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1.
Blood Adv ; 6(24): 6249-6262, 2022 12 27.
Artigo em Inglês | MEDLINE | ID: mdl-35977099

RESUMO

Clinical manifestations of severe COVID-19 include coagulopathies that are exacerbated by the formation of neutrophil extracellular traps (NETs). Here, we report that pulmonary lymphatic vessels, which traffic neutrophils and other immune cells to the lung-draining lymph node (LDLN), can also be blocked by fibrin clots in severe COVID-19. Immunostained tissue sections from COVID-19 decedents revealed widespread lymphatic clotting not only in the lung but also in the LDLN, where the extent of clotting correlated with the presence of abnormal, regressed, or missing germinal centers (GCs). It strongly correlated with the presence of intralymphatic NETs. In mice, tumor necrosis factor α induced intralymphatic fibrin clots; this could be inhibited by DNase I, which degrades NETs. In vitro, TNF-α induced lymphatic endothelial cell upregulation of ICAM-1 and CXCL8, among other neutrophil-recruiting factors, as well as thrombomodulin downregulation; in decedents, lymphatic clotting in LDLNs. In a separate cohort of hospitalized patients, serum levels of Myeloperoxidase-DNA (MPO-DNA, a NET marker) inversely correlated with antiviral antibody titers, but D-dimer levels, indicative of blood thrombosis, did not correlate with either. Patients with high MPO-DNA but low D-dimer levels generated poor antiviral antibody titers. This study introduces lymphatic coagulation in lungs and LDLNs as a clinical manifestation of severe COVID-19 and suggests the involvement of NETosis of lymphatic-trafficking neutrophils. It further suggests that lymphatic clotting may correlate with impaired formation or maintenance of GCs necessary for robust antiviral antibody responses, although further studies are needed to determine whether and how lymphatic coagulation affects adaptive immune responses.


Assuntos
COVID-19 , Armadilhas Extracelulares , Trombose , Camundongos , Animais , Trombose/metabolismo , Pulmão/metabolismo , DNA/metabolismo , Linfonodos
2.
Cells ; 11(6)2022 03 12.
Artigo em Inglês | MEDLINE | ID: mdl-35326430

RESUMO

Lymphatic vessels provide a critical line of communication between peripheral tissues and their draining lymph nodes, which is necessary for robust immune responses against infectious agents. At the same time, lymphatics help shape the nature and kinetics of immune responses to ensure resolution, limit tissue damage, and prevent autoimmune responses. A variety of pathogens have developed strategies to exploit these functions, from multicellular organisms like nematodes to bacteria, viruses, and prions. While lymphatic vessels serve as transport routes for the dissemination of many pathogens, their hypoxic and immune-suppressive environments can provide survival niches for others. Lymphatics can be exploited as perineural niches, for inter-organ distribution among highly motile carrier cells, as effective replicative niches, and as alternative routes in response to therapy. Recent studies have broadened our understanding of lymphatic involvement in pathogenic spread to include a wider range of pathogens, as well as new mechanisms of exploitation, which we summarize here.


Assuntos
Linfonodos , Vasos Linfáticos , Autoimunidade , Imunidade , Sistema Linfático
3.
PLoS One ; 4(9): e6952, 2009 Sep 18.
Artigo em Inglês | MEDLINE | ID: mdl-19763259

RESUMO

BACKGROUND: Processing by gamma-secretase of many type-I membrane protein substrates triggers signaling cascades by releasing intracellular domains (ICDs) that, following nuclear translocation, modulate the transcription of different genes regulating a diverse array of cellular and biological processes. Because the list of gamma-secretase substrates is growing quickly and this enzyme is a cancer and Alzheimer's disease therapeutic target, the mapping of gamma-secretase activity susceptible gene transcription is important for sharpening our view of specific affected genes, molecular functions and biological pathways. METHODOLOGY/PRINCIPAL FINDINGS: To identify genes and molecular functions transcriptionally affected by gamma-secretase activity, the cellular transcriptomes of Chinese hamster ovary (CHO) cells with enhanced and inhibited gamma-secretase activity were analyzed and compared by cDNA microarray. The functional clustering by FatiGO of the 1,981 identified genes revealed over- and under-represented groups with multiple activities and functions. Single genes with the most pronounced transcriptional susceptibility to gamma-secretase activity were evaluated by real-time PCR. Among the 21 validated genes, the strikingly decreased transcription of PTPRG and AMN1 and increased transcription of UPP1 potentially support data on cell cycle disturbances relevant to cancer, stem cell and neurodegenerative diseases' research. The mapping of interactions of proteins encoded by the validated genes exclusively relied on evidence-based data and revealed broad effects on Wnt pathway members, including WNT3A and DVL3. Intriguingly, the transcription of TERA, a gene of unknown function, is affected by gamma-secretase activity and was significantly altered in the analyzed human Alzheimer's disease brain cortices. CONCLUSIONS/SIGNIFICANCE: Investigating the effects of gamma-secretase activity on gene transcription has revealed several affected clusters of molecular functions and, more specifically, 21 genes that hold significant potential for a better understanding of the biology of gamma-secretase and its roles in cancer and Alzheimer's disease pathology.


Assuntos
Secretases da Proteína Precursora do Amiloide/biossíntese , Perfilação da Expressão Gênica , Regulação Enzimológica da Expressão Gênica , Doença de Alzheimer/metabolismo , Animais , Células CHO , Análise por Conglomerados , Cricetinae , Cricetulus , Predisposição Genética para Doença , Humanos , Proteínas de Neoplasias/biossíntese , Análise de Sequência com Séries de Oligonucleotídeos , Fosfoproteínas/biossíntese , Estrutura Terciária de Proteína , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Proteínas Wnt/metabolismo
4.
Muscle Nerve ; 38(3): 1184-91, 2008 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-18720506

RESUMO

Ullrich disease (congenital muscular dystrophy type Ullrich, UCMD) is a severe congenital disorder of muscle caused by recessive and dominant mutations in the three genes that encode the alpha-chains of collagen type VI. Little is known about the early pathogenesis of this myopathy. The aim of this study was to investigate early histological changes in muscle of patients with molecularly confirmed UCMD. Muscle biopsies were analyzed from 8 UCMD patients ranging in age from 6 to 30 months. Type I fiber atrophy and predominance were seen early, together with a widening of the fiber diameter spectrum, whereas no dystrophic features were apparent. A subpopulation of more severely atrophic type I fibers was apparent subsequently, including one biopsy that fulfilled the formal diagnostic criteria of histopathological fiber type disproportion (FTD). Thus, early in the disease, UCMD presents as a non-dystrophic myopathy with predominant fiber atrophy. Collagen VI mutations also qualify as a cause of fiber type disproportion.


Assuntos
Fibras Musculares Esqueléticas/patologia , Atrofia Muscular/etiologia , Atrofia Muscular/patologia , Distrofia Miotônica/complicações , Adenosina Trifosfatases/metabolismo , Biópsia/métodos , Pré-Escolar , Colágeno Tipo VI/metabolismo , Feminino , Humanos , Indóis , Lactente , Laminina/metabolismo , Masculino , Fibras Musculares Esqueléticas/metabolismo , Cadeias Pesadas de Miosina/metabolismo , Distrofia Miotônica/patologia
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