PDS-aAb in thyroid patients seems not to be of diagnostic value (yet).


Assuntos
Autoimunidade/fisiologia , Transportadores de Sulfato/sangue , Simportadores/sangue , Doenças da Glândula Tireoide/sangue , Adulto , Estudos de Coortes , Estudos Transversais , Feminino , Células HEK293 , Humanos , Masculino , Transportadores de Sulfato/imunologia , Simportadores/imunologia , Doenças da Glândula Tireoide/imunologia , Hormônios Tireóideos/sangue , Hormônios Tireóideos/imunologia , Adulto Jovem
18.
Indian J Dent Res ; 31(4): 615-620, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33107465

RESUMO

Currently, there is a growing interest in studying systemic conditions associated with periodontal disease such as autoimmune disorders. Periodontal disease is a destructive inflammatory disease of the dental supporting tissues. The microorganisms associated with periodontal disease constitute diverse species that can colonize the oral cavity and influence the emergence or evolution of autoimmunity, characterized by a breakdown in the mechanisms of tolerance to self-antigens. Here, we reviewed and discussed a possible correlation between periodontal disease and autoimmunity, placing periodontal-pathogenic microorganisms as orchestrators of these pathological conditions.


Assuntos
Doenças Autoimunes , Doenças Periodontais , Autoimunidade , Humanos
19.
Nat Commun ; 11(1): 5341, 2020 10 21.
Artigo em Inglês | MEDLINE | ID: mdl-33087723

RESUMO

Autoimmunity can occur when a checkpoint of self-tolerance fails. The study of familial autoimmune diseases can reveal pathophysiological mechanisms involved in more common autoimmune diseases. Here, by whole-exome/genome sequencing we identify heterozygous, autosomal-dominant, germline loss-of-function mutations in the SOCS1 gene in ten patients from five unrelated families with early onset autoimmune manifestations. The intracellular protein SOCS1 is known to downregulate cytokine signaling by inhibiting the JAK-STAT pathway. Accordingly, patient-derived lymphocytes exhibit increased STAT activation in vitro in response to interferon-γ, IL-2 and IL-4 that is reverted by the JAK1/JAK2 inhibitor ruxolitinib. This effect is associated with a series of in vitro and in vivo immune abnormalities consistent with lymphocyte hyperactivity. Hence, SOCS1 haploinsufficiency causes a dominantly inherited predisposition to early onset autoimmune diseases related to cytokine hypersensitivity of immune cells.


Assuntos
Doenças Autoimunes/genética , Doenças Autoimunes/imunologia , Autoimunidade/genética , Proteína 1 Supressora da Sinalização de Citocina/deficiência , Proteína 1 Supressora da Sinalização de Citocina/genética , Adolescente , Adulto , Idade de Início , Doenças Autoimunes/metabolismo , Criança , Pré-Escolar , Citocinas/metabolismo , Feminino , Haploinsuficiência , Humanos , Masculino , Modelos Moleculares , Mutação , Linhagem , Fatores de Transcrição STAT/metabolismo , Transdução de Sinais , Proteína 1 Supressora da Sinalização de Citocina/química , Linfócitos T/imunologia
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