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 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. We also identified common as well as divergent features of the B cell response to the self-antigen desmoglein 3 and the rotavirus VP6 antigen, which suggests shared VH gene usage in the immune response to foreign and self antigens as a potential basis for triggering pathologic autoimmune reactions. Ongoing projects aim to better understand the features of the autoimmune response in pemphigus, including isotype-specific lineage tracing of pemphigus autoantibody repertoires and characterization of the B cell subsets that contribute to autoimmunity in pemphigus.
Our laboratory has also elucidated the cell regulatory pathways that promote desmosome adhesion. We have shown that the p38 MAPK/MK2 axis governs keratinocyte desmosomal adhesion and that inhibition of this pathway can ameliorate pemphigus skin blistering. We identified STAT3 as a key regulator of desmoglein 3 transcription in keratinocytes, which contributes to the rapid therapeutic effect of corticosteroids in pemphigus and may explain the loss of desmoglein 3 expression in advanced head and neck squamous cell cancers.
Ultimately, a better understanding of the shared structural elements of pemphigus B cell repertoires 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 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 of 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 CAAR technology forward to human clinical trials.
Xuming Mao, MD/PhD, senior research investigator
Eun Jung Choi, MS, lab manager and research specialist
Jinmin Lee, PhD, postdoctoral fellow
Sangwook Oh, postdoctoral fellow
Baomei Wang, MD, PhD, senior research investigator
Daniel Lundgren, research specialist
Ellyssa Sherman, masters 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, Milan)
Arielle Nagler, MD (Dermatology faculty, New York University)
Michael Jeffrey Cho, PhD (Senior clinical research consultant)
Sara Farber, MD (Dermatology resident, University of Pennsylvania)
Courtney Rubin, MD (Dermatology resident, University of Pennsylvania)
Eric Mukherjee, MD, PhD (Yale internal medicine internship)
Christoph Ellebrecht, MD (Dermatology resident, University of Pennsylvania)
Nina Ran, MD, MTR (Dermatology resident, University of Pennsylvania)
Carolyn Kushner (PGY1,Dermatology resident, New York University)
Other Penn Appointments:
Director, Penn Clinical Autoimmunity Center of Excellence
Associate Director, Medical Scientist Training Program
Faculty Advisor, Association for Women Student MD-PhDs (AWSM)
Immunology Graduate Group
Cell and Molecular Biology Graduate Group
Ellebrecht CT, Mukherjee EM, Zheng Q, Choi EJ, Reddy SG, Mao X, Payne AS: Autoreactive IgG and IgA B cells evolve through distinct subclass switch pathways in the autoimmune disease pemphigus vulgaris Cell Rep 24 (9): 2370-2380,2018.
Mao X, Cho MJ, Ellebrecht CT, Mukherjee EM, Payne AS: 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, Amagai M: Pemphigus Nat Rev Dis Primers 3 : 17026,2017.
Ellebrecht CT, Payne AS: 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, Stanley JR: Proteomic analysis of pemphigus autoantibodies indicates a larger, more diverse, and more dynamic repertoire than determined by B cell genetics Cell Rep 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, Payne AS: Reengineering chimeric antigen receptor T cells for targeted therapy of autoimmune disease Science 353 (6295): 179-184,2016.
Cho MJ, Ellebrecht CT, Hammers CM, Mukherjee EM, Sapparapu G, Boudreaux CE, McDonald SM, Crowe JE, Jr., Payne AS: Determinants of VH1-46 cross-reactivity to pemphigus vulgaris autoantigen desmoglein 3 and rotavirus antigen VP6 J Immunol 197 (4): 1065-1073,2016.
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, Payne AS: Shared VH1-46 gene usage by pemphigus vulgaris autoantibodies indicates common humoral immune responses among patients Nature Commun 5 : 4167,2014.
Mao X, Li H, Sano Y, Gaestel M, Park JM, Payne AS: MAPKAP kinase 2 (MK2)-dependent and independent models of blister formation in pemphigus vulgaris J Invest Dermatol 134 (1): 68-76,2014.
Funakoshi T, Lunardon L, Ellebrecht CT, Nagler AR, O’Leary CE, Payne AS: Enrichment of total serum IgG4 in patients with pemphigus Br J Dermatol 167 (6): 1245-1253,2012.
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