A5024002311- IL-33, ST2, and ILC Pathways
- Asthma and respiratory diseases
- T-cell and B-cell Immunology
- Eosinophilic Esophagitis
- Immune Cell Function and Interaction
- Immunodeficiency and Autoimmune Disorders
- Psoriasis: Treatment and Pathogenesis
- Sphingolipid Metabolism and Signaling
- Chronic Lymphocytic Leukemia Research
- Monoclonal and Polyclonal Antibodies Research
- Dermatology and Skin Diseases
- Pneumonia and Respiratory Infections
- Respiratory viral infections research
- Cytomegalovirus and herpesvirus research
- Cytokine Signaling Pathways and Interactions
- PI3K/AKT/mTOR signaling in cancer
- Lymphatic System and Diseases
- Axon Guidance and Neuronal Signaling
- Mast cells and histamine
- Ubiquitin and proteasome pathways
- Phagocytosis and Immune Regulation
- Immune cells in cancer
- Systemic Lupus Erythematosus Research
- Hippo pathway signaling and YAP/TAZ
- Protein Kinase Regulation and GTPase Signaling
Indira Gandhi Institute of Medical Sciences
2016
Genentech
2010-2014
Howard Hughes Medical Institute
1999-2009
University of California, San Francisco
2007-2009
Cardiovascular Institute Hospital
2009
Neurological Surgery
2008
Washington University in St. Louis
1998-2003
Institute of Immunology
1999
Center for Rheumatology
1999
Lymphocytes require sphingosine-1-phosphate (S1P) receptor-1 to exit lymphoid organs, but the source(s) of extracellular S1P and whether directly promotes egress are unknown. By using mice in which two kinases that generate were conditionally ablated, we find plasma is mainly hematopoietic origin, with erythrocytes a major contributor, whereas lymph from distinct radiation-resistant source. Lymphocyte thymus secondary organs was markedly reduced kinase-deficient mice. Restoration rescued...
Lymphocyte egress from lymph nodes (LNs) is dependent on sphingosine-1-phosphate (S1P), but the cellular source of this S1P not defined. We generated mice that expressed Cre lymphatic vessel endothelial hyaluronan receptor 1 (Lyve-1) locus and showed efficient recombination loxP-flanked genes in endothelium. report with Lyve-1 CRE-mediated ablation sphingosine kinase (Sphk) lacking Sphk2 have a loss while maintaining normal plasma S1P. In Cre+ Sphk-deficient mice, lymphocyte LNs Peyer's...
Maintenance of vascular integrity is critical for homeostasis, and temporally spatially regulated leak a central feature inflammation. Sphingosine-1-phosphate (S1P) can regulate endothelial barrier function, but the sources S1P that provide this activity in vivo its importance modulating different inflammatory responses are unknown. We report here mutant mice engineered to selectively lack plasma displayed increased impaired survival after anaphylaxis, administration platelet-activating...
The IL-33/ST2 pathway is linked with asthma susceptibility. Inhaled allergens, pollutants, and respiratory viruses, which trigger exacerbations, induce release of IL-33, an epithelial-derived "alarmin." Astegolimab, a human IgG2 mAb, selectively inhibits the IL-33 receptor, ST2. Approved biologic therapies for severe mainly benefit patients elevated blood eosinophils (type 2-high), but limited options are available low 2-low). Inhibiting signaling may target pathogenic pathways in wider...
The signal transduction events that control the progenitor B cell (pro-B cell) to precursor (pre-B transition have not been well delineated. In evaluating patients with absent cells, a male homozygous splice defect in cytoplasmic adapter protein BLNK (B linker protein) was identified. Although this patient had normal numbers of pro-B he no pre-B cells or mature indicating plays critical role orchestrating transition. immune system and overall growth development were otherwise patient,...
Linker proteins function as molecular scaffolds to localize enzymes with substrates. In B cells, cell linker protein (BLNK) links the receptor (BCR)–activated Syk kinase phosphoinositide and mitogen-activated pathways. To examine in vivo role of BLNK, mice deficient BLNK were generated. development −/− was blocked at transition from B220 + CD43 progenitor − precursor cells. Only a small percentage immunoglobulin M ++ (IgM ), but not mature IgM lo IgD hi , cells detected periphery. Hence, is...
Immune responses at mucosal barriers are regulated by innate type 2 lymphoid cells (ILC2s) that elaborate effector cytokines interleukins 5 and 13 (IL5 IL13). IL25 IL33 key support ILC2s; however, mice deficient in these pathways retain some functional ILC2s. Analysis of human murine revealed ILC2s highly express tumor necrosis factor (TNF)-receptor superfamily member DR3 (TNFRSF25). Engagement with cognate ligand TL1A promoted ILC2 expansion, survival, function. Exogenous protein or genetic...
Bacterial-associated LPS drives oncostatin M–dependent airway inflammation and mucus hypersecretion in severe asthma.
Abstract IL-13 can bind to two distinct receptors: a heterodimer of IL-13Rα1/IL-4Rα and IL-13Rα2. Whereas engagement by leads the activation STAT6, molecular events triggered binding IL-13Rα2 remain incompletely understood. IL-4 signal through complex but does not interact with Idiopathic pulmonary fibrosis is progressive generally fatal parenchymal lung disease unknown etiology no current pharmacologic treatment options that substantially prolong survival. Preclinical models fibrotic...
The epidermis is a barrier that prevents water loss while keeping harmful substances from penetrating the host. impermeable cornified layer of stratum corneum maintained by balancing continuous turnover driven epidermal basal cell proliferation, suprabasal differentiation, and corneal shedding. desquamation process tightly regulated balance activities serine proteases Kallikrein-related peptidases (KLK) family their cognate inhibitor lymphoepithelial Kazal type-related (LEKTI), which encoded...
Abstract IL-17 family cytokines are critical to host defense responses at cutaneous and mucosal surfaces. Whereas IL-17A, IL-17F, IL-17C induce overlapping inflammatory cascades promote neutrophil-mediated immunity, IL-17E/IL-25 drives type 2 immune pathways eosinophil activity. Genetic pharmacological studies reveal the significant contribution these play in antimicrobial autoimmune mechanisms. However, little is known about related member, IL-17B, with contrasting reports of both pro-...
The pan-proteasome inhibitor bortezomib demonstrated clinical efficacy in off-label trials of Systemic Lupus Erythematosus. One potential mechanism this benefit is from the depletion pathogenic immune cells (plasmablasts and plasmacytoid dendritic cells). However, cytotoxic against nonimmune cells, which limits its use for autoimmune diseases. An attractive alternative to selectively inhibit cell-specific immunoproteasome deplete spare nonhematopoietic cells. Here, we disclose development...
Inhibiting the kinase IRAK4 may suppress a multicellular autoinflammatory loop in patients with lupus.
In latently infected B lymphocytes, the Epstein-Barr virus (EBV) suppresses signal transduction from antigen receptor through expression of integral latent membrane protein 2A (LMP2A). At same time, LMP2A triggers cell survival by a yet uncharacterized maintenance that is normally provided receptor. The molecular mechanisms are unknown as LMP2A-regulated signaling cascades have not been described so far. Using novel mouse model we identified intracellular adaptor Src homology 2 (SH2)...
OBJECTIVES: Severe cases of COVID-19 pneumonia can lead to acute respiratory distress syndrome (ARDS). Release interleukin (IL)-33, an epithelial-derived alarmin, and IL-33/ST2 pathway activation are linked with ARDS development in other viral infections. IL-22, a cytokine that modulates innate immunity through multiple regenerative protective mechanisms lung epithelial cells, is reduced patients ARDS. This study aimed evaluate safety efficacy astegolimab, human immunoglobulin G2 monoclonal...