A5003918487- Neutrophil, Myeloperoxidase and Oxidative Mechanisms
- TGF-β signaling in diseases
- Virus-based gene therapy research
- Bone Metabolism and Diseases
- Cell Adhesion Molecules Research
- Autoimmune and Inflammatory Disorders Research
- Immune Response and Inflammation
- Systemic Lupus Erythematosus Research
- CAR-T cell therapy research
- Reproductive tract infections research
- T-cell and B-cell Immunology
- Immune Cell Function and Interaction
- Tuberculosis Research and Epidemiology
- RNA Interference and Gene Delivery
- Viral Infections and Vectors
- Blood disorders and treatments
- Inflammasome and immune disorders
- IL-33, ST2, and ILC Pathways
- Cervical Cancer and HPV Research
- Immunotherapy and Immune Responses
- interferon and immune responses
- Diagnosis and treatment of tuberculosis
- Mycobacterium research and diagnosis
- Diphtheria, Corynebacterium, and Tetanus
- Cancer Research and Treatments
University of Pittsburgh
2006-2024
Children's Hospital of Pittsburgh
2006-2018
University of Pittsburgh Medical Center
2010-2011
Research Institute for Genetic and Human Therapy
2004
Novartis (United States)
2004
VA Connecticut Healthcare System
1997
Howard Hughes Medical Institute
1997
Yale University
1997
Airway inflammation is believed to stimulate mucus production in asthmatic patients. Increased secretion an important clinical symptom and contributes airway obstruction asthma. Activated CD4 Th1 Th2 cells have both been identified biopsies of asthmatics but their role not clear. Using T from mice transgenic for the OVA-specific TCR, we studied production. induced by was comprised eosinophils lymphocytes; features found Additionally, there a marked increase that received inhaled OVA, cells....
Age-associated B cells (ABCs) are formed under inflammatory conditions and considered a type of memory cell (MBC) expressing the transcription factor T-bet. In SLE, ABC frequency is correlated with disease, they thought to be source autoantibody-secreting cells. However, in conditions, whether autoreactive can become resting MBCs uncertain. Further, phenotypic identity ABCs their relationship other subsets, such as plasmablasts, unclear. Whether directly promote disease untested. Here we...
Abstract IFN-β has been implicated as an effector of oviduct pathology resulting from genital chlamydial infection in the mouse model. In this study, we investigated role cytosolic DNA and engagement sensors expression during infection. We determined that three-prime repair exonuclease-1, a host 3′ to 5′ exonuclease, reduced significantly using small interfering RNA gene knockout fibroblasts, implicating ligand for response. The sensor cyclic GMP–AMP synthase (cGAS) shown bind generate...
Though recent reports suggest that neutrophil extracellular traps (NETs) are a source of antigenic nucleic acids in systemic lupus erythematosus (SLE), we recently showed inhibition NETs by targeting the NADPH oxidase complex via cytochrome b-245, β polypeptide (cybb) deletion exacerbated disease MRL.Faslpr mouse model. While these data challenge paradigm promote lupus, it is conceivable global regulatory properties cybb and cybb-independent confound findings. Furthermore, indicate...
Abstract While analyzing gene expression in collagen-induced arthritis, we discovered that a poorly characterized gene, follistatin-like protein 1 (FSTL-1), is highly overexpressed mouse paws during early especially at the interface of synovial pannus and eroding bone. In this study, show FSTL-1 novel proinflammatory molecule with previously unrecognized role inflammation. Transfection into macrophages fibroblasts leads to up-regulation cytokines, including IL-1β, TNF-α, IL-6. Overexpression...
Follistatin-like protein-1 (FSTL-1) is a poorly characterized protein that up-regulated in the early stage of collagen-induced arthritis and exacerbates when delivered by gene transfer. The current study was designed to determine mechanism which FSTL-1 promotes arthritis. injected into mouse paws, resulting severe paw swelling associated with up-regulation IFN-gamma transcript IFN-gamma-induced chemokine, CXCL10. Mice depleted T cells were protected. A central role for confirmed finding mice...
To examine both the source of follistatin-like protein 1 (FSTL-1) and factors that induce its expression in arthritis, to determine whether juvenile rheumatoid arthritis (JRA) is characterized by overexpression FSTL-1.FSTL-1 patterns were analyzed immunohistochemical staining joint tissue derived from mice with collagen-induced arthritis. Induction FSTL-1 secretion was assessed osteoblasts, adipocytes, human fibroblast-like synoviocytes response transforming growth factor beta (TGFbeta),...
FSTL1 is a secreted glycoprotein that exacerbates murine arthritis and overexpressed in human arthritis. The aim of this study was to determine the mechanism by which promotes arthritis.Collagen-induced induced mice hypomorphic for FSTL1, generated with gene trap-targeted mutant embryonic stem cell line. Arthritis assessed measuring paw swelling using qualitative index. Bone marrow-derived mesenchymal stromal cells from mice, as well mouse ST2 transduced short hairpin RNA suppress...
Follistatin-like protein 1 (FSTL-1) is overexpressed in a number of inflammatory conditions characterized by elevated IL-1β. Here, we found that FSTL-1 serum concentration was increased threefold patients with bacterial sepsis and fourfold following administration LPS to mice. To test the contribution IL-1β secretion, WT FSTL-1-deficient mice were injected LPS. While induced sera mice, it low or undetectable Monocytes/macrophages, key source IL-1β, do not normally express FSTL-1. However,...
Depleting pathogenic B cells could treat systemic lupus erythematosus (SLE). However, depleting in an inflammatory setting such as is difficult. This study was undertaken to investigate whether a type II anti-CD20 monoclonal antibody (mAb) with different mechanism of action, obinutuzumab (GA101), more effective than I mAb, rituximab (RTX), cell depletion lupus, and efficient results amelioration disease.We treated lupus-prone MRL/lpr mice expressing human CD20 on (hCD20 mice) either RTX or...
Objectives Chondrocytes, the only cells in articular cartilage, play a pivotal role osteoarthritis (OA) because they are responsible for maintenance of extracellular matrix (ECM). Follistatin-like protein 1 (FSTL1) is secreted found mesenchymal stem (MSCs) and cartilage but whose function unclear. FSTL1 has been shown to modify cell growth survival. In this work, we sought determine whether could regulate chondrogenesis chondrogenic differentiation MSCs. Methods To study chondrogenesis, used...
To explore the potential applicability of recombinant adeno-associated virus (rAAV) vectors in treatment rheumatoid arthritis (RA), primary human fibroblast-like synoviocytes (FLS) derived from patients with RA were infected rAAV encoding mouse IL-10 under control CMV promoter. Addition proteasome inhibitor carbobenzoxy-l-leucyl-l-leucyl-l-leucinal (zLLL) to cultures dramatically enhanced expression transgene, a dose-dependent manner. The increased was transient, peaking at 3 days and...
Loss of NADPH oxidase (NOX2) exacerbates systemic lupus erythematosus (SLE) in mice and humans, but the mechanisms underlying this effect remain unclear. To identify cell lineages which NOX2 deficiency drives SLE, we employed conditional KO chimeric approaches to delete Cybb several hematopoietic MRL.Faslpr SLE-prone mice. Deletion macrophages/monocytes exacerbated SLE nephritis, though not degree observed global KOs. Unexpectedly, absence B cells resulted profound glomerulonephritis...
Abstract Objective Juvenile idiopathic arthritis (JIA) is a heterogeneous group of inflammatory diseases, and no clinically useful prognostic markers to predict disease outcome in children with JIA are currently available. Synovial fluid likely reflects the proteins present inflamed synovium. The purpose this study was delineate synovial proteome determine whether protein expression differs different subtypes JIA. Methods samples obtained from oligoarticular JIA, polyarticular or systemic...
CD4 T cells and antibody are required for optimal acquired immunity to
NADPH oxidase deficiency exacerbates lupus in murine models and patients, but the mechanisms remain unknown. It is hypothesized that suppresses autoimmunity by facilitating dead cell clearance via LC3-associated phagocytosis (LAP). The absence of LAP reportedly causes an autoinflammatory syndrome aged, nonautoimmune mice. Prior work implicated cytochrome b-245, β polypeptide (CYBB), a component complex, RUN cysteine-rich domain-containing Beclin 1-interacting protein (RUBICON) as requisite...
Loss of tolerance to nuclear antigens and multisystem tissue destruction is a hallmark systemic lupus erythematosus (SLE). Although the source autoantigen in remains elusive, compelling hypothetical dead cell debris that drives autoimmune activation. Prior reports suggest neutrophil extracellular traps (NETs) their associated death pathway, NETosis, are sources SLE. However, others we have shown inhibition NETs by targeting NADPH oxidase complex peptidylarginine deiminase 4 (PADI4) did not...
Abstract Autoreactive B cells can be tolerized by deletion, receptor editing, and anergy. Nuclear antigen-specific (such as anti-DNA) may subject to unique regulation, their autoantigens also signal via Toll-like receptors 7 or 9. Indeed, we previously showed that anti-DNA lacking TLR9 were not deleted, but instead became long-lived, yet anergic, follicular cells. Here report the regulatory effect of on development is due Faslpr mutation. However, genetic background plays a role, C57BL/6...
Abstract IFNβ has been implicated as an effector of oviduct pathology resulting from genital Chlamydia infection in the mouse model. In this study, we investigated role cytosolic DNA and engagement sensors expression during infection. Using siRNA technique gene knock out fibroblasts, determined that TREX-1, a host 3’exonuclease reduced significantly infection, implicating ligand for response. STING is signaling adaptor required sensor, cGAS binds to generate cGAMP. We establish multiple cell...