A5102740662- T-cell and B-cell Immunology
- Immune Cell Function and Interaction
- Immunotherapy and Immune Responses
- Psoriasis: Treatment and Pathogenesis
- Cell Adhesion Molecules Research
- Immunodeficiency and Autoimmune Disorders
- Immune Response and Inflammation
- Systemic Lupus Erythematosus Research
- Mycobacterium research and diagnosis
- Diabetes Management and Research
- CAR-T cell therapy research
- Atherosclerosis and Cardiovascular Diseases
- 3D Printing in Biomedical Research
- Single-cell and spatial transcriptomics
- Sphingolipid Metabolism and Signaling
- Lymphatic System and Diseases
- Neuroinflammation and Neurodegeneration Mechanisms
- Multiple Sclerosis Research Studies
- Diabetes and associated disorders
- Whipple's Disease and Interleukins
- Pancreatic function and diabetes
- Gene Regulatory Network Analysis
- Monoclonal and Polyclonal Antibodies Research
- Spaceflight effects on biology
- Galectins and Cancer Biology
Benaroya Research Institute
2010-2020
University of Washington
2011-2019
Amsterdam UMC Location University of Amsterdam
2010
Brigham and Women's Hospital
1998-2009
Harvard University
1998-2009
Max Planck Society
2005
Max Planck Innovation
2005
Heidelberg University
2002
Hôpital Paul-Brousse
2000
Inserm
2000
Experimental autoimmune encephalomyelitis (EAE) is a model of human multiple sclerosis induced by autoreactive Th cells that mediate tissue inflammation and demyelination in the CNS. Initially, IFN-gamma-producing Th1 and, more recently, IL-17-producing Th17 with specificity for myelin Ags have been implicated EAE induction, but whether are encephalitogenic has controversial. Moreover, new effector T cell subset, Th9 cells, identified; however, ability this subset to induce not investigated....
Abstract Experimental autoimmune encephalomyelitis (EAE) and other organ-specific diseases are induced by autoantigen-specific Th1 cells. In contrast, transfer of autoantigen-reactive Th2 cells that produce IL-4 IL-10 can prevent and/or reverse EAE. The relative roles these two cytokines in the regulation EAE has not been evaluated. Utilizing knockout mice deficient for transgenic overexpressing cytokines, we demonstrate IL-10-deficient (IL-10−/−) more susceptible develop a severe when...
T helper type 17 (TH17) cells are highly proinflammatory effector that characterized by the production of high amounts IL-17A, IL-17F, IL-21, and IL-22. Furthermore, TH17 have been associated with a number autoimmune diseases. However, it is not clear whether can also serve as effective cells. Here we show function B-cell helpers in they only induce strong proliferative response B vitro but trigger antibody class switch recombination vivo. Transfer into WT or T-cell receptor α–deficient...
The development of T helper (T(H))17 and regulatory (T(reg)) cells is reciprocally regulated by cytokines. Transforming growth factor (TGF)-beta alone induces FoxP3(+) T(reg) cells, but together with IL-6 or IL-21 T(H)17 cells. Here we demonstrate that IL-9 a key molecule affects differentiation function. predominantly produced synergizes TGF-beta1 to differentiate naïve CD4(+) into while secretion IL-23. Interestingly, enhances the suppressive functions in vitro, absence signaling weakens...
During the development of experimental autoimmune encephalomyelitis (EAE), proportion pathogenic and myelin-specific cells within CNS-infiltrating cytokine-producing Th is unknown. Using an IL-17A/IFN-γ double reporter mouse I-A(b)/myelin oligodendrocyte glycoprotein 38-49 tetramer, we show in this study that IL-17(+)IFN-γ(+) cells, which are expanded CNS during EAE, highly enriched myelin glycoprotein-specific T cells. We further demonstrate IL-23 essential for generation expansion...
Traditionally, CD4(+) T cells have been separated into two different subsets named helper (Th)1 and Th2. A new IL-23-driven subset of Th called Th(IL-17) has now described. The data suggest that IL-23 plays an important role in the differentiation autoreactive pathogenic cells. Whether these IL-23-induced are a unique or related to other is discussed.
Abatacept is a CTLA-4-Ig fusion protein that binds to the costimulatory ligands CD80 and CD86 blocks their interaction with CD28 CTLA-4 receptors expressed by T cells, therefore inhibiting cell activation function. has shown clinical efficacy in treating some autoimmune diseases but failed show benefit other conditions. The reasons for these disparate results are not clear warrant further investigation of abatacept's mode action. Longitudinal specimens from Immune Tolerance Network's A...
The neutralization of α4 integrin is currently used as treatment in several autoimmune diseases and thought to prevent the entry most immune cells target tissues. In this study, we showed that selective deletion T did not but delayed development experimental encephalomyelitis. Whereas both Th1 Th17 infiltrate CNS wild-type mice, present mice lacking were mainly enriched cells, suggesting cell subset uses other integrins access CNS. contrast, expression important for enter stability their...
Abstract The catalytic subunit of the serine/threonine phosphatase 2A (PP2A) can interact with cytoplasmic tail CTLA-4. However, molecular basis and biological significance this interaction are unknown. In study, we report that regulatory PP2A (PP2AA) also interacts Interestingly, TCR ligation induces tyrosine phosphorylation PP2AA its dissociation from CTLA-4 when coligated. association between involves a conserved three-lysine motif in juxtamembrane portion Mutations these lysine residues...
Abstract IL-17–producing CD4+ T (Th17) cells, along with IFN-γ–expressing Th1 represent two major pathogenic cell subsets in experimental autoimmune encephalomyelitis (EAE), the animal model of multiple sclerosis (MS). The cytokines and transcription factors involved development effector functions Th17 cells have been largely characterized. Among them, IL-23 is essential for generation stable encephalitogenic EAE. IL-7/IL-7R signaling axis participates survival, perturbation this pathway has...
Podoplanin (PDPN, also known as Gp38) is highly expressed on the surface of lymphatic endothelial cells, where it regulates development vessels. We have recently observed that PDPN effector T cells infiltrate target tissues during autoimmune inflammation; however, function in largely unclear. Here, we demonstrated global deletion Pdpn results exaggerated cell responses and spontaneous experimental encephalomyelitis (EAE) mice with a susceptible genetic background. In contrast, cell-specific...
Experimental autoimmune encephalomyelitis (EAE), the animal model of multiple sclerosis (MS), results from an attack central nervous system (CNS) by effector T helper (Th) 1 and Th17 cells. Regulatory cells (Treg) can control limit progression CNS autoimmunity. Integrin alpha 4 (Itga4) is critical for entry Th1 but not into during EAE. Whether Itga4 controls homing Tregs in whether Th17-mediated EAE has, however, been addressed. Through selective elimination Foxp3-expressing cells, we show...
Foxp3+ Tregs possess potent immunosuppressive activity, which is critical for maintaining immune homeostasis and self-tolerance. Defects in Treg development or function result inadvertent activation autoimmunity. Despite recent advances biology, we still do not completely understand the molecular cellular mechanisms governing suppressive of these cells. Here, have demonstrated an essential role dedicator cytokinesis 8 (DOCK8), guanine nucleotide exchange factors required cytoskeleton...
The neutralization of integrin α4 (Itga4) is currently used as treatment in multiple sclerosis. Although most studies have focused on its function lymphocyte migration to the CNS, we uncovered importance Itga4 for generation regulatory B cells peripheral immune organs and their control pathogenic T cell response CNS pathology. Our study underscores looking at dual role autoimmunity provides important perspectives regarding efficacy side effects associated with other cell-targeting therapies.
Autoreactive CD4+ T lymphocytes are critical to the induction of autoimmune disease, but because degenerate nature cell receptor (TCR) activation such receptors also respond other ligands. Interaction autoreactive cells with non–self-ligands has been shown activate and expand self-reactive induce autoimmunity. To understand effect on autoreactivity naive cross-reactive a potent nonself ligand, we have generated TCR transgenic mouse which expresses broad cross-reactivity number ligands...