RESUMO
Chemokines and other chemoattractants direct leukocyte migration and are essential for the development and delivery of immune and inflammatory responses. To probe the molecular mechanisms that underlie chemoattractant-guided migration, we did an RNA-mediated interference screen that identified several members of the synaptotagmin family of calcium-sensing vesicle-fusion proteins as mediators of cell migration: SYT7 and SYTL5 were positive regulators of chemotaxis, whereas SYT2 was a negative regulator of chemotaxis. SYT7-deficient leukocytes showed less migration in vitro and in a gout model in vivo. Chemoattractant-induced calcium-dependent lysosomal fusion was impaired in SYT7-deficient neutrophils. In a chemokine gradient, SYT7-deficient lymphocytes accumulated lysosomes in their uropods and had impaired uropod release. Our data identify a molecular pathway required for chemotaxis that links chemoattractant-induced calcium flux to exocytosis and uropod release.
Assuntos
Movimento Celular/fisiologia , Sinaptotagminas/metabolismo , Animais , Quimiocina CXCL12/metabolismo , Quimiotaxia , Immunoblotting , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Reação em Cadeia da Polimerase , Receptores CXCR4/metabolismo , Sinaptotagmina II/metabolismo , Sinaptotagminas/genética , Linfócitos T/imunologiaAssuntos
Esclerodermia Difusa/diagnóstico , Pele/patologia , Idoso , Artralgia/etiologia , Transtornos de Deglutição/etiologia , Diagnóstico Diferencial , Edema/etiologia , Evolução Fatal , Humanos , Hiperpigmentação/etiologia , Nefropatias/diagnóstico , Pulmão/diagnóstico por imagem , Pulmão/patologia , Masculino , Mieloma Múltiplo/complicações , Esclerodermia Difusa/complicações , Esclerodermia Difusa/patologia , Escleromixedema/diagnóstico , Tomografia Computadorizada por Raios XAssuntos
Síndrome de Behçet/patologia , Encefalopatias/patologia , Encéfalo/patologia , Adulto , Anti-Inflamatórios/uso terapêutico , Síndrome de Behçet/complicações , Síndrome de Behçet/tratamento farmacológico , Encefalopatias/tratamento farmacológico , Líquido Cefalorraquidiano/química , Líquido Cefalorraquidiano/citologia , Doenças Transmissíveis/diagnóstico , Doenças Desmielinizantes/diagnóstico , Diagnóstico Diferencial , Eritema/etiologia , Evolução Fatal , Doenças dos Genitais Masculinos , Humanos , Imunossupressores/uso terapêutico , Imageamento por Ressonância Magnética , Masculino , Doenças do Sistema Nervoso/etiologia , Vasculite/diagnósticoAssuntos
Hidroxicloroquina/administração & dosagem , Doenças Retinianas/prevenção & controle , Smartphone , Telemedicina/instrumentação , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/administração & dosagem , Inibidores Enzimáticos/efeitos adversos , Humanos , Hidroxicloroquina/efeitos adversos , Doenças Retinianas/diagnóstico , Doenças Retinianas/etiologia , Inquéritos e QuestionáriosRESUMO
Wegener's granulomatosis (WG) is a complex autoimmune disorder that has been transformed from a uniformly lethal process to a chronic disease with a relapsing-remitting course. In the setting of frequent relapses, the need to manage cumulative disease damage and drug toxicities has spurred the identification and development of new potent and directed therapies. Biologic agents, which offer the potential for remission-induction and drug-sparing approaches to treat WG, have been studied in several small, open-label clinical series and one large, randomized, placebo-controlled clinical trial. This article discusses the results of these trials and the potential of these biologic agents to treat WG.
Assuntos
Terapia Biológica , Granulomatose com Poliangiite/tratamento farmacológico , Fatores Imunológicos/uso terapêutico , Animais , Ensaios Clínicos Controlados como Assunto , Modelos Animais de Doenças , Granulomatose com Poliangiite/etiologia , HumanosRESUMO
Islet cell autoantigen 69-kDa (ICA69), protein product of the human ICA1 gene, is one target of the immune processes defining the pathogenesis of Type 1 diabetes. We have characterized the genomic structure and functional promoters within the 5'-regulatory region of ICA1. 5'-RNA ligase-mediated rapid amplification of cDNA ends evaluation of ICA1 transcripts expressed in human islets, testis, heart, and cultured neuroblastoma cells reveals that three 5'-untranslated region exons are variably expressed from the ICA1 gene in a tissue-specific manner. Surrounding the transcription initiation sites are motifs characteristic of non-TATA, non-CAAT, GC-rich promoters, including consensus Sp1/GC boxes, an initiator element, cAMP-responsive element-binding protein (CREB) sites, and clusters of other putative transcription factor sites within a genomic CpG island. Luciferase reporter constructs demonstrate that the first two ICA1 exon promoters reciprocally stimulate luciferase expression within islet- (RIN 1046-38 cells) and brain-derived (NMB7) cells in culture; the exon A promoter exhibits greater activity in islet cells, whereas the exon B promoter more efficiently activates transcription in neuronal cells. Mutation of a CREB site within the ICA1 exon B promoter significantly enhances transcriptional activity in both cell lines. Our basic understanding of expression from the functional core promoter elements of ICA1 is an important advance that will not only add to our knowledge of the ICA69 autoantigen but will also facilitate a rational approach to discover the function of ICA69 and to identify relevant ICA1 promoter polymorphisms and their potential associations with disease.