Cryoglobulinemic Glomerulonephritis in Thymic Stromal Lymphopoietin Transgenic Mice

Abstract

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.

Imatinib Suppresses Cryoglobulinemia and Secondary Membranoproliferative Glomerulonephritis

“…8,30 In mice treated beginning at weaning, the total amount of circulating cryoglobulins, as determined by volume of serum cryoprecipitate, was markedly reduced and frequently undetectable in imatinib-treated TSLP-Tg mice compared with untreated control mice, assessed by both visual examination ( Figure 1A) and measured cryocrit ( Figure 1B). The serum IgM, IgG1, and IgG2a concentrations in TSLP-Tg mice were markedly increased compared with those of wild-type (WT) mice.…”

“…Mice Tg for TSLP have been previously described in detail. 8 Female mice were used in the first part of the study examining the effects of imatinib early in the disease course, because of the shorter time frame in which the MPGN develops in the female gender. Both TSLP-Tg and WT mice were randomly assigned to four groups: Treated TSLP-Tg mice, untreated TSLP-Tg mice, treated WT mice, and untreated WT mice.…”

“…Tissue was collected in halfstrength Karnovsky fixative for electron microscopy as described previously. 8 Immunohistochemical and Immunofluorescence Analysis Mac-2, ␣-SMA, and collagen IV immunostaining were performed as described previously. 30,35 We performed immunofluorescence analysis for IgM, IgG, IgA, and C3 as described previously.…”

“…Through still undetermined mechanisms, transgenic mice that express TSLP under the control of the proximal lck promoter have been shown to develop reliably a disorder in which B cells produce abnormal Ig that result in a mixed cryoglobulinemia and a cryoglobulinemic membranoproliferative glomerulonephritis (MPGN) that closely resembles human MPGN. 8 Humans afflicted with mixed cryoglobulinemia (a disorder in which complexes of Ig precipitate in the cold) develop various manifestations, including small vessel vasculitis affecting the skin and visceral organs, and MPGN. In severely affected patients, this disorder can be fatal.…”

Emerging Paradigms in the Renal Pathology of Viral Diseases

“…One of these, the thymic stromal lymphopoietin (TSLP) transgenic mouse, develops cryoglobulinemia and a cryoglobulinemic MPGN that closely resembles that of human HCV-associated MPGN (37). Studies from this model have strongly implicated the engagement of Fc receptors as a major regulator of glomerulonephritis.…”