Molecular and Cellular Mechanisms of Antibody Activity by Falk Nimmerjahn

Author:Falk Nimmerjahn
Language: eng
Format: epub
Publisher: Springer New York, New York, NY

6.3.2 Induction of Glomerular and Vascular Lesions by IgG3 Anti-IgG2a RF Cryoglobulins

Cryoglobulins have long been suggested to be a potential contributor to tissue injuries in SLE, rheumatoid arthritis, and related autoimmune diseases (Brouet et al. 1974). Indeed, a fraction of cryoprecipitating IgG3 anti-IgG2a RF and anti-DNA mAbs derived from lupus-prone mice are highly pathogenic, generating glomerular and vascular lesions (Gyotoku et al. 1987; Berney et al. 1992; Lemoine et al. 1992; Itoh et al. 1993; Takahashi et al. 1993). For example, the implantation of hybridoma cells secreting IgG3 anti-IgG2a RF derived from MRL-Fas lpr mice into non-autoimmune mice rapidly induces the development of “wire-loop”-like glomerular lesions characterized by subendothelial immune deposits in glomeruli (Fig. 6.2a) and of cutaneous leukocytoclastic vasculitis (Fig. 6.2b, c) which are also observed in patients with SLE and mixed cryoglobulinemia. The pathogenic potential of IgG3 autoantibodies in association with cryoglobulin activity has been supported by the analysis of a panel of anti-IgG2a RF mAbs including Ig class-switch variants of 6–19 anti-IgG2a RF mAb (Berney et al. 1992; Fulpius et al. 1993; Moll et al. 1995). Moreover, the essential role of cryoglobulin activity for the pathogenic potential of IgG3 autoantibodies has been confirmed by the finding that the highly sialylated 6–19 IgG3 F243A mutant lacking cryoglobulin activity induces neither glomerular nor skin vascular lesions (Otani et al. 2012).

Fig. 6.2 Induction of glomerulonephritis and cutaneous vasculitis in mice after intraperitoneal implantation of 6–19 IgG3 anti-IgG2a RF hybridoma cells. (a) Representative histological appearance of glomerular lesions 8 days after injection of 6–19 hybridoma cells. Note the presence of PAS-positive deposits along the glomerular capillary walls (arrows), resembling “wire-loop” lesions (PAS staining). (b) Development of vascular purpura in the skin of ears 5 days after injection of 6–19 hybridoma cells. (c) Representative histological appearance of skin lesions induced by 6–19 IgG3 RF mAb. Leukocytoclastic vasculitis is characterized by the infiltration of PMN and the extravasation of RBC (HE staining)

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