Description of Research Expertise:
Genetic and functional characterization of human anti-desmoglein B cell repertoires
Targeted therapy for pemphigus
Regulation of desmosome adhesion
Key words: autoimmunity, human immunology, CAR T cells, adoptive immunotherapy, cell adhesion, dermatology, skin, cadherin, p38 MAPK
Description of Research:
Pemphigus vulgaris is a potentially fatal disorder in which autoantibodies against desmosomal cell adhesion molecules known as desmogleins cause blistering of the skin and mucous membranes. Our laboratory is interested in better understanding pathogenic mechanisms in this model organ-specific autoimmune disease, from both the immunologic and cell biologic perspectives.
A fundamental question in organ-specific autoimmune disease is why the immune system breaks tolerance against only a limited number of self-antigens. We have cloned B cell repertoires from pemphigus vulgaris patients to understand how they developed desmoglein autoreactivity. We have identified shared VH1-46 gene usage in anti-desmoglein 3 B cells from different pemphigus patients and defined acidic amino acid residues that are necessary and sufficient to confer desmoglein 3 autoreactivity. These VH1-46 B cells are autoreactive to the disease antigen in the absence of somatic mutation or require very few mutations to develop autoreactivity, which may favor their selection early in the immune response. Common VH gene usage is significant, because it may indicate common mechanisms for developing autoimmunity in pemphigus vulgaris. Ongoing projects aim to identify common features of the autoimmune response to desmogleins and the immune response to foreign antigens, perform lineage tracing of pemphigus autoantibody repertoires, and characterize the B cell subsets that produce the pathogenic autoantibodies.
Ultimately, a better understanding of the shared structural elements of pemphigus B cell repertoires (e.g., VH or CH gene usage) can lead to better targeted therapies for disease. Current methods for treating autoimmunity require general immune suppression to reduce antibody production, but this approach impairs protective immune responses, which can lead to potentially fatal infections and secondary cancers. We recently described a novel method for re-engineering chimeric antigen receptor T cells for targeted immunotherapy of pemphigus vulgaris. By using the pemphigus autoantigen desmoglein 3 as the extracellular domain (the “bait”) on a chimeric autoantibody receptor (CAAR), we can direct a patient’s T cells to specifically seek out and kill the pemphigus-specific B cells, while sparing the good immune cells that protect from infection. We are currently in the process of moving forward CAAR technology to clinical trials in dogs and humans with pemphigus. The full text of this work is available at Science online.
Our laboratory is also investigating the cell regulatory pathways that promote desmosomal adhesion. We have shown that the p38 MAPK/MK2 axis is a critical regulator of desmosomal adhesion in keratinocytes and that inhibition of this pathway can ameliorate pemphigus skin blistering. Ongoing projects are studying the regulation of desmosomal adhesion and desmosomal protein expression in keratinocytes to better understand how anti-desmoglein antibodies cause the loss of cell adhesion and how we might interfere with these pathways to improve disease.
Xuming Mao, MD/PhD, senior research investigator
Eun Jung Choi, MS, research specialist
Nina Ran, Masters in Translational Research thesis student
Jinmin Lee, PhD, postdoctoral fellow
Daniel Xu (MD/PhD rotation student)
Suna Li (VMD/PhD rotation student)
Carolyn Kushner (Penn medical student)
Adam Alghalith (Penn undergraduate student)
Lab alumni (current position):
Preety M. Sharma, PhD (Associate Research Scientist, Columbia University)
Takeru Funakoshi, MD, PhD (Dermatology faculty, Keio University, Japan)
Luisa Lunardon, MD (Dermatology faculty, University of Milan)
Arielle Nagler, MD (Dermatology faculty, New York University)
Michael Jeffrey Cho, PhD (Healthcare consultant)
Sara Farber, MD (Dermatology resident, University of Pennsylvania)
Courtney Rubin, MD (Dermatology resident, University of Pennsylvania)
Michael Stephens (Penn MS2)
Eric Mukherjee (Penn MSTP thesis student, MS7)
Christoph Ellebrecht, MD (PGY1 resident)
Other Penn Appointments:
Associate Director, Medical Scientist Training Program
Immunology Graduate Group
Cell and Molecular Biology Graduate Group
Institute for Translational Medicine and Therapeutics
Mao X, Cho MJ, Ellebrecht CT, Mukherjee EM: Stat3 regulates desmoglein 3 transcription in epithelial keratinocytes JCI Insight 2 (9): e92253,2017.
Kasperkiewicz M, Ellebrecht CT, Takahashi H, Yamagami J, Zillikens D, Payne AS: Pemphigus Nature Reviews Disease Primers 11 (3): 17026,2017.
Ellebrecht CT: Setting the target for pemphigus vulgaris therapy JCI Insight 2 (5): e92021,2017.
Chen J, Zheng Q, Hammers CM, Ellebrecht CT, Mukherjee EM, Tang HY, Lin C, Yuan H, Pan M, Langenhan J, Komorowski L, Siegel DL, Payne AS: Proteomic analysis of pemphigus autoantibodies indicates a larger, more diverse, and more dynamic repertoire than determined by B cell genetics Cell Reports 18 (1): 237-247,2017.
Ellebrecht CT, Bhoj VG, Nace A, Choi EJ, Mao X, Cho MJ, Di Zenzo G, Lanzavecchia A, Seykora JT, Cotsarelis G, Milone MC: Reengineering chimeric antigen receptor T cells for targeted therapy of autoimmune disease Science 353 : 179-184,2016.
Cho MJ, Ellebrecht CT, Hammers CM, Mukherjee EM, Sapparapu G, Boudreaux CE, McDonald SM, Crowe JE, Jr.: Determinants of VH1-46 cross-reactivity to pemphigus vulgaris autoantigen desmoglein 3 and rotavirus antigen VP6 J. Immunol. 197 (4): 1065-73,2016.
Cho MJ, Lo ASY, Mao X, Nagler AR, Ellebrecht CT, Mukherjee EM, Hammers CM, Choi EJ, Sharma PM, Uduman M, Li H, Rux AH, Farber SA, Rubin CB, Kleinstein SH, Sachais BS, Posner MR, Cavacini LA: Shared VH1-46 gene usage by pemphigus vulgaris autoantibodies indicates common humoral immune responses among patients Nature Commun. 5 : 4167,2014.
Ellebrecht CT, Choi EJ, Allman DM, Tsai DE, Wegener WA, Goldenberg DM: Subcutaneous veltuzumab, a humanized anti-CD20 antibody, for treatment of refractory pemphigus vulgaris JAMA Dermatol. 150 : 1331-1335,2014.
Mao X, Li H, Sano Y, Gaestel M, Park JM: MAPKAP kinase 2 (MK2)-dependent and independent models of blister formation in pemphigus vulgaris. J. Invest. Dermatol. 134 : 68-76,2014.
Funakoshi T, Lunardon L, Ellebrecht CT, Nagler AR, O’Leary CE: Enrichment of total serum IgG4 in pemphigus patients Br.J.Dermatol. 167 : 1245-1253,2012.
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