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1.
Medicine (Baltimore) ; 99(1): e18503, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31895784

RESUMO

Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening disease. In clinical practice, we have observed that some HLH patients who have features of systemic autoinflammatory diseases (SAIDs) exhibit unique clinical manifestations and outcomes different from other HLH patients.We analyzed data from 25 HLH patients who were considered to have SAIDs; data were collected from patients of our center between January 1, 2015 and September 1, 2018.The median age of the patients was 1.75 years. In the early phase, all patients had a fever and 92% of patients had a rash; 96% of patients had high white blood cell count (WBC), C-reaction protein, and erythrocyte sedimentation rate. With progression, the above laboratory results decreased gradually. During the HLH period, we compared SAIDs-related HLH and Epstein-Barr virus (EBV)-related HLH and found that rash was more common (92%, P < .001) and splenomegaly was less common (64%, P = .023) in SAIDs-related HLH. Further, WBC, ferritin, and Interleukin-6 levels in SAIDs-related HLH patients were higher than those in EBV-related HLH patients. In contrast, hemoglobin, triglyceride, sCD25, Interleukin-10, and interferon-γ levels in SAIDs-related HLH patients were lower compared with those in EBV-related HLH patients. SAIDs-related HLH patients received a modified HLH-2004 protocol at our center. Most patients had a good prognosis.We provide a summary of the unique clinical and laboratory features, treatment protocols, and outcomes of SAIDs patients with HLH at onset. The findings indicate that these patients had a better response to corticosteroids and cyclosporin compared with EBV-related HLH patients.


Assuntos
Doenças Autoimunes/patologia , Infecções por Vírus Epstein-Barr/patologia , Exantema/etiologia , Herpesvirus Humano 4 , Linfo-Histiocitose Hemofagocítica/patologia , Corticosteroides/uso terapêutico , Doenças Autoimunes/imunologia , Doenças Autoimunes/virologia , Sedimentação Sanguínea , Proteína C-Reativa , Ciclosporina/uso terapêutico , Infecções por Vírus Epstein-Barr/imunologia , Infecções por Vírus Epstein-Barr/virologia , Exantema/patologia , Exantema/virologia , Feminino , Humanos , Lactente , Contagem de Leucócitos , Linfo-Histiocitose Hemofagocítica/imunologia , Linfo-Histiocitose Hemofagocítica/virologia , Masculino , Esplenomegalia/imunologia , Esplenomegalia/virologia , Resultado do Tratamento
2.
Pathologe ; 40(6): 619-626, 2019 Nov.
Artigo em Alemão | MEDLINE | ID: mdl-31641859

RESUMO

IgG4-related disease (IgG4-RD) is a potentially systemic inflammatory and fibrosing disease. Independent of the affected organ, the main histological features are a dense lymphoplasmacytic infiltrate, storiform fibrosis, and obliterative phlebitis. These features are weighted slightly different, dependent on the respective organ. If several of these features are present and changes inconsistent with IgG4-RD are absent, the diagnosis is further supported by the immunohistochemical demonstration of increased IgG4-positive plasma cells and an elevated IgG4-IgG ratio, as well as serologically by elevated IgG4 levels. A tissue biopsy is often mandatory for the diagnosis, as IgG4-RD clinically and radiologically can imitate a malignant tumor.


Assuntos
Doenças Autoimunes , Doença Relacionada a Imunoglobulina G4 , Doenças Autoimunes/patologia , Diagnóstico Diferencial , Humanos , Imunoglobulina G , Doença Relacionada a Imunoglobulina G4/patologia , Plasmócitos
4.
Intern Med ; 58(20): 2907-2913, 2019 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-31292380

RESUMO

Objective To evaluate the prevalence of autoimmune gastritis in patients with histologically proven nonalcoholic steatohepatitis (NASH). Methods A total of 33 patients with NASH and 143 patients with chronic liver disease (66, 24, 22, 10, 1, and 21 patients with hepatitis C, hepatitis B, autoimmune hepatitis/primary biliary cholangitis, non-B/non-C hepatitis, fatty liver, and alcoholic disease, respectively) who underwent upper gastrointestinal endoscopy between January 2013 and August 2016 were retrospectively assessed to determine the prevalence of autoimmune gastritis. The clinical characteristics of these patients with NASH and autoimmune gastritis were examined, and the clinical characteristic and biomarkers were compared between patients with NASH with and without autoimmune gastritis. Results Six of the 33 patients with NASH (19.4%) were diagnosed with autoimmune gastritis. The prevalence of autoimmune gastritis was higher in patients with NASH than in those with other chronic liver diseases [4/143 (2.8%), p=0.002]. All six patients with NASH and autoimmune gastritis exhibited high serum gastrin levels; five of the patients were positive for anti-parietal cell antibodies, and one was negative for anti-parietal cell antibodies but positive for intrinsic factor antibody. Furthermore, 1 patient presented with iron-deficiency anemia (hemoglobin <11 g/dL), but none developed pernicious anemia. Endocrine cell micronests were found in four patients. Patients with NASH and autoimmune gastritis tended to be older with lower ferritin levels than the other patients. Conclusion The prevalence of NASH with concomitant autoimmune gastritis was high, highlighting the need for upper endoscopy for the diagnosis of autoimmune gastritis and gastric malignancies.


Assuntos
Doenças Autoimunes/complicações , Gastrite/complicações , Hepatopatia Gordurosa não Alcoólica/complicações , Adulto , Idoso , Anemia Ferropriva/complicações , Autoanticorpos/sangue , Doenças Autoimunes/diagnóstico , Doenças Autoimunes/patologia , Biópsia , Endoscopia Gastrointestinal , Feminino , Gastrite/diagnóstico , Gastrite/patologia , Humanos , Fígado/patologia , Masculino , Pessoa de Meia-Idade , Hepatopatia Gordurosa não Alcoólica/patologia , Prevalência , Estudos Retrospectivos
5.
Mini Rev Med Chem ; 19(18): 1531-1543, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31288716

RESUMO

The search for inhibitors of the Janus kinase family (JAK1, JAK2, JAK3 and TYK2) has been ongoing for several decades and has resulted in a number of JAK inhibitors being approved for use in patients, such as tofacitinib for the treatment of autoimmune diseases such as Rheumatoid Arthritis (RA). Although initially thought to be a JAK3 selective inhibitor, tofacitinib was subsequently found to possess significant activity to inhibit JAK1 and JAK2 which has contributed to some adverse side effects. A selective JAK3 inhibitor should only have an effect within the immune system since JAK3 is solely expressed in lymphoid tissue; this makes JAK3 a target of interest in the search for treatments of autoimmune diseases. A method to obtain selectivity for JAK3 over the other JAK family members, which has attracted more scientific attention recently, is the targeting of the active site cysteine residue, unique in JAK3 within the JAK family, with compounds containing electrophilic warheads which can form a covalent bond with the nucleophilic thiol of the cysteine residue. This review encompasses the historical search for a covalent JAK3 inhibitor and the most recently published research which hasn't been reviewed to date. The most important compounds from the publications reviewed the activity and selectivity of these compounds together with some of the more important biological results are condensed in to an easily digested form that should prove useful for those interested in the field.


Assuntos
Janus Quinase 3/antagonistas & inibidores , Inibidores de Proteínas Quinases/química , Amidas/química , Amidas/metabolismo , Amidas/uso terapêutico , Doenças Autoimunes/tratamento farmacológico , Doenças Autoimunes/patologia , Derivados de Benzeno/química , Derivados de Benzeno/metabolismo , Derivados de Benzeno/uso terapêutico , Avaliação Pré-Clínica de Medicamentos , Humanos , Janus Quinase 3/metabolismo , Ligação Proteica , Inibidores de Proteínas Quinases/metabolismo , Inibidores de Proteínas Quinases/uso terapêutico
6.
Muscle Nerve ; 60(3): 315-327, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31172530

RESUMO

INTRODUCTION: The molecular mechanism of immune-mediated necrotizing myopathy (IMNM) remains unknown. Autophagy impairment, described in autoimmune diseases, is a key process in myofiber protein degradation flux and muscle integrity and has not been studied in IMNM. METHODS: Muscle biopsies from patients with IMNM (n = 40), dermatomyositis (DM; 24), polymyositis (PM; 8), polymyositis with mitochondrial pathology (4), sporadic inclusion body myositis (8), and controls (6) were compared by immunohistochemistry. RESULTS: The proportions of myofibers containing autophagy markers LC3b and p62 were higher in IMNM than in DM or PM and correlated with creatine kinase levels. In IMNM, compartmentalized LC3b puncta were located in regenerating and degenerating myofibers surrounded by major histocompatibility complex type II+ inflammatory cells. Several IMNM myofibers accumulated ubiquitin and misfolded protein. DISCUSSION: The detection of LC3b+ or p62+ myofibers could be used in differentiating IMNM from PM. The identification of autophagy-modifying molecules potentially could improve patients' outcomes. Muscle Nerve, 2019.


Assuntos
Autofagia/imunologia , Músculo Esquelético/patologia , Miosite/imunologia , Miosite/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Doenças Autoimunes/imunologia , Doenças Autoimunes/patologia , Biópsia , Dermatomiosite/patologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Miosite de Corpos de Inclusão/patologia , Polimiosite/imunologia , Polimiosite/patologia
7.
J Low Genit Tract Dis ; 23(3): 235-240, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31149956

RESUMO

OBJECTIVES: The aim of the study was to review uncommon foreskin dermatopathology conditions clinically and pathologically. METHODS: A database search of PubMed and Google Scholar were extracted between March 1, 2009, and March 1, 2019, using the search terms "foreskin," "prepuce," "penis," "pathology," "dermatology," and "rare." The search was limited to "humans" and "dermatopathology." Full article texts were reviewed. Reference lists were screened for additional articles. Patient details (diagnosis, dermatopathology, treatment, and follow-up if available) were extracted. We excluded articles written in the non-English language, unusual variants of common conditions, and cases of common dermatologic conditions. RESULTS: A list of 369 articles was identified and another screening identified 30 articles for rare foreskin pathologies. Those are divided into categories based on the following etiologies: (a) benign, including congenital (e.g., aposthia), infectious (graft versus host disease and histoplasma), autoimmune (Crohn's disease and pyoderma gangrenosum), and benign neoplasms (neurofibroma, apocrine hidrocystoma, verruciform xanthoma, porokeratosis, penile cutaneous horn, localized amyloidosis) and (b) malignancies, including primary (myeloid sarcoma, basal cell carcinoma, Kaposi's sarcoma, mucosal-associated lymphoid tissue lymphoma), and metastasis. CONCLUSIONS: We reviewed and discussed unusual benign and malignant dermatopathology conditions that can affect the foreskin.


Assuntos
Doenças Autoimunes/patologia , Dermatite/patologia , Prepúcio do Pênis/anormalidades , Prepúcio do Pênis/patologia , Neoplasias/patologia , Neoplasias Penianas/patologia , Adulto , Idoso , Doenças Autoimunes/epidemiologia , Criança , Pré-Escolar , Dermatite/epidemiologia , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias/epidemiologia , Neoplasias Penianas/epidemiologia
8.
MAbs ; 11(6): 1175-1190, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31181988

RESUMO

We describe a bispecific dual-antagonist antibody against human B cell activating factor (BAFF) and interleukin 17A (IL-17). An anti-IL-17 single-chain variable fragment (scFv) derived from ixekizumab (Taltz®) was fused via a glycine-rich linker to anti-BAFF tabalumab. The IgG-scFv bound both BAFF and IL-17 simultaneously with identical stoichiometry as the parental mAbs. Stability studies of the initial IgG-scFv revealed chemical degradation and aggregation not observed in either parental antibody. The anti-IL-17 scFv showed a high melting temperature (Tm) by differential scanning calorimetry (73.1°C), but also concentration-dependent, initially reversible, protein self-association. To engineer scFv stability, three parallel approaches were taken: labile complementary-determining region (CDR) residues were replaced by stable, affinity-neutral amino acids, CDR charge distribution was balanced, and a H44-L100 interface disulfide bond was introduced. The Tm of the disulfide-stabilized scFv was largely unperturbed, yet it remained monodispersed at high protein concentration. Fluorescent dye binding titrations indicated reduced solvent exposure of hydrophobic residues and decreased proteolytic susceptibility was observed, both indicative of enhanced conformational stability. Superimposition of the H44-L100 scFv (PDB id: 6NOU) and ixekizumab antigen-binding fragment (PDB id: 6NOV) crystal structures revealed nearly identical orientation of the frameworks and CDR loops. The stabilized bispecific molecule LY3090106 (tibulizumab) potently antagonized both BAFF and IL-17 in cell-based and in vivo mouse models. In cynomolgus monkey, it suppressed B cell development and survival and remained functionally intact in circulation, with a prolonged half-life. In summary, we engineered a potent bispecific antibody targeting two key cytokines involved in human autoimmunity amenable to clinical development.


Assuntos
Anticorpos Biespecíficos , Doenças Autoimunes/tratamento farmacológico , Fator Ativador de Células B/antagonistas & inibidores , Interleucina-17/antagonistas & inibidores , Anticorpos de Cadeia Única , Animais , Anticorpos Biespecíficos/imunologia , Anticorpos Biespecíficos/farmacologia , Anticorpos Monoclonais Humanizados/imunologia , Anticorpos Monoclonais Humanizados/farmacologia , Doenças Autoimunes/imunologia , Doenças Autoimunes/patologia , Fator Ativador de Células B/imunologia , Feminino , Células HEK293 , Células HT29 , Humanos , Interleucina-17/imunologia , Macaca fascicularis , Camundongos , Camundongos Transgênicos , Anticorpos de Cadeia Única/imunologia , Anticorpos de Cadeia Única/farmacologia
9.
Zhonghua Gan Zang Bing Za Zhi ; 27(5): 393-396, 2019 May 20.
Artigo em Chinês | MEDLINE | ID: mdl-31177668

RESUMO

Autoimmune cholangitis (AIC) was first reported in 1987 as a chronic cholestatic disease that occurs predominantly in middle-aged women and has a common clinical manifestations, biochemical abnormalities and pathological changes with primary biliary cholangitis (PBC). However, serum anti-mitochondrial antibodies (AMA) are negative, and ANA and/or smooth muscle antibody positive rates are higher. The treatment response and prognosis with ursodeoxycholic acid and steroids is poor, thus it needs to be treated with immunosuppressive agents. Presently, the exact pathological mechanism of AIC is still unclear, and there is no unified assertion that classifies it as a new autoimmune liver disease or AMA-negative PBC. This article reviews the worldwide published work on AIC and compares them with PBC.


Assuntos
Autoanticorpos/imunologia , Doenças Autoimunes/patologia , Colangite/patologia , Cirrose Hepática Biliar/imunologia , Anticorpos Antinucleares/imunologia , Doenças Autoimunes/imunologia , Colangite/imunologia , Feminino , Humanos , Pessoa de Meia-Idade
10.
Prostate ; 79(12): 1439-1449, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31233226

RESUMO

BACKGROUND: Chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) is a prevalent disease of the urogenital system. Alcohol has been reported to be closely related to CP/CPPS. Thus, we intended to verify the role of alcohol in CP/CPPS and determine the underlying mechanism. METHODS: We induced experimental autoimmune prostatitis (EAP) mouse model by intradermally injecting a mixture of prostate antigens (PAgs) and complete Freund's adjuvant on days 0 and 28. Mice were treated with alcohol (control-alcohol and EAP-alcohol groups) or vehicle (control-vehicle, and EAP-vehicle groups) from day 32 to 42. Forty-two days after PAg injection, the pathological appearance of the prostate tissues was evaluated, and histological analyses of the prostate were performed. Chronic pelvic pain was assessed by applying von Frey filaments to the lower abdomen. Proinflammatory cytokines were detected by enzyme-linked immunosorbent assay tests. Then, we explored the effects of the NLRP3 inhibitor MCC950 on chronic pelvic pain and prostatic inflammation in this model. RESULTS: Histological analyses showed diffuse inflammation in the stromal tissues that were characterized by severe infiltration of neutrophils and mononuclear cells in mice in the EAP-alcohol group compared with EAP-vehicle group. Chronic pain tests showed that the response frequency was significantly increased using a von Frey filament at forces of 0.4, 1.0, and 4.0 g in EAP-alcohol group compared with EAP-vehicle (P < .05). The levels of proinflammatory cytokines, including interferon (IFN)-γ, tumor necrosis factor (TNF)-α, IL-17, and IL-1ß were all significantly elevated in EAP-alcohol group compared with the EAP-vehicle group (P < .05). However, between the control-alcohol and control-vehicle groups, chronic pain tests, histological assays, and cytokine determinations showed no differences. Furthermore, our results demonstrated that MCC950 could decrease the expression level of NLRP3 inflammasome-related proteins including NLRP3, ASC, and caspase-1. The chronic pain tests, histological assays, and cytokine determinations showed that MCC950 could attenuate the chronic pain and prostatic inflammation through the inhibition of the NLRP3 inflammasome. CONCLUSIONS: This study indicated that alcohol could aggravate the severity of prostatic inflammation in EAP model though activating the NLRP3 inflammasome. Furthermore, the role of MCC950 in inhibiting NLRP3 inflammasome and decreasing IL-1ß secretion to alleviate EAP severity may show that it is a promising therapeutic agent for CP/CPPS.


Assuntos
Doenças Autoimunes/imunologia , Etanol/farmacologia , Dor Pélvica/imunologia , Próstata/imunologia , Prostatite/imunologia , Álcoois/farmacologia , Animais , Doenças Autoimunes/patologia , Dor Crônica/imunologia , Citocinas/imunologia , Modelos Animais de Doenças , Furanos/farmacologia , Inflamassomos/imunologia , Inflamação/imunologia , Masculino , Camundongos , Proteína 3 que Contém Domínio de Pirina da Família NLR/imunologia , Próstata/efeitos dos fármacos , Próstata/patologia , Prostatite/patologia , Ratos , Ratos Wistar , Sulfonamidas/farmacologia
12.
Mol Med Rep ; 20(1): 171-181, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31115534

RESUMO

Circulating microRNAs (miRNAs) have been suggested as non­invasive biomarkers for the diagnosis of several autoimmune diseases. However, to the best of our knowledge, no studies have yet examined the miRNA expression profiles in autoimmune inner ear disease (AIED). The present study aimed to use an miRNA sequencing assay to detect the miRNA expression profiles of serum samples from 3 control mice and 3 antigen­induced AIED model mice. Differentially expressed miRNAs (DE­miRNAs) were screened using a t­test. miRNA target prediction was performed using TargetScan Mouse. Then, the miRNA­target gene interaction network was constructed and visualized using Cytoscape software. The underlying functions of the target genes of the DE­miRNAs were predicted using the clusterProfiler package. As a result, 22 miRNAs were identified as DE­miRNAs between AIED and control mice, including 10 upregulated and 12 downregulated genes. Based on the TargetScan Mouse prediction, 1,958 genes were identified as the targets for the 22 DE­miRNAs. Functional analysis indicated that only the target genes of 8 miRNAs were respectively enriched for Gene Ontology terms and Kyoto Encyclopedia of Genes and Genomes pathways, among which miR­10b­3p, let­7j and miR­8112 were shared between the two pathway analyses. These 3 miRNAs may be involved in AIED by affecting inflammatory chemokine (miR­10b­3p­C­C motif chemokine 12), Wnt signaling (miR­8112­Wnt9b/Wnt 3a/Wnt2b) and Mucin type O­glycan biosynthesis pathways (let­7j­Galnt2/Galnt12). In conclusion, miR­10b­3p, miR­8112 and let­7j may be underlying biomarkers for diagnosing AIED.


Assuntos
Doenças Autoimunes/sangue , Doenças do Labirinto/sangue , MicroRNAs/sangue , Animais , Doenças Autoimunes/genética , Doenças Autoimunes/patologia , Biomarcadores/sangue , MicroRNA Circulante/sangue , Biologia Computacional , Feminino , Perfilação da Expressão Gênica/métodos , Redes Reguladoras de Genes , Humanos , Doenças do Labirinto/genética , Doenças do Labirinto/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , MicroRNAs/genética , Transdução de Sinais/genética , Software
13.
BMJ Case Rep ; 12(5)2019 May 28.
Artigo em Inglês | MEDLINE | ID: mdl-31142488

RESUMO

Necrotising autoimmune myopathy (NAM) is characterised by a common phenotype of profound symmetrical proximal muscle weakness, elevated creatine kinase levels, irritable myopathy on electromyography and histological findings of myocyte necrosis and regeneration without remarkable inflammation. NAM is associated with autoimmune antibodies including anti-3-hydroxy-3-methylglutaryl-coenzyme receptor, which is strongly associated with statin use. We report a case of statin-associated NAM with an atypical presentation of severe oropharyngeal dysphagia and no remarkable proximal muscle weakness at initial presentation but with rapid progression to severe quadriparesis in weeks. This case expands the spectrum of presentation patterns of this rare disease and highlights the need for a high index of suspicion in patients with a remote history of statin use.


Assuntos
Doenças Autoimunes/complicações , Debilidade Muscular/etiologia , Miosite/complicações , Idoso , Autoanticorpos/metabolismo , Doenças Autoimunes/patologia , Doenças Autoimunes/terapia , Transtornos de Deglutição/etiologia , Transtornos de Deglutição/patologia , Transtornos de Deglutição/terapia , Diagnóstico Diferencial , Evolução Fatal , Humanos , Masculino , Fibras Musculares Esqueléticas/fisiologia , Debilidade Muscular/patologia , Debilidade Muscular/terapia , Miosite/patologia , Miosite/terapia , Necrose/patologia , Doenças Raras
14.
Nat Commun ; 10(1): 2261, 2019 05 21.
Artigo em Inglês | MEDLINE | ID: mdl-31113940

RESUMO

Cyclic GMP-AMP synthase (cGAS) is the primary sensor for aberrant intracellular dsDNA producing the cyclic dinucleotide cGAMP, a second messenger initiating cytokine production in subsets of myeloid lineage cell types. Therefore, inhibition of the enzyme cGAS may act anti-inflammatory. Here we report the discovery of human-cGAS-specific small-molecule inhibitors by high-throughput screening and the targeted medicinal chemistry optimization for two molecular scaffolds. Lead compounds from one scaffold co-crystallize with human cGAS and occupy the ATP- and GTP-binding active site. The specificity and potency of these drug candidates is further documented in human myeloid cells including primary macrophages. These novel cGAS inhibitors with cell-based activity will serve as probes into cGAS-dependent innate immune pathways and warrant future pharmacological studies for treatment of cGAS-dependent inflammatory diseases.


Assuntos
Descoberta de Drogas/métodos , Inibidores Enzimáticos/farmacologia , Nucleotidiltransferases/antagonistas & inibidores , Doenças Autoimunes/tratamento farmacológico , Doenças Autoimunes/imunologia , Doenças Autoimunes/patologia , Células Cultivadas , Cristalografia por Raios X , DNA/imunologia , DNA/metabolismo , Inibidores Enzimáticos/química , Inibidores Enzimáticos/uso terapêutico , Ensaios de Triagem em Larga Escala/métodos , Humanos , Imunidade Inata/efeitos dos fármacos , Interferons/imunologia , Interferons/metabolismo , Macrófagos , Modelos Moleculares , Nucleotídeos Cíclicos/imunologia , Nucleotídeos Cíclicos/metabolismo , Nucleotidiltransferases/imunologia , Nucleotidiltransferases/isolamento & purificação , Nucleotidiltransferases/metabolismo , Cultura Primária de Células , Proteínas Recombinantes/imunologia , Proteínas Recombinantes/isolamento & purificação , Proteínas Recombinantes/metabolismo
15.
EBioMedicine ; 43: 620-631, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31076346

RESUMO

BACKGROUND: Bone destruction is one of many severe complications that occurs in patients with rheumatoid arthritis (RA) and current therapies are unable to cure this manifestation. This study here aims to determine whether GMSC can directly inhibit osteoclast formation and eventually attenuate osteoclastogenesis and bone erosion in an inflammatory milieu. METHOD: GMSC were co-cultured with osteoclast precursors with or without CD39 inhibitor, CD73 inhibitor or adenosine receptors inhibitors pretreatment and osteoclast formation were evaluated in vitro. 2×10^6 GMSC per mouse were transferred to CIA mice and pathology scores, the frequency of osteoclasts, bone erosion in joints were assessed in vivo. FINDING: GMSC but not control cells, markedly suppressed human or mice osteoclastogenesis in vitro. GMSC treatment also resulted in a dramatically decreased level of NF-κB p65/p50 in osteoclasts in vitro. Infusion of GMSC to CIA significantly attenuated the severity of arthritis, pathology scores, frequency of osteoclasts, particularly bone erosion, as well as a decreased expression of RANKL in synovial tissues in vivo. Blockade of CD39/CD73 or adenosine receptors has significantly abrogated the suppressive ability of GMSC in vitro and therapeutic effect of GMSC on bone erosion during CIA in vivo. INTERPRETATION: GMSC inhibit osteoclast formation in vitro and in vivo partially via CD39-CD73-adenosine signals. Manipulation of GMSC may have a therapeutic implication on rheumatoid arthritis and other bone erosion related diseases. FUND: This study was supported by grants from the National Key R&D Program of China (2017YFA0105801 to F.H); the Zhujiang Innovative and Entrepreneurial Talent Team Award of Guangdong Province (2016 ZT 06S 252 to F·H) and National Institutes of Health (R01 AR059103, R61 AR073409 and NIH Star Award to S.G.Z).


Assuntos
Adenosina/metabolismo , Antígenos CD/metabolismo , Apirase/metabolismo , Gengiva/citologia , Células-Tronco Mesenquimais/citologia , Células-Tronco Mesenquimais/metabolismo , Osteogênese , Transdução de Sinais , Animais , Artrite Experimental , Artrite Reumatoide/diagnóstico por imagem , Artrite Reumatoide/etiologia , Artrite Reumatoide/metabolismo , Artrite Reumatoide/patologia , Doenças Autoimunes/diagnóstico por imagem , Doenças Autoimunes/etiologia , Doenças Autoimunes/metabolismo , Doenças Autoimunes/patologia , Biomarcadores , Linhagem Celular , Feminino , Fibroblastos/metabolismo , Humanos , Camundongos , Osteoclastos/metabolismo , Tomografia Computadorizada por Raios X
16.
Dig Dis ; 37(5): 416-421, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31079114

RESUMO

BACKGROUND: Diagnosis of pancreatic cancer (PC) in early stages is still challenging for gastroenterologists. The early detection of cancer is one of the utmost importance for the successful therapy of this malignancy. An accurate differential diagnosis of focal pancreatic lesions plays also an important role, whether it is differential diagnosis of chronic pancreatitis from PC or autoimmune pancreatitis (AIP) from PC. Raised serum immunoglobulin G4 (IgG4) levels to twice the normal value are considered one of significant diagnostic features of type 1 AIP. However, IgG4 can be increased also in patients with PC, but levels usually do not exceed twice the normal value. METHODS: In years 2012-2017, IgG4 serum levels were examined in 115 patients with histologically confirmed PC. Patients with PC and elevated IgG4 level (above 135 mg/dL) had tested their histological resection specimens or bioptic specimens from pancreatic lesion, with targeted detection of the presence of IgG4 and plasmocytes in the pancreatic tissue and changes characteristic for type 1 AIP. RESULTS: A plasmatic IgG4 level in 115 patients with diagnosed PC was higher than 135 mg/dL in 14 patients (12.2%). Out of them, 2 patients (1.7%) revealed a serum IgG4 level higher than double the normal value, that is, higher than 270.0 mg/dL (suggestive of AIP). One patient met histological criteria for diagnosis of AIP in the simultaneous presence of PC. CONCLUSION: Diagnosis of early cancer stages, particularly differentiating AIP from PC can be sometimes problematic. IgG4 levels can be slightly elevated also in case of PC. A targeted biopsy of the pancreas is the method of choice in cases suspected from a focal form of AIP and we recommend to prefer it over other modalities, such as, for example, response to steroid therapy.


Assuntos
Doenças Autoimunes/diagnóstico , Neoplasias Pancreáticas/diagnóstico , Pancreatite Crônica/diagnóstico , Idoso , Doenças Autoimunes/sangue , Doenças Autoimunes/diagnóstico por imagem , Doenças Autoimunes/patologia , Doença Crônica , Diagnóstico Diferencial , Endossonografia , Feminino , Humanos , Imunoglobulina G/sangue , Masculino , Pessoa de Meia-Idade , Neoplasias Pancreáticas/sangue , Neoplasias Pancreáticas/diagnóstico por imagem , Neoplasias Pancreáticas/patologia , Pancreatite Crônica/sangue , Pancreatite Crônica/diagnóstico por imagem , Pancreatite Crônica/patologia
17.
J Am Acad Dermatol ; 81(2): 355-363, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31009674

RESUMO

BACKGROUND: Nonbullous pemphigoid is an under-recognized phenotype of the autoimmune bullous disease pemphigoid, characterized by the absence of blisters. Several disease aspects have not been studied previously. OBJECTIVE: To describe the characteristics of nonbullous pemphigoid. METHODS: A retrospective review study of medical records. The diagnosis of pemphigoid was based on meeting 2 of the following 3 criteria: (1) pruritus, (2) positive direct immunofluorescence microscopy, or (3) positive indirect immunofluorescence microscopy on salt-split skin. RESULTS: The review included 69 patients. The mean delay in diagnosis was 29 months. Skin examination most often showed pruritic papules/nodules (37%) or pruritus without primary skin lesions (22%). Histopathologic findings were mainly nonspecific. Results of direct and indirect immunofluorescence microscopy were positive in 60% and 69%, respectively. During follow-up, blisters formed in 17%, which was associated with a positive indirect immunofluorescence microscopy (P = .014) and a positive BP180 immunoblot result (P = .032). The Kaplan-Meier estimates of mortality at 1, 2, and 3 years were 14%, 34%, and 46%, respectively, with an 8.6-fold increased all-cause mortality risk. LIMITATIONS: The retrospective study design. CONCLUSIONS: Nonbullous pemphigoid presented with heterogeneous pruritic skin lesions, resulting in delayed diagnosis. Direct and indirect immunofluorescence microscopy are essential to diagnose nonbullous pemphigoid, in contrast to histopathology, mainly showing nonspecific findings. An increased all-cause mortality risk was observed during follow-up.


Assuntos
Autoanticorpos/sangue , Autoantígenos/imunologia , Doenças Autoimunes/diagnóstico , Distonina/imunologia , Colágenos não Fibrilares/imunologia , Dermatopatias/diagnóstico , Adulto , Idoso , Idoso de 80 Anos ou mais , Doenças Autoimunes/imunologia , Doenças Autoimunes/patologia , Diagnóstico Tardio , Feminino , Técnica Direta de Fluorescência para Anticorpo , Técnica Indireta de Fluorescência para Anticorpo , Humanos , Estimativa de Kaplan-Meier , Masculino , Microscopia de Fluorescência , Pessoa de Meia-Idade , Prognóstico , Prurido/etiologia , Estudos Retrospectivos , Dermatopatias/imunologia , Dermatopatias/patologia , Taxa de Sobrevida
18.
Autoimmun Rev ; 18(6): 593-606, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30959208

RESUMO

Systemic vasculitis is diverse group of autoimmune disorders which are characterized by inflammation of blood vessel walls with deep aching and burning pain. Their underlying etiology and pathophysiology still remain poorly understood. Extracellular vesicles (EVs), including exosomes, microvesicles (MVs), and apoptotic bodies, are membrane vesicular structures that are released either during cell activation, or when cells undergo programmed cell death, including apoptosis, necroptosis, and pyroptosis. Although EVs were thought as cell dusts, but now they have been found to be potently active since they harbor bioactive molecules, such as proteins, lipids, nucleic acids, or multi-molecular complexes. EVs can serve as novel mediators for cell-to-cell communications by delivery bioactive molecules from their parental cells to the recipient cells. Earlier studies mainly focused on MVs budding from membrane surface. Recent studies demonstrated that EVs may also carry molecules from cytoplasm or even from nucleus of their parental cells, and these EVs may carry autoantigens and are important in vasculitis. EVs may play important roles in vasculitis through their potential pathogenic involvements in inflammation, autoimmune responses, procoagulation, endothelial dysfunction/damage, angiogenesis, and intimal hyperplasia. EVs have also been used as specific biomarkers for diagnostic use or disease severity monitoring. In this review, we have focused on the aspects of EV biology most relevant to the pathogenesis of vasculitis, discussed their perspective insights, and summarized the exist literature on EV relevant studies in vasculitis, therefore provides an integration of current knowledge regarding the novel role of EVs in systemic vasculitis.


Assuntos
Doenças Autoimunes/patologia , Vesículas Extracelulares/patologia , Vasculite Sistêmica/patologia , Humanos
19.
J Cutan Pathol ; 46(9): 653-658, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30989699

RESUMO

BACKGROUND: Alopecia areata (AA) is believed to have an autoimmune mechanism in which the hair follicles are targeted by CD4+ and CD8+ lymphocytes. Studies investigating the autoimmune mechanism of other cutaneous diseases, including vitiligo, showed that Treg is a component of cutaneous immune privilege. Our study uses immunohistochemical staining in formalin-fixed, paraffin-embedded tissue to examine the percentage of CD4+ FoxP3+ , CD25+ FoxP3+ , and CD8+ FoxP3+ Treg in AA in human specimens. METHODS: Immunohistochemical double staining for CD4+ FoxP3+ , CD25+ FoxP3+ , and CD8+ FoxP3+ was performed on 12 AA cases and 12 other autoimmune and non-autoimmune cutaneous diseases. The frequency of CD4+ FoxP3+ , CD25+ FoxP3+ , and CD8+ FoxP3+ Treg was counted and expressed as a percentage of total CD4+ , CD25+ , and CD8+ lymphocytes, respectively, in order to account for intersample inflammatory response variability. RESULTS: There was a significant reduction in the mean frequency of CD4+ FoxP3+ and CD25+ FoxP3+ in AA when compared to other autoimmune and non-autoimmune cutaneous diseases. CONCLUSION: Treg is significantly lower in AA when compared to other cutaneous diseases. Additionally, this immunohistochemical-staining protocol may be useful to evaluate Treg in formalin-fixed, paraffin-embedded specimens for other cutaneous diseases. Studies examining Treg in AA and other cutaneous diseases may have implications for future interventions.


Assuntos
Alopecia em Áreas/imunologia , Doenças Autoimunes/imunologia , Folículo Piloso/imunologia , Linfócitos T Reguladores/imunologia , Alopecia em Áreas/patologia , Doenças Autoimunes/patologia , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/patologia , Feminino , Folículo Piloso/patologia , Humanos , Masculino , Linfócitos T Reguladores/patologia
20.
J Immunol ; 202(8): 2177-2187, 2019 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-30962309

RESUMO

Inflammasomes are protein complexes that respond to a wide range of pathogens and cellular damage signals. Their activation prompts the caspase-1-mediated cleavage of the proinflammatory cytokines IL-1ß and IL-18. Inflammasome dysregulation has been demonstrated to play a role in a range of diseases involving the adaptive immune system like multiple sclerosis, rheumatic diseases, and type 1 diabetes. Priming and activation of inflammasomes can be modulated by microRNAs (miRNAs), small noncoding RNAs that regulate gene expression posttranscriptionally. miRNAs, such as miR-223-3p, have been demonstrated to directly target the inflammasome components NLRP3, caspase-1, and caspase-8. Other miRNAs like miR-155-5p modulate TLR-, IL-1R-, TNFR-, and IFNAR-mediated signaling pathways upstream of the inflammasomes. In this study, we discuss how a more detailed elucidation of miRNA-driven inflammasome regulation helps in understanding the molecular processes underlying immune-mediated human diseases, holds potential for the identification of biomarkers and may offer novel targets for the development of future therapeutics.


Assuntos
Doenças Autoimunes/imunologia , Inflamassomos/imunologia , MicroRNAs/imunologia , Transdução de Sinais/imunologia , Doenças Autoimunes/patologia , Caspase 1/imunologia , Caspase 8/imunologia , Humanos , Proteína 3 que Contém Domínio de Pirina da Família NLR/imunologia , Receptores de Interleucina/imunologia , Receptores Toll-Like/imunologia
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