Subject(s)
Hydroxychloroquine/administration & dosage , Retinal Diseases/prevention & control , Smartphone , Telemedicine/instrumentation , Dose-Response Relationship, Drug , Enzyme Inhibitors/administration & dosage , Enzyme Inhibitors/adverse effects , Humans , Hydroxychloroquine/adverse effects , Retinal Diseases/diagnosis , Retinal Diseases/etiology , Surveys and QuestionnairesSubject(s)
Scleroderma, Diffuse/diagnosis , Skin/pathology , Aged , Arthralgia/etiology , Deglutition Disorders/etiology , Diagnosis, Differential , Edema/etiology , Fatal Outcome , Humans , Hyperpigmentation/etiology , Kidney Diseases/diagnosis , Lung/diagnostic imaging , Lung/pathology , Male , Multiple Myeloma/complications , Scleroderma, Diffuse/complications , Scleroderma, Diffuse/pathology , Scleromyxedema/diagnosis , Tomography, X-Ray ComputedABSTRACT
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.
Subject(s)
Cell Movement/physiology , Synaptotagmins/metabolism , Animals , Chemokine CXCL12/metabolism , Chemotaxis , Immunoblotting , Mice , Mice, Inbred C57BL , Mice, Knockout , Polymerase Chain Reaction , Receptors, CXCR4/metabolism , Synaptotagmin II/metabolism , Synaptotagmins/genetics , T-Lymphocytes/immunologySubject(s)
Behcet Syndrome/pathology , Brain Diseases/pathology , Brain/pathology , Adult , Anti-Inflammatory Agents/therapeutic use , Behcet Syndrome/complications , Behcet Syndrome/drug therapy , Brain Diseases/drug therapy , Cerebrospinal Fluid/chemistry , Cerebrospinal Fluid/cytology , Communicable Diseases/diagnosis , Demyelinating Diseases/diagnosis , Diagnosis, Differential , Erythema/etiology , Fatal Outcome , Genital Diseases, Male , Humans , Immunosuppressive Agents/therapeutic use , Magnetic Resonance Imaging , Male , Nervous System Diseases/etiology , Vasculitis/diagnosisABSTRACT
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.
Subject(s)
Biological Therapy , Granulomatosis with Polyangiitis/drug therapy , Immunologic Factors/therapeutic use , Animals , Controlled Clinical Trials as Topic , Disease Models, Animal , Granulomatosis with Polyangiitis/etiology , HumansABSTRACT
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.
