Document Detail


Negative role of colony-stimulating factor-1 in macrophage, T cell, and B cell mediated autoimmune disease in MRL-Fas(lpr) mice.
MedLine Citation:
PMID:  15383612     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Inflammation in the kidney and other tissues (lung, and salivary and lacrimal glands) is characteristic of MRL-Fas(lpr) mice with features of lupus. Macrophages (Mphi) are prominent in these tissues. Given that 1) Mphi survival, recruitment, proliferation, and activation during inflammation is dependent on CSF-1, 2) Mphi mediate renal resident cell apoptosis, and 3) CSF-1 is up-regulated in MRL-Fas(lpr) mice before, and during nephritis, we hypothesized that CSF-1-deficient MRL-Fas(lpr) mice would be protected from Mphi-mediated nephritis, and the systemic illness. To test this hypothesis, we compared CSF-1-deficient MRL-Fas(lpr) with wild-type strains. Renal pathology is suppressed and function improved in CSF-1-deficient MRL-Fas(lpr) mice. There are far fewer intrarenal Mphi and T cells in CSF-1-deficient MRL-Fas(lpr) vs wild-type kidneys. This leukocytic reduction results from suppressed infiltration, and intrarenal proliferation, but not enhanced apoptosis. The CSF-1-deficient MRL-Fas(lpr) kidneys remain preserved as indicated by greatly reduced indices of injury (nephritogenic cytokines, tubular apoptosis, and proliferation). The renal protective mechanism in CSF-1-deficient mice is not limited to reduced intrarenal leukocytes; circulating Igs and autoantibodies, and renal Ig deposits are decreased. This may result from enhanced B cell apoptosis and fewer B cells in CSF-1-deficient MRL-Fas(lpr) mice. Furthermore, the systemic illness including, skin, lung, and lacrimal and salivary glands pathology, lymphadenopathy, and splenomegaly are dramatically suppressed in CSF-1-deficient MRL-Fas(lpr) as compared with wild-type mice. These results indicate that CSF-1 is an attractive therapeutic target to combat Mphi-, T cell-, and B cell-mediated autoimmune lupus.
Authors:
Deborah M Lenda; E Richard Stanley; Vicki R Kelley
Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, P.H.S.    
Journal Detail:
Title:  Journal of immunology (Baltimore, Md. : 1950)     Volume:  173     ISSN:  0022-1767     ISO Abbreviation:  J. Immunol.     Publication Date:  2004 Oct 
Date Detail:
Created Date:  2004-09-22     Completed Date:  2004-11-15     Revised Date:  2007-11-14    
Medline Journal Info:
Nlm Unique ID:  2985117R     Medline TA:  J Immunol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  4744-54     Citation Subset:  AIM; IM    
Affiliation:
Laboratory of Molecular Autoimmune Disease, Renal Division, Brigham and Women's Hospital, Harvard University Medical School, Boston, MA 02115, USA.
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MeSH Terms
Descriptor/Qualifier:
Animals
Apoptosis / genetics,  immunology
B-Lymphocytes / immunology*,  pathology
Bone Marrow / immunology,  pathology
Cell Migration Inhibition
Chemokines / antagonists & inhibitors,  physiology
Complement C3 / metabolism
Cytokines / antagonists & inhibitors,  physiology
Down-Regulation / genetics,  immunology*
Epithelium / immunology,  pathology
Growth Inhibitors / deficiency,  genetics,  physiology
Immunoglobulin G / metabolism
Immunoglobulin Isotypes / biosynthesis
Kidney Glomerulus / immunology,  metabolism,  pathology
Kidney Tubules / immunology,  pathology
Lacrimal Apparatus / immunology,  pathology
Leukocytes / pathology
Leukopenia / genetics,  immunology,  pathology
Lung / immunology,  pathology
Lupus Nephritis / genetics,  immunology*,  pathology,  prevention & control
Lymphatic Diseases / genetics,  immunology,  pathology,  prevention & control
Macrophage Activation / genetics,  immunology
Macrophage Colony-Stimulating Factor / deficiency,  genetics,  physiology*
Macrophages / immunology*,  pathology
Mice
Mice, Inbred C3H
Mice, Inbred C57BL
Mice, Inbred MRL lpr
Mice, Knockout
Mice, Transgenic
Salivary Glands / immunology,  pathology
Severity of Illness Index
Skin / immunology,  pathology
Spleen / immunology,  pathology
Splenomegaly / genetics,  immunology,  prevention & control
T-Lymphocytes / immunology*,  pathology
Grant Support
ID/Acronym/Agency:
1F32DK-6029101/DK/NIDDK NIH HHS; 5P30-CA13330/CA/NCI NIH HHS; CA26504/CA/NCI NIH HHS; CA32551/CA/NCI NIH HHS; DK-36149/DK/NIDDK NIH HHS; DK-52369/DK/NIDDK NIH HHS; DK-56848/DK/NIDDK NIH HHS
Chemical
Reg. No./Substance:
0/Chemokines; 0/Complement C3; 0/Cytokines; 0/Growth Inhibitors; 0/Immunoglobulin G; 0/Immunoglobulin Isotypes; 81627-83-0/Macrophage Colony-Stimulating Factor

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