Abstract
Individuals suffering from autoimmune disorders possess a hyperactive cellular phenotype where tolerance to self-antigens is lost. Autophagy has been implicated in both the induction and prevention of autoimmunity, and modulators of this cellular recycling process hold high potential for the treatment of autoimmune diseases. In this study, we determine the effects of a loss of autophagy in dendritic cells (DCs), as well as both B cells and DCs, in a TLR7-mediated model of autoimmunity, similar to systemic lupus erythematosus, where both cell types are critical for disease. Although a loss of DC autophagy slowed disease, the combined loss of autophagy in both cell types resulted in a lethal sepsis-like environment, which included tissue inflammation and hyperproduction of inflammasome-associated cytokines. Ablation of B cell signaling reversed this phenotype, indicating that activation of these cells is an essential step in disease induction. Thus, autophagy plays a dichotomous role in this model of disease.
Footnotes
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This work was supported in part by National Institutes of Health/Clinical and Translational Science Institute Grant UL1TR001064 (to B.T.H.).
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The online version of this article contains supplemental material.
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Abbreviations used in this article:
- ANA
- antinuclear Ab
- APS
- antiphospholipid syndrome
- ATG
- autophagy-related gene
- Bko
- Cd19-cre+/−Atg5f/f
- CL
- cardiolipin
- DBko
- Cd11c-cre+/−Cd19-cre+/−Atg5f/f
- DC
- dendritic cell
- Dko
- Cd11c-cre+/−Atg5f/f
- EMH
- extramedullary hematopoiesis
- ko
- knockout
- LAP
- LC3-associated phagocytosis
- LN
- lymph node
- mDC
- myeloid DC
- mtDNA
- mitochondrial DNA
- MZ
- marginal zone
- PAS
- periodic acid–Schiff
- pDC
- plasmacytoid DC
- SLE
- systemic lupus erythematosus
- tg
- transgenic.
- Received August 8, 2016.
- Accepted November 21, 2016.
- Copyright © 2017 by The American Association of Immunologists, Inc.