Targeting Multiple Lupus-Associated Pathologies by Restoring Lysosome Function
Abstract
Background: Dying cells are rapidly cleared from the body and then degraded in an intracellular organelle called a lysosome. This process is vital to proper immune function and is achieved through multiple cell surface receptors including Fcgamma receptors (FcgRs). FcgRs capture antibody-coated cell debris from blood or lymphatic fluid, transport it into the cell, and then through intracellular vesicles that eventually fuse with lysosomes and the cargo is degraded. For lysosomes to degrade cell debris, they must first acidify (decrease pH), because lysosomal enzymes that degrade proteins and lipids contained within cell debris can only be activated in an acidic (low pH) environment. Rationale: We have found that lysosome acidification is disrupted in genetically unrelated murine lupus models and in systemic lupus erythematosus (SLE) patients experiencing active disease. By analyzing cells whose function is to clear dying cells, we discovered that the inability of lysosomes to effectively acidify causes cell debris that reaches the lysosomes to be sent back to the cell surface in an undegraded form, and still bound to FcgRs. This induces chronic activation of FcgRs, which in turn, diminish the ability of lysosomes to acidify. Thus, the lysosome defect is part of a vicious cycle (or feedforward loop, where lysosome dysfunction results from, and leads to, chronic FcgRI activation) sustaining immune responses that normally are meant to be transient. We have shown in published work that the sustained activation of FcgRs promotes multiple events associated with SLE including elevating the levels of cytokines such as B cell activating factor (BAFF) and interferon-alpha, expanding autoreactive B cells, increasing autoantibody levels, and inducing immune cells to migrate to the kidney. Hence, assessing whether attenuating the lysosome defect affects immune cell activation in human blood cells, or whether it affects the course of disease in murine lupus is important. Objective and Aims: Our study will test a strategy designed to attenuate the vicious cycle and restore lysosome function and immune regulation in lupus mice (Aim 1). This will be accomplished using a bispecific antibody that crosslinks activating FcgRI with inhibitory FcgRIIb as a design to engage the off switch used in normal cells. Preliminary data show this strategy is efficacious in vitro, but whether the strategy is effective in vivo or able to affect lupus-related pathologies is unknown. It is also important to establish whether crosslinking FcgRI and/or FcgRIIa with FcgRIIb on human cells restores lysosome function and decreases cellular activation if this strategy were to have potential as a therapy (Aim 2). Our preliminary data show that SLE patient in active, but not inactive disease, exhibit diminished lysosome acidification. This is consistent with findings in mice that lysosome dysfunction is inducible as we find that inhibiting FcgRI signaling restores lysosome function. Thus, the inducible nature of the lysosome defect, and the elucidation of the underlying molecular events (shown in preliminary data), position us to assess whether this defect could be target for therapy. In summary, the proposed project is important to the LRP Focus Area of understanding lupus disease mechanisms and could identify a novel target for intervention (lysosome dysfunction) and a potential strategy for therapy (crosslinking FcgRI and/or FcgRIIa with FcgRIIb). Applicability: The impact of this proposal is on the treatment of lupus. If attenuating the vicious cycle created by lysosome dysfunction through crosslinking FcgR1with FcgRIIb prevents disease or attenuates disease progression in mice, it raises the possibility that such a strategy may be therapeutically efficacious in restoring lysosome function in active SLE, or in preventing dysfunction in inactive patients. The important component to this idea is how many patients harbor this defect? Our ongoing cross-sect
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Nov 19, 2019
- Source ID
- W81XWH1910328
Entities
People
- Barbara J Vilen
Organizations
- United States Army
- University of North Carolina at Chapel Hill