Cryoglobulinemic glomerulonephritis in thymic stromal lymphopoietin transgenic mice

Mixed cryoglobulins are complexes of immunoglobulins that reversibly precip itate in the cold and lead to a systemic disease in humans. Renal involveme nt usually manifests as a membranoproliferative glomerulonephritis with mar ked monocyte infiltration and, at times, intracapillary thrombi. Thymic str omal lymphopoietin (TSLP) is a recently cloned cytokine that supports diffe rentiation and long-term growth of B cells. Here we report that TSLP overex pression in mice results in the development of mixed cryoglobulins, with re nal involvement closely resembling cryoglobulinemic glomerulonephritis as i t occurs in humans. One hundred twenty-three mice were sacrificed at monthl y intervals, with at least five TSLP transgenic mice and five controls in e ach group. Blood, kidneys, spleen, liver, lung, and ear were collected and studied by routine microscopy, immunofluorescence, immunohistochemistry, an d electron microscopy. TSLP transgenic animals developed polyclonal mixed c ryoglobulinemia (type III) and a systemic inflammatory disease involving th e kidney, spleen, liver, lung, and cars. Renal involvement was of a membran oproliferative type demonstrating thickened capillary walls with cellular i nterposition 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 mo nocyte/macrophage influx. In contrast to the severe glomerular lesions, the tubulointerstitium. was not involved in the disease process. The renal les ions and the disease course were more severe in females when compared to ma les. We describe a mouse strain in which a B-cell-promoting cytokine leads to formation of large amounts of mixed cryoglobulins and a systemic inflamm atory injury that resembles important aspects of human cryoglobulinemia. Th is is the first reproducible mouse model of renal involvement in mixed cryo globulinemia, which enables detailed studies of a membranoproliferative pat tern of glomerular injury.