Stephen H Clarke, PhD

Clarke, Stephen

Professor

626 Mary Ellen Jones Bldg, CB #7290

919.966.3131

shl@med.unc.edu

 


Research

The major interest of this laboratory is the differentiation and regulation of autoreactive B cells in health and disease. The molecular genetic process that determines B cell specificity inevitably results in B cells specific for self-antigens. Thus, mechanisms have evolved to eliminate these cells or render them non-functional. However, these mechanisms fail in individuals who develop autoimmune disease. Our long-range goal is to identify and understand the mechanisms that regulate autoreactive B cells and how they fail in disease. Such information is key to devise rational new therapeutic strategies for the treatment of autoimmune diseases.

Our research focuses on the regulation of B cells specific for the ribonucleoprotein antigen Sm, a target of the immune system in systemic lupus erythematosus (SLE). The presence of anti-Sm antibodies in serum is diagnostic of SLE and an indicator of more severe disease and poorer outcome. We have generated anti-Sm transgenic mice that produce a high frequency of anti-Sm B cells, making it possible to examine and follow the differentiation of these cells. We have identified multiple mechanisms of regulation. Some are eliminated by cell death, while others are rendered non-functional. Paradoxically, some anti-Sm B cells are positively selected for long-term survival and are functional. We seek to understand how these cells are regulated. Current evidence indicates that it is these positively selected and functional anti-Sm B cells that are activated in mouse SLE. Efforts are underway to understand how these cells are activated; the roles of T cells, dendritic cells, and the components of the complement system, all of which are strongly implicated in the etiology of SLE in humans and mice, are currently being examined.

We have also begun an analysis of how Epstein Barr virus (EBV) contributes to SLE. EBV is strongly associated with SLE in humans, but the mechanism is unknown. The current paradigm holds that molecular mimicry is responsible for anti-self B cell activation. Although this may occur, we think it is insufficient to explain the association, and argue that EBV infection of B cells alters the regulation of anti-self B cells. LMP2A encoded by the EBV genome, is known to affect B cell differentiation and we have recently demonstrated that LMP2A affects the regulation of anti-Sm B cells, allowing their activation and anti-Sm antibody production in mice. Efforts are underway to understand the underlying molecular and cellular mechanisms involved.

Finally, we have initiated studies in human SLE and determined that many patients with high titers of anti-Sm antibody in their serum also had high frequencies of anti-Sm B cells in their blood. These cells are predominantly memory B cells that have undergone somatic hypermutation. Interestingly, we identified abnormalities with their B cell receptor that may provide clues to how these cells are activated in human lupus. Current efforts are to understand the ability of these cells to be activated.

Publications

Lee SR, Rutan JA, Monteith AJ, Jones SZ, Kang SA, Krum KN, Kilmon MA, Roques JR, Wagner NJ, Clarke SH, Vilen BJ. Receptor cross-talk spatially restricts p-ERK during TLR4 stimulation of autoreactive B cells. J Immunol. 2012 Oct 15;189(8):3859-68.

Clarke SH. Reducing the public health risk of cryptosporidiosis by optimizing treatment processes at a military water system. US Army Med Dep J. 2011 Jul-Sep:50-61.

Qian Y, Clarke SH, Aoki V, Hans-Filhio G, Rivitti EA, Diaz LA. Antigen selection of anti-DSG1 autoantibodies during and before the onset of endemic pemphigus foliaceus. J Invest Dermatol. 2009 Dec;129(12):2823-34.

Dasu T, Sindhava V, Clarke SH, Bondada S. CD19 signaling is impaired in murine peritoneal and splenic B-1 B lymphocytes. Mol Immunol. 2009 Aug;46(13):2655-65.

Diz R, McCray SK, Clarke SH. B cell receptor affinity and B cell subset identity integrate to define the effectiveness, affinity threshold, and mechanism of anergy. J Immunol. 2008 Sep 15;181(6):3834-40.

Bunch DO, Silver JS, Majure MC, Sullivan P, Alcorta DA, Chin H, Hogan SL, Lindstrom YI, Clarke SH, Falk RJ, Nachman PH. Maintenance of tolerance by regulation of anti-myeloperoxidase B cells. J Am Soc Nephrol. 2008 Sep;19(9):1763-73.

Clarke SH. Anti-Sm B c ell tolerance and tolerance loss in systemic lupus erythematosus. Immunol Res. 2008;41(3):203-16.

Nicholas MW, Dooley MA, Hogan SL, Anolik J, Looney J, Sanz I, Clarke SH. A novel subset of memory B cells is enriched in autoreactivity and correlates with adverse outcomes in SLE. Clin Immunol. 2008 Feb;126(2):189-201.

Wang H, Feng J, Qi CF, Li Z, Morse HC 3rd, Clarke SH. Transitional B cells lose their ability to receptor edit but retain their potential for positive and negative selection. J Immunol. 2007 Dec 1;179(11):7544-52.

Contreras CM, Halcomb KE, Randle L, Hinman RM, Gutierrez T, Clarke SH, Satterthwaite AB. Btk regulates multiple stages in the development and survival of B-1 cells. Mol Immunol. 2007 Apr;44(10):2719-28.

Qian Y, Diaz LA, Ye J, Clarke SH. Dissecting the anti-desmoglein autoreactive B cell repertoire in pemphigus vulgaris patients. J Immunol. 2007 May 1;178(9):5982-90.

Culton DA, Nicholas MW, Bunch DO, Zhen QL, Kepler TB, Dooley MA, Mohan C, Nachman PH, Clarke SH. Similar CD19 dysregulation in two autoantibody-associated autoimmune diseases suggests a shared mechanism of B-cell tolerance loss. J Clin Immunol. 2007 Jan;27(1):53-68.

Wang H, Clarke SH. Association of the pre-B cell receptor (BCR) expression level with the quality of pre-BII cell differentiation reveals hierarchical pre-BCR function. Mol Immunol. 2007 Mar;44(7):1765-74.

pubmed Complete list of publications.