This Article Full Text Full Text (PDF) Purchase Article View Shopping Cart Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Taneda, S. Articles by Alpers, C. E. Search for Related Content PubMed PubMed Citation Articles by Taneda, S. Articles by Alpers, C. E.

(American Journal of Pathology. 2001;159:2355-2369.)
© 2001 American Society for Investigative Pathology

Animal Model

Cryoglobulinemic Glomerulonephritis in Thymic Stromal Lymphopoietin Transgenic Mice

Sekiko Taneda^*, Stephan Segerer^*, Kelly L. Hudkins^*, Yan Cui^*, Min Wen^*, Manuela Segerer^*, Mark H. Wener, Christian G. Khairallah, Andrew G. Farr and Charles E. Alpers^*

From the Departments of Pathology,^*
Laboratory Medicine,
and Biological Structure,
University of Washington, Seattle, Washington

Mixed cryoglobulins are complexes of immunoglobulins that reversibly precipitate in the cold and lead to a systemic disease in humans. Renal involvement usually manifests as a membranoproliferative glomerulonephritis with marked monocyte infiltration and, at times, intracapillary thrombi. Thymic stromal lymphopoietin (TSLP) is a recently cloned cytokine that supports differentiation and long-term growth of B cells. Here we report that TSLP overexpression in mice results in the development of mixed cryoglobulins, with renal involvement closely resembling cryoglobulinemic glomerulonephritis as it occurs in humans. One hundred twenty-three mice were sacrificed at monthly intervals, with at least five TSLP transgenic mice and five controls in each group. Blood, kidneys, spleen, liver, lung, and ear were collected and studied by routine microscopy, immunofluorescence, immunohistochemistry, and electron microscopy. TSLP transgenic animals developed polyclonal mixed cryoglobulinemia (type III) and a systemic inflammatory disease involving the kidney, spleen, liver, lung, and ears. Renal involvement was of a membranoproliferative type demonstrating thickened capillary walls with cellular interposition and double contours of the basement membrane, expansion of the mesangium because of increased matrix and accumulation of immune-deposits, subendothelial immune-deposits, focal occlusion of capillary loops, and monocyte/macrophage influx. In contrast to the severe glomerular lesions, the tubulointerstitium was not involved in the disease process. The renal lesions and the disease course were more severe in females when compared to males. We describe a mouse strain in which a B-cell-promoting cytokine leads to formation of large amounts of mixed cryoglobulins and a systemic inflammatory injury that resembles important aspects of human cryoglobulinemia. This is the first reproducible mouse model of renal involvement in mixed cryoglobulinemia, which enables detailed studies of a membranoproliferative pattern of glomerular injury.

This article has been cited by other articles:

				H. K. Jessup, A. W. Brewer, M. Omori, E. A. Rickel, A. L. Budelsky, B.-R. P. Yoon, S. F. Ziegler, and M. R. Comeau Intradermal Administration of Thymic Stromal Lymphopoietin Induces a T Cell- and Eosinophil-Dependent Systemic Th2 Inflammatory Response J. Immunol., September 15, 2008; 181(6): 4311 - 4319. [Abstract] [Full Text] [PDF]

				S. Guo, J. Kowalewska, T. A. Wietecha, M. Iyoda, L. Wang, K. Yi, M. Spencer, M. Banas, S. Alexandrescu, K. L. Hudkins, et al. Renin-Angiotensin System Blockade Is Renoprotective in Immune Complex-Mediated Glomerulonephritis J. Am. Soc. Nephrol., June 1, 2008; 19(6): 1168 - 1176. [Abstract] [Full Text] [PDF]

				G. M. Hunninghake, J. Lasky-Su, M. E. Soto-Quiros, L. Avila, C. Liang, S. L. Lake, T. J. Hudson, M. Spesny, E. Fournier, J. S. Sylvia, et al. Sex-stratified Linkage Analysis Identifies a Female-specific Locus for IgE to Cockroach in Costa Ricans Am. J. Respir. Crit. Care Med., April 15, 2008; 177(8): 830 - 836. [Abstract] [Full Text] [PDF]

				M. C. Banas, B. Banas, K. L. Hudkins, T. A. Wietecha, M. Iyoda, E. Bock, P. Hauser, J. W. Pippin, S. J. Shankland, K. D. Smith, et al. TLR4 Links Podocytes with the Innate Immune System to Mediate Glomerular Injury J. Am. Soc. Nephrol., April 1, 2008; 19(4): 704 - 713. [Abstract] [Full Text] [PDF]

				S. Taneda, K. L. Hudkins, A. S. Muhlfeld, J. Kowalewska, J. W. Pippin, S. J. Shankland, and C. E. Alpers Protease Nexin-1, tPA, and PAI-1 are Upregulated in Cryoglobulinemic Membranoproliferative Glomerulonephritis J. Am. Soc. Nephrol., February 1, 2008; 19(2): 243 - 251. [Full Text] [PDF]

				M. Iyoda, K. L. Hudkins, T. A. Wietecha, M. C. Banas, S. Guo, G. Liu, L. Wang, J. Kowalewska, and C. E. Alpers All-trans-retinoic acid aggravates cryoglobulin-associated membranoproliferative glomerulonephritis in mice Nephrol. Dial. Transplant., December 1, 2007; 22(12): 3451 - 3461. [Abstract] [Full Text] [PDF]

				C. E. Alpers and J. Kowalewska Emerging Paradigms in the Renal Pathology of Viral Diseases Clin. J. Am. Soc. Nephrol., July 1, 2007; 2(Supplement_1): S6 - S12. [Abstract] [Full Text] [PDF]

				D. Sansonno, A. Carbone, V. De Re, and F. Dammacco Hepatitis C virus infection, cryoglobulinaemia, and beyond Rheumatology, April 1, 2007; 46(4): 572 - 578. [Abstract] [Full Text] [PDF]

				J. Kowalewska, A. S. Muhlfeld, K. L. Hudkins, M. M. Yeh, A. G. Farr, J. V. Ravetch, and C. E. Alpers Thymic Stromal Lymphopoietin Transgenic Mice Develop Cryoglobulinemia and Hepatitis with Similarities to Human Hepatitis C Liver Disease Am. J. Pathol., March 1, 2007; 170(3): 981 - 989. [Abstract] [Full Text] [PDF]

				N. Carpino, W. E. Thierfelder, M.-s. Chang, C. Saris, S. J. Turner, S. F. Ziegler, and J. N. Ihle Absence of an Essential Role for Thymic Stromal Lymphopoietin Receptor in Murine B-Cell Development Mol. Cell. Biol., March 15, 2004; 24(6): 2584 - 2592. [Abstract] [Full Text] [PDF]

				K. L. Hudkins, D. G. Gilbertson, M. Carling, S. Taneda, S. D. Hughes, M. S. Holdren, T. E. Palmer, S. Topouzis, A. C. Haran, A. L. Feldhaus, et al. Exogenous PDGF-D Is a Potent Mesangial Cell Mitogen and Causes a Severe Mesangial Proliferative Glomerulopathy J. Am. Soc. Nephrol., February 1, 2004; 15(2): 286 - 298. [Abstract] [Full Text] [PDF]

				M. J. Osborn, P. L. Ryan, N. Kirchhof, A. Panoskaltsis-Mortari, F. Mortari, and K.-S. R. S. Tudor Overexpression of murine TSLP impairs lymphopoiesis and myelopoiesis Blood, February 1, 2004; 103(3): 843 - 851. [Abstract] [Full Text] [PDF]

				A. S. Muhlfeld, S. Segerer, K. Hudkins, M. D. Carling, M. Wen, A. G. Farr, J. V. Ravetch, and C. E. Alpers Deletion of the Fc{gamma} Receptor IIb in Thymic Stromal Lymphopoietin Transgenic Mice Aggravates Membranoproliferative Glomerulonephritis Am. J. Pathol., September 1, 2003; 163(3): 1127 - 1136. [Abstract] [Full Text] [PDF]

				S. Taneda, J. W. Pippin, E. H. Sage, K. L. Hudkins, Y. Takeuchi, W. G. Couser, and C. E. Alpers Amelioration of Diabetic Nephropathy in SPARC-Null Mice J. Am. Soc. Nephrol., April 1, 2003; 14(4): 968 - 980. [Abstract] [Full Text] [PDF]