The defective clearance of apoptotic cells and the increase in circulating immune complexes (ICs) have repeatedly been implicated in heightened cytokine secretion in systemic lupus erythematosus (SLE). Despite evidence of clearance defects, and presumably diminished access of TLR ligands to the endosome, cytokine secretion has been found to result from activated endosomal TLRs. This paradox raised the possibility that a more complicated model involving TLR-dependent and TLR-independent mechanisms regulates cytokine secretion. Our preliminary data show that IgG-ICs (IgG-apop ICs) bound in part via Fc?Rs are elevated 30-fold on the surface of DCs and MFs from autoimmune prone MRL/lpr mice. We show that this accumulation results from a degradation defect that promotes the recycling of internalized Fc?Rs bound IgG-ICs. In vivo and in vitro, the accumulation of ICs heightens BAFF secretion. In this application we will test the central hypothesis that IgG-apop ICs accumulate on DCs and MFs due to defects in targeting or degrading ICs within the endocytic/phagocytic pathway. This leads to pathogenic cytokine production as a consequence of genetic predisposition and chronic TLR and/or Fc?Rs signaling. We propose in aim 1 to identify where in the degradative pathway the progression of ICs is attenuated.
In aim 2, we postulate that chronic Fc?Rs signaling results when ICs bound to Fc?Rs remain aggregated during the recycling process, and that chronic TLR signaling results when the IC-loaded Fc?Rs spend prolonged time within these pathways. Lastly, we propose that although genetic predisposition might underlie the defects leading to the recycling of ICs, genetic events might also be required for heightened cytokine secretion. We will separate these putative genetic events by pharmacologically inducing IC recycling in non-autoimmune mice and assessing whether this leads to heightened cytokine production. Overall, this proposal is significant because it identifies that ICs accumulate on DCs and MFs and defines a more intricate mechanism for how TLR-dependent and TLR- independent mechanisms might contribute to elevated levels of lupus-related cytokines.

Public Health Relevance

These exploratory studies are relevant to tolerance for two reasons. First, they may provide a mechanism that links the recycling of immune complexes bound by Fcgamma receptors the heightened cytokine production seen in autoimmune disease. Secondly, they will begin to define a previously unappreciated defect that attenuates the degradation of immune complexes allowing their accumulation on the cell surface and activation of the immune system.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21AI105613-02
Application #
8605169
Study Section
Special Emphasis Panel (ZRG1-IMM-K (02))
Program Officer
Johnson, David R
Project Start
2013-01-15
Project End
2014-12-31
Budget Start
2014-01-01
Budget End
2014-12-31
Support Year
2
Fiscal Year
2014
Total Cost
$136,800
Indirect Cost
$46,800
Name
University of North Carolina Chapel Hill
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
608195277
City
Chapel Hill
State
NC
Country
United States
Zip Code
27599