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(American Journal of Pathology. 2003;163:1127-1136.)
© 2003 American Society for Investigative Pathology

Deletion of the Fc Receptor IIb in Thymic Stromal Lymphopoietin Transgenic Mice Aggravates Membranoproliferative Glomerulonephritis

Anja S. Mühlfeld^*, Stephan Segerer, Kelly Hudkins^*, Matthew D. Carling^*, Min Wen^*, Andrew G. Farr, Jeffrey V. Ravetch^¶ and Charles E. Alpers^*

From the Departments of Pathology^* and Biological Structure, University of Washington, Seattle, Washington; the Laboratory of Molecular Genetics and Immunology,^¶ Rockefeller University, New York, New York; the Division of Nephrology and Immunology, University of Aachen, Aachen, Germany; and the Medizinische Poliklinik, Klinikum der Innenstadt, University of Munich, Munich, Germany

Engagement of immunoglobulin-binding receptors (FcR) on leukocytes and other cell types is one means by which immunoglobulins and immune complexes activate effector cells. One of these FcRs, FcRIIb, 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 FcRIIb 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 FcRIIb on the same genetic background (C57BL/6). Renal pathology was assessed in female and male animals (wild-type, FcRIIb-/-, TSLP transgenic, and combined TSLP transgenic/FcRIIb-/- mice) after 50 and 120 days, respectively. FcRIIb-/- mice had no significant renal pathology, whereas overexpression of TSLP induced a membranoproliferative glomerulonephritis, as previously established. TSLP transgenic FcRIIb-/- 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 FcRIIb in regulating immune responses and suggest that modulation of Fc receptor activation or expression may be a useful therapeutic approach for treating glomerular diseases.

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