A rationally engineered DNase1-Fc fusion protein ameliorates autoimmune glomerulonephritis
| Autor: | Maria Mouchess, Eric Suto, Sara Chan, Bingbing Dai, Christine Tam, Yi Cao, Martine Darwish, Dongping He, Susan Haller, Jeffrey Eastham-Anderson, Yvonne Franke, Craig Blanchette, Wyne Lee, Cary Austin, Robert Lazarus, Tangsheng Yi |
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| Rok vydání: | 2019 |
| Předmět: | |
| Zdroj: | The Journal of Immunology. 202:132.4-132.4 |
| ISSN: | 1550-6606 0022-1767 |
| Popis: | Loss of B cell tolerance and generation of autoreactive anti-nuclear antibodies are hallmarks of systemic lupus erythematosus and lupus nephritis. The mechanism of anti-nuclear immunoglobulin accumulation and clearance in lupus nephritis pathogenesis remains largely uncharacterized. Here, we show that innate immune activation in the NZB/W F1 mouse model and human lupus nephritis biopsies rapidly reduces expression of DNase1 (also called DNase I) in renal cortex proximal tubular cells. Unexpectedly, kidney DNase1 levels were no longer affected by TLR ligand agonism upon depletion of macrophages, indicating that local macrophage activation is required for the downmodulation of DNase1 in kidney epithelial cells. To overcome the loss of endogenous DNase1, we rationally designed a hyperactive actin-resistant variant of DNase1 with improved catalytic activity and acceptable in vivo pharmacokinetics. The engineered DNase1-Fc fusion protein ameliorates nephritis in a murine model of lupus and reduces immune complex deposition/complement fixation. Our data suggest that the loss of renal DNase1 through TLR signaling or other innate immune activation impairs clearance of autoreactive anti-nuclear immune complex deposits in the kidney to promote nephritis progression. While autoantibodies and autoreactive B cell activation are central to lupus pathogenesis, we hypothesize that renal cortical epithelial cells expressing high levels of DNase1 serve as gatekeepers to prevent detrimental nuclear immune complex deposition. Our findings provide a therapeutic rationale for using an engineered hyperactive actin-resistant DNase1-Fc for lupus nephritis. |
| Databáze: | OpenAIRE |
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