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Barbara Vilen, PhD

Associate Professor, Microbiology and Immunology

Member, Lineberger Comprehensive Cancer Center

 

University of North Carolina at Chapel Hill
Chapel Hill, NC  27599-7290

 

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, particularly systemic lupus erythematosus (SLE).  Our contributions to this effort are outlined below, with contribution #4 describing the current lab focus.

Contributions To Science  * denotes equal contribution by authors

  1. An early interest was in mechanisms of B cell tolerance involving the B cell antigen receptor (BCR).  These studies identified that the Ig-alpha/Ig-beta signal transducing complex dissociated from mu-heavy chain to desensitize the BCR.  Subsequent co-aggregation of sheathed BCR (mu-heavy chains + Ig-alpha/Ig-beta) with mu-heavy chains lacking Ig-alpha/Ig-beta attenuated continued BCR signaling.  Mechanistically, the unsheathing of mu-heavy chain was required for clathrin-mediated endocytosis and delivery of antigen to the lysosome for antigen processing/presentation.

 

 

 

2.  Subsequent studies of tolerance addressed how autoreactive B cells were regulated during innate immune responses.  Although TLR4 activation was known as a polyclonal activator of B cells, it remained unclear how autoreactive B cells remained unresponsive during TLR4 stimulation since TLR4 is expressed on autoreactive and naïve B cells.  We found that concurrent TLR4 stimulation of dendritic cells and macrophages induced their secretion of IL-6 and soluble CD40L, which selectively repressed Ig secretion by autoreactive B cells.  Mechanistically, chronic BCR signaling limited nuclear translocation of phospho-ERK.  Thus, autoreactive B cells remain anergic because of receptor cross-talk between chronic BCR signaling and IL-6 receptor/CD40 signaling.  This regulates Ig secretion by TLR4. 

 

 

 

 

3.  B cell memory is an important aspect of humoral immunity and autoreactive memory cells play a role in perpetuating autoimmune response.  Our studies of B cell memory responses during immune activation to foreign antigens and pathogens identified that BAFF secretion, elicited by productive antigen-antibody immune complexes, is a key cytokine involved in upregulating Bcl-6 expression in activated T and B cells. We hypothesized that the lack of long-lasting protection following Staphylococcus aureus infection is disrupt because Protein A inhibits binding of immune complexes to Fcgamma receptors (FcgRs).  Instead we found that memory responses formed; however, S. aureus Protein A disrupted formation of long-lived plasma cells.  This led to a decline in S. aureus-specific antibody.  This occurred by limiting the proliferation of B cells that arrive in the bone marrow; thus, preventing cells from establishing long-lived bone marrow niches.  Instead, the presence of S. aureus Protein A expanded the short-lived extrafollicular B cell response.

 

 

 

 

4.  Apoptotic debris accumulates on the surface of murine and human hematopoietic cells in SLE. On myeloid cells this represents IgG-immune complexes that promote heightened BAFF secretion, autoantibody, migration of cells to the kidney and renal disease (SLE phenotypes).  Reducing BAFF to levels found in normal mice protects glomeruli from T cell infiltration and prevents renal disease. Mechanistically we find that the accumulation of ICs results from diminished acidification of the lysosome impairing degradation and promoting the recycling of Fcgamma receptor (FcgR)-bound ICs back to the cell membrane where they accumulate and sustain Fcgamma receptor I (FcgRI) signal transduction. The prolonged intracellular residency of nucleic acid and IgG from internalized IgG-ICs leads to TLR activation and causes the phagosome to leak cargo into the cytosol, promoting activation of AIM2 and TRIM21. Mechanistically, chronic mTOR activation is central to lysosome dysfunction, and mislocalization of mTOR within MRL/lpr macrophages dysregulates caspase1/11 impeding caspase 1 activation and the cleavage of Rab39a, a key event in lysosomal maturation.

 

 

 

 

 

 

 

 

Our current research focuses on defining whether human SLE has an underlying underlying lysosome defect that is similar to that identified in mice.  We have also identified targets to restore lysosome function in mice and are working to test whether this strategy affects the course of murine disease.  For more information on current research connect to the Vilen page on the Microbiol/Immunol site with this link:  https://www.med.unc.edu/microimm/directory/barbara-vilen-phd/

a.  Vilen, BJ, T Nakamura, JC Cambier.  (1999)  Immunity 10: 239-248. PMID: 10072076.

b.  Vilen, BJ, KM Burke, M Sleater, JC Cambier.  (2002)   J. Immunol. 168:4344-4351.  PMID: 11970976, PMCID:  3726184.

c.  Kim, J-H, L Cramer, H Mueller, B Wilson, BJ Vilen.  (2005)  J. Immunol. 175:147-154. PMID: 15972641, PMCID 3895480.

d.  Kim J-H, JA Rutan, and BJ Vilen.  (2007)  Int. Immunol. 19(12):1403-1412.  PMID: 17981794, PMCID:  3716379.

a.   Kilmon, MA, JA Rutan, SH Clarke, BJ Vilen. (2005) J. Immunol-Cutting Edge 175:37-41. PMID:15972629, PMCID: 3724409.

b.   Kilmon, MA, NJ Wagner, AL Garland, L Lin, K Aviszus, LK Wysocki, BJ Vilen. (2007) Blood 110:1595-1602. PMID: 17712049.

c.  Gilbert, MR*, Wagner, NJ,* SZ Jones, AB Wisz, J Roques, KN Krum, S-Y Lee, V Nickeleit, C Hulbert, JW Thomas, SB Gauld,       and BJ  Vilen.  (2012)  J. Immunol. 189: 711-20. PMID: 22675201, PMCID: 3392546.

d.  Lee, S-R*, Rutan, JA*, MA Kilmon, NJ Wagner, SZ Jones, SH Clarke, and BJ Vilen.  (2012) J. Immunol. 189: 3859-68.                  PMID:  22984080.

a.  Gohlke, PR, JC Williams, BJ Vilen, SR Dillon, R. Tisch, GK Matsushima.  (2009)   Autoimmunity 42:183-97 PMID: 19301199.

b.  Kang, SA*, AB Keener*, SZ Jones*, RJ Benschop, AC Maldonado, JC Rathmell, SH Clarke, GK Matsushima, JK Whitmire,               and BJ Vilen.  (2015)   J. Immunol. 196: 196-206.  PMID: 26621863; PMCID: 4684997.

c.  Keener, AB, LT Thurlow, NA Spidale, KM Cunnion, R Tisch, AR Richardson, and BJ Vilen. (2017) J. Immunol. 198:1263-73.             PMID: 28031339, PMCID: PMC5266639.

a.   Kang, SA, JL Rogers, A Monteith, C Jiang, T Tarrant, R Roubey, M Dooley, R Falk, J Schmitz, M Diaz, G Fedoriw, and BJ               Vilen. (2016) J. Immunol. 196:4030-9. PMID: 27059595, PMCID: 4868781.

b.   Monteith, AJ, SA, Kang, E Scott, K Hillman, Z Rajfur, KA Jacobson, MJ Costello, and BJ Vilen. (2016) Proc Natl Acad Sci USA        113: 2142-51. PMID: 27035940. PMCID: 4839468.

c.   Kang, SA, G Fedoriw, K Kikly, M Diaz, BJ Vilen. (2017)  J. Immunol. 198:2602-11 PMID: 28235864. PMCID:5360485

d.   Monteith, AJ, HA Vincent, SA Kang,P Li, TM Claiborne, NJ Moorman, BJ Vilen. (2018) J. Immunol. 201:371-382 PMID:                    29866702, PMCID: 6039264.