Deletion of the fcgamma receptor IIb in thymic stromal lymphopoietin transgenic mice aggravates membranoproliferative glomerulonephritis.
Engagement of immunoglobulin-binding receptors (FcgammaR) on leukocytes and other cell types is one means by which immunoglobulins and immune complexes activate effector cells. One of these FcgammaRs, FcgammaRIIb, is thought to contribute to protection from autoimmune disease by down-regulation of B-cell responsiveness and myeloid cell activation. We assessed the role of FcgammaRIIb in a mouse model of cryoglobulin-associated membranoproliferative glomerulonephritis induced by overexpression of thymic stromal lymphopoietin (TSLP). TSLP transgenic mice were crossbred with animals deficient for FcgammaRIIb on the same genetic background (C57BL/6). Renal pathology was assessed in female and male animals (wild-type, FcgammaRIIb-/-, TSLP transgenic, and combined TSLP transgenic/FcgammaRIIb-/- mice) after 50 and 120 days, respectively. FcgammaRIIb-/- mice had no significant renal pathology, whereas overexpression of TSLP induced a membranoproliferative glomerulonephritis, as previously established. TSLP transgenic FcgammaRIIb-/- mice appeared sick with increased mortality. Kidney function was significantly impaired in male mice corresponding to aggravated glomerular pathology with increases in glomerular matrix and cellularity. This resulted from both a large influx of infiltrating macrophages and increased cellular proliferation. These results emphasize the important role of FcgammaRIIb in regulating immune responses and suggest that modulation of Fcgamma receptor activation or expression may be a useful therapeutic approach for treating glomerular diseases.
Mühlfeld
Anja S
AS
Department of Pathology, University of Washington, 1959 NE Pacific Street, Seattle, WA 98195, USA.
Segerer
Stephan
S
Hudkins
Kelly
K
Carling
Matthew D
MD
Wen
Min
M
Farr
Andrew G
AG
Ravetch
Jeffrey V
JV
Alpers
Charles E
CE
D000818:Animals; D000936:Antigen-Antibody Complex; D015703:Antigens, CD / Q000235:genetics*; D003165:Complement System Proteins / Q000378:metabolism; D016207:Cytokines / Q000235:genetics / Q000378:metabolism*; D005260:Female; D017353:Gene Deletion; D015432:Glomerulonephritis, Membranoproliferative / Q000276:immunology / Q000401:mortality / Q000503:physiopathology*; D007136:Immunoglobulins / Q000378:metabolism; D007668:Kidney / Q000503:physiopathology; D007678:Kidney Glomerulus / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009017:Morbidity; D017452:Receptors, IgG / Q000235:genetics*; D012720:Severity of Illness Index; D017154:Stromal Cells / Q000378:metabolism*; D013950:Thymus Gland / Q000378:metabolism*; D000094632:Thymic Stromal Lymphopoietin
D000936:Antigen-Antibody Complex; D015703:Antigens, CD; D016207:Cytokines; C080571:Fc gamma receptor IIB; D007136:Immunoglobulins; D017452:Receptors, IgG; D003165:Complement System Proteins; D000094632:Thymic Stromal Lymphopoietin; C000721967:TSLP protein, mouse