The Vilen Lab
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Highlights of our findings on Lysosome Dysfunction in Lupus:
Kang, SA, JL Rogers, A Monteith, C Jiang, T Tarrant, R Roubey, M Dooley, R Falk, J Schmitz, M Diaz, G Fedoriw, and BJ Vilen. (2016) Apoptotic debris accumulates on hematopoietic cells and promotes disease in murine and human systemic lupus erythematosus. J. Immunol. 196:4030-9. PMID: 27059595, PMCID: 4868781.
This paper is the first to describe that nuclear self-antigens accumulate on the surface of hematopoietic cells in murine and human systemic lupus erythematosus (SLE). Using genetic manipulation (FcgRI-/-/MRL/lpr) and a passive antibody transfer model (anti-nucleosome into mice lacking IgG; AID-/-/MRL/lpr), it establishes that IgG-immune complexes (IgG-ICs) and Fcgamma receptor I (FcgRI) are biologically relevant in the murine lupus model (MRL/lpr). We conclude that:
· IgG-ICs and FcgRI (on myeloid cells) are important in the onset of SLE.
· Activation of myeloid cells precedes B cell expansion and fulminant production of autoantibody. This raises the possibility that myeloid cells (in addition to B cells) are key early effectors in SLE.
Monteith, AJ, SA, Kang, E Scott, K Hillman, Z Rajfur, KA Jacobson, MJ Costello, and BJ Vilen. (2016) Defects in lysosomal maturation facilitate the activation of innate sensors in systemic lupus erythematosus. Proc Natl Acad Sci USA 113: 2142-51. PMID: 27035940. PMCID: 4839468.
This paper is the first to describe a lysosome defect in systemic lupus erythematosus (SLE). It links with the Kang JI paper (above) by showing that the accumulated nuclear antigens seen on hematopoietic cells derive from phagocytosed IgG-ICs that failed to be degraded in the lysosome due to diminished acidification. As a consequence, the undegraded IgG-ICs (still bound to FcgRI) recycle back to the cell surface where they accumulate. We conclude that:
· Lysosome defects promote the recycling and accumulation of undegraded IgG-ICs bound to FcgRI. This raises the possibility that the link between IgG- ICs, nuclear self-antigens and past studies of diminished phagocytosis may reflect the recycling of IgG-ICs because of diminished lysosomal acidification.
· It has never been clear how cytosolic sensors gain access to their ligands. This study shows that in SLE, activation of cytosolic innate sensors reflects permeabilization of the phagosomal membrane allowing IgG-ICs to leak into the cytosol. This occurs when IgG-ICs fail to be efficiently degraded.
Monteith, AJ, HA Vincent, SA Kang,P Li, TM Claiborne, NJ Moorman, BJ Vilen. (2018) mTORC2 activity disrupts lysosome acidification in systemic lupus erythematosus by impairing caspase-1 cleavage of Rab39a. J. Immunol. 201:371-382 PMID: 29866702, PMCID: 6039264.
Is the lysosome defect genetically encoded, or induced? This paper shows that the lysosome defect is induced. Lysosome dysfunction is part of a feedforward loop wherein diminished lysosome acidification results from, and leads to, chronic FcgRI signal transduction. Mechanistically, chronic mTORC2 activity disrupts a previously unappreciated signal transduction cascade that normally induces lysosome maturation through cleavage of Rab39a. We conclude:
· Lysosome defects in lupus are induced and part of a feedforward loop.
· Chronic FcgRI signaling induces and perpetuates the feedforward loop. Disrupting mTORC2 activation restores lysosome function. This raises the possibility that attenuating the feedforward loop could be a therapeutic strategy for treating lupus.
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Complete List of Published Work in "My Bibliography":
http://www.ncbi.nlm.nih.gov/sites/myncbi/barbara.vilen.1/bibliography/41141027/public/?sort=date&direction=ascending
Patents
1. Issued patent: Product and method for treatment of conditions associated with receptor-desensitization. Patent #00914700.0-2116. Issued 2002.
2. Issued patent: Compositions and Methods for Repressing B cell Autoantibody Secretion and Treating Autoimmune Disease. Patent # 8,795,653. Issued 2014.
3. Provisional patent: Method for Treating SLE by Crosslinking Receptors. September 2017.
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Press Releases
https://www.rheumatologynetwork.com/q-and-a/dead-cells-disrupted-lysosomes-and-lupus
https://www.sciencemag.org/careers/2009/12/translating-lupus-research