title: Immunological cell type characterization and Th1-Th17 cytokine production in a mouse model of Gaucher disease.
abstract: Gaucher disease is a lysosomal storage disease resulting from insufficient acid β-glucosidase (glucocerebrosidase, GCase, EC 4.2.1.25) activity and the resultant accumulation of glucosylceramide. Macrophage (Mϕ) lineage cells are thought to be the major disease effectors because of their secretion of numerous cytokines and chemokines that influence other poorly defined immunological cell populations. Increases in several such populations were identified in a Gba1 mouse model (D409V/null; 9V/null) of Gaucher disease including antigen presenting cells (APCs), i.e., Mϕ, dendritic cells (DCs), neutrophils (PMNs), and CD4(+) T cells. FACS analyses showed increases in these cell types in 9V/null liver, spleen lung, and bone marrow. T-cells or APCs enhanced activations were evident by positivity of CD40L, CD69, as well as CD40, CD80, CD86, and MHCII on the respective cells. Mϕ, and, unexpectedly, DCs, PMNs, and T cells, from 9V/null mice showed excess glucosylceramides as potential bases for activation of APCs and T cells to induce Th1 (IFNγ, IL12, TNFα,) and Th17 (IL17A/F) cytokine production. These data imply that excess glucosylceramides in these cells are pivotal for activation of APCs and T cell induction of Th1 and Th17 responses and PMN recruitment in multiple organs of this model of Gaucher disease.
authors.affiliation: Division of Human Genetics, Cincinnati Children's Hospital Medical Center, and Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH 45229‐3039, USA.
authors.forename: Manoj Kumar
authors.initials: MK
authors.lastname: Pandey
authors.forename: Reena
authors.initials: R
authors.lastname: Rani
authors.forename: Wujuan
authors.initials: W
authors.lastname: Zhang
authors.forename: Kenneth
authors.initials: K
authors.lastname: Setchell
authors.forename: Gregory A
authors.initials: GA
authors.lastname: Grabowski
mesh_terms: D000818:Animals; D000938:Antigen-Presenting Cells / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D018106:CD28 Antigens / Q000378:metabolism; D017252:CD3 Complex / Q000378:metabolism; D016207:Cytokines / Q000096:biosynthesis*; D003713:Dendritic Cells / Q000166:cytology / Q000378:metabolism; D004195:Disease Models, Animal; D005776:Gaucher Disease / Q000378:metabolism*; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D008815:Mice, Inbred Strains; D013154:Spleen / Q000378:metabolism; D018417:Th1 Cells / Q000166:cytology / Q000276:immunology* / Q000378:metabolism*; D058504:Th17 Cells / Q000166:cytology / Q000276:immunology* / Q000378:metabolism
chemical_list: D018106:CD28 Antigens; D017252:CD3 Complex; D016207:Cytokines