Gaucher disease: chemotactic factors and immunological cell invasion in a mouse model.
Gaucher disease results from mutations in GBA1 that cause functional disruption of the encoded lysosomal enzyme, acid β-glucosidase. The consequent excess accumulation of glucosylceramide and glucosylsphingosine in lysosomes is central to the disease pathogenesis with classical involvement of macrophage (Mфs) lineage cells of visceral organs, bone, or brain. Several studies have implicated the increased secretion of chemokines and infiltration of a variety of immunological cells into tissues of Gaucher disease patients. Trafficking of immunological cells to the sites of inflammation requires the presence of chemokines. Although increases of different immunological cells and several chemokines are present in Gaucher disease, the specific chemoattractants that cause the increased influx of immunological cells are not fully defined. Here, increased levels of I-309, MCP-5, CXCL-2, CXCL-9, CXCL-10, CXCL-11, CXCL-13, and their corresponding leukocytes, i.e., MOs (monocytes), Mфs, dendritic cells (DCs), polymorphonuclear neutrophils (PMNs), and T, and B cells were identified in the circulation of mice with Gba1 mutations (D409V/null). Sera from D409V/null mice contained chemoattractants for a variety of immunological cells as shown by ex vivo chemotaxis studies and by flow cytometry. Enhanced chemotaxis towards 9V/null sera was found for 9V/null lung-, spleen-, liver-, and bone marrow-derived Mфs (CD11b(+) F480(+)), PMNs (Gr1(high) CD11b(+)), DCs (CD11c(+) CD11b(+)), T lymphocytes (CD3(+) TCRB(+)), and B lymphocytes (B220(+) CD19(+)). These data support these chemotactic factors as causative to increased tissue infiltration of leukocytes in Gaucher disease.
Division of Human Genetics, Cincinnati Children's Hospital Medical Center, USA; Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH 45229, USA.
Manoj Kumar
MK
Pandey
Division of Human Genetics, Cincinnati Children's Hospital Medical Center, USA; University Hospitals Case Medical Center, 11100 Euclid Ave., Cleveland, OH 44106, USA.
Nicholas A
NA
Jabre
Division of Human Genetics, Cincinnati Children's Hospital Medical Center, USA; Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH 45229, USA.
You-Hai
YH
Xu
Pathology and Laboratory Medicine, Cincinnati Children's Hospital Medical Center, USA.
Wujuan
W
Zhang
Pathology and Laboratory Medicine, Cincinnati Children's Hospital Medical Center, USA; Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH 45229, USA.
Kenneth D R
KD
Setchell
Division of Human Genetics, Cincinnati Children's Hospital Medical Center, USA; Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH 45229, USA. Electronic address: greg.grabowski@cchmc.org.
Gregory A
GA
Grabowski
D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology / Q000473:pathology; D001853:Bone Marrow / Q000201:enzymology / Q000276:immunology / Q000473:pathology; D002465:Cell Movement; D018925:Chemokines / Q000276:immunology* / Q000378:metabolism; D003713:Dendritic Cells / Q000276:immunology / Q000473:pathology; D004195:Disease Models, Animal; D005260:Female; D005776:Gaucher Disease / Q000201:enzymology / Q000276:immunology* / Q000473:pathology; D005962:Glucosylceramidase / Q000172:deficiency*; D006801:Humans; D057131:Immune Evasion; D008099:Liver / Q000201:enzymology / Q000276:immunology / Q000473:pathology; D008168:Lung / Q000201:enzymology / Q000276:immunology / Q000473:pathology; D008247:Lysosomes / Q000201:enzymology / Q000276:immunology* / Q000473:pathology; D008264:Macrophages / Q000276:immunology / Q000473:pathology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009504:Neutrophils / Q000276:immunology / Q000473:pathology; D013154:Spleen / Q000201:enzymology / Q000276:immunology / Q000473:pathology; D013601:T-Lymphocytes / Q000276:immunology / Q000473:pathology
D018925:Chemokines; D005962:Glucosylceramidase
Chemokines; Glucosylceramide; Inborn errors of metabolism; Lysosomal storage disease