Barbara Vilen, PhD

Associate Professor
6110 Marsico Hall


Goals Statement:  The goals of my research are to elucidate the mechanisms that regulate immune responses to self- and foreign-antigen, and to identify how these mechanisms are dysregulated in autoimmunity and autoimmune diseases.

Murine Studies: 
The immune system protects the host during infection; yet, it must remain quiescent when encountering self-antigens.  In T and B cells, this process of “immune tolerance” is important in protecting the host from autoimmune disease.  In SLE, the breakdown in B cell tolerance is associated with the production of autoantibody. Heightened autoantibody and excessive nuclear self-antigens from dead cell debris (DNA, nucleosomes, ribonucleoproteins) promote the formation of pathogenic IgG immune complexes (IgG-ICs) associated with systemic lupus erythematosus (SLE).  IgG-ICs are found as renal deposits in lupus-prone mice and in SLE patients with lupus nephritis; however, the deposits are not sufficient for disease pathology.  Our laboratory found that in addition to the accumulation of IgG-ICs in kidney, nuclear antigens accumulate on the surface of hematopoietic cells (dendritic cells (DCs), macrophages (MFs) T and B cells).  On myeloid cells (DCs and MFs) the surface nuclear antigens are part of IgG-ICs that are bound to Fcgamma receptor I (FcgRI).  Following phagocytosis, internalized IgG-ICs recycle back to the cell surface where they accumulate.  This is a consequence of a lysosome defect that diminishes lysosomal acidification thereby reducing degradation of phagocytosed cargo.  The undegraded IgG-ICs that recycle and accumulate on the plasma membrane remain bound by FcgRI, perpetuating signal transduction. Chronic FcgRI signaling heightens lupus-associated cytokines (BAFF, Type 1 IFN), and accumulation of immune complexes containing nuclear antigens provides a source of membrane-bound self-antigen to activate autoreactive B cells.

Chronic FcgRI activation is important in lupus based on studies in FcgRI-/-/MRL/lpr mice showing that loss of FcgRI is sufficient to prevent onset of disease. These mice show diminished B cell activation, low autoantibody titers, and low serum BAFF levels. This is consistent with a link between FcgRI activation and the pathologies associated with SLE, and suggests that the lysosome defect is upstream of these phenotypes.  To assess whether lysosome dysfunction was induced, we inhibited the PI3k/mTOR pathway (kinase inhibitors) and found it restored lysosomal acidification. This is consistent with an induced, rather than genetically encoded defect, at the level of the lysosome.  We also showed that the lysosome defect is part of a feedforward loop where lysosome dysfunction and the subsequent recycling of FcgRI-bound cargo perpetuated FcgRI signaling, and chronic FcgRI signaling dysregulated lysosome acidification. We are currently defining the underlying molecular events that perpetuate FcgRI signal transduction.


Human Studies:  Attenuating the feedforward loop could be efficacious in treating SLE.  Another project focuses on defining whether lysosome dysfunction is evident in patients with SLE, and whether it correlates with disease activity.  Pilot data show that lysosome dysfunction is evident in SLE patients experiencing active disease; however, patients in inactive disease have normal lysosome function.  This supports the murine data showing that lysosome dysfunction is induced.  Our current focus is to define whether the correlation between lysosome function and disease activity is evident longitudinally, whether the underlying molecular events in human SLE parallel those in lupus-prone mice, and to define the frequency of the lysosome defect in SLE.


The Feedforward Loop as a Therapeutic Target:  We identified targets that attenuate the feedforward loop and restore lysosome function.  We are testing whether these targets affect the course of disease in lupus mice, and whether they restore lysosome function in isolated peripheral blood cells from SLE patients.


Other Studies in Development

  • Identify the receptors on B and T cells that accumulate nuclear antigens, since T and B cells do not express activating Fcg Define how these receptors contribute to disease
  • Identify the genetics that drive lysosome dysfunction using Collaborative Cross mice and genetically unique murine models of lupus.


Complete List of Published Work in My Bibliography: