Session Type: Abstract Submissions (ACR)
Background/Purpose: Failure to clear apoptotic bodies is a central pathogenic mechanism for SLE. We have observed that spontaneous systemic autoimmunity and lupus in BXD2 mice is associated with large germinal centers (GC) and development of highly pathogenic autoantibodies. The increased GCs in the spleen are promoted by increased Th17 cell, which is promoted by IL-23 in BXD2 mice. As anti-IL-23 therapy is under development for chronic inflammation and autoimmune diseases, we investigated the therapeutic potential of complete blocking IL-23 in BXD2 mice. We made an unexpected finding that complete deficiency of IL-23 accelerated and exacerbated systemic autoimmune disease in BXD2 mice.
Methods: Wild type (WT) BXD2 mice were treated with isotype control, anti-IL-17 or anti-IL-23 (100 ug iv Q3D x 3 doses). BXD2 mice were crossed to IL-23 p19 deficient (p19-/-) mice to generate BXD2-p19-/- mice. Confocal microscope analysis and/or FACS analysis were carried out to determine the clearance of GFP+ apoptotic cells (ACs), the percentages of PNA+ GC B cells, SIGN-R1+ marginal zone macrophages (MZMs), PDCA1+ plasmacytoid dendritic cells (pDCs), CD68+ red pulp macrophages, and IL-17+ or IFNγ+ CD4 T cells. ELISA assay was used to determine autoAb titers and protein urine levels in vivo. Quantitative RT-PCR was used to determine the expression of Il23, Il23r, Ifnα1, Ifnα4, Ifnα7, and Ifnα11. Depletion of MZMs was carried out by administration of clondronate liposome (167 ug/week x 8wk).
Results: Anti-IL-17 blocked development of GCs in BXD2 mice. Surprisingly, anti-IL-23 enhanced GC development and anti-dsDNA antibody production. Similarly, there was accelerated development of spontaneous GCs, production of anti-dsDNA antibody and IC deposition in the glomerulus of BXD2-p19-/-, compared with WT mice. While IL-23R was mainly expressed by MZMs, IL-23 was mainly produced by red pulp macrophages that were in close proximity to the MZM in the extra-follicular region of the spleen of BXD2 mice. Deficiency of IL-23 was associated with a dramatic reduction of MZMs in the spleen of BXD2-p19-/- mice. In contrast, expression of IL-23 by adenovirus in BXD2-p19-/- mice at early age prevented the loss of MZM and the initiation of glomerulonephritis. Clondronate liposome treatment mimicked the effects of p19-/-, leading to depletion of MZMs, impaired clearance of ACs and severely accelerated autoimmune disease. This was associated with dramatically elevated serum levels of type I IFN genes including Ifnα1, Ifnα4, Ifnα7, Ifnα11. Although there was diminished Th17 cells in BXD2-p19-/- mice, defective clearance of ACs was associated with greatly elevated production of type I IFNs by pDCs and IFNγ by Th1 cells.
Conclusion: Our results suggest a novel concept that IL-23 can act as a double edge sword to control the development and severity of autoimmunity. Overexpression of IL-23 may provoke autoimmunity through the induction/maintenance of Th17 yet a complete deficiency of IL-23 also induced autoimmunity through the loss of the MZM barrier that clears ACs and prevents follicular invasion of apoptotic autoantigens. Our results suggest that caution should be used when considering IL-23 blockade for treatment of autoimmune disease.
H. C. Hsu,
Merck Research Laboratory,
J. D. Mountz,
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ACR Meeting Abstracts - https://acrabstracts.org/abstract/il-23-controls-autoimmunity-by-facilitating-clearance-of-apoptotic-bodies-in-the-marginal-zone-in-lupus-prone-bxd2-mice/