Noncanonical Autophagy and Toll-Like Receptor Signaling in SLE
Abstract
Systemic Lupus Erythematosus (SLE or Lupus) is characterized by the presence of high levels of antibodies that can bind to the nucleic acids DNA and RNA, which are normal constituents of almost all of the cells in the body. These autoantibodies contribute to SLE by lodging in organs such as the kidney, where they activate immune cells, which in turn cause organ damage. Recently, a specific subset of white blood cells, known as plasmacytoid dendritic cells (pDCs) have been implicated in SLE. pDCs form part of the "innate immune system," which is poised to respond rapidly to infection or tissue damage. pDCs are highly specialized to respond to viruses and contain receptors that can recognize the nucleic acids DNA and RNA, which are present in all viruses. pDCs respond to viruses by activating other arms of the immune response, including "T cells" that kill infected cells and "B cells" that make antibodies. However, DNA and RNA are also found in almost all cells in the body, and activation of pDCs by recognition of "self" DNA and RNA released from dying or damaged cells is thought to trigger the production of autoantibodies and drive development of SLE. We have recently identified a mechanism by which these responses to self-derived nucleic acids are prevented in pDCs, which relies on a process of waste disposal in the cell known as "autophagy". We have found that disruption of this process promotes autoantibody production and development of SLE-like disease in mouse models. Furthermore, variants in a gene involved in this autophagy process, ATG5, increase the risk of SLE in humans, suggesting this same pathway may be important in SLE. The objective of this grant is to determine whether variants in ATG5 affect autophagy and responses to RNA in pDCs and whether this regulatory pathway is disrupted in SLE. In Aim 1, we will measure responses of pDCs from healthy people with different variants of ATG5 to RNA, to understand how this gene affects autophagy and signaling. In Aim 2, we will investigate pDCs from SLE patients to determine whether the autophagy pathway is disrupted and how this affects markers of disease. This grant is designed to address the following focus areas: (1) Understand lupus heterogeneity by understanding basic disease mechanisms (2) Understand how the underlying genetic components of lupus relate to clinical disease characteristics using functional genomic studies The major immediate impact of this study is likely to be in understanding the mechanisms that underlie lupus and, in particular, help to explain why people with variants in ATG5 and related genes develop disease. This research is also likely to have longer term clinical impacts on potential patient therapy. One of the most effective current therapies for lupus is hydroxychloroquine, an inhibitor of autophagy; however, it remains unclear how hydroxychloroquine is effective against lupus. If successful, our research will provide new insights into how autophagy, and hence hydroxychloroquine, affects lupus. This, in turn, will allow development of better versions of hydroxychloroquine, as well as new potential therapies.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1810747
Entities
People
- Adam Lacy-Hulbert
Organizations
- Benaroya Research Institute
- United States Army