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
Christoph Ellebrecht, MD, postdoctoral fellow
Eun Jung Choi, MS, research specialist
Eric Mukherjee, CAMB/MSTP thesis student
Nina Ran, Masters in Translational Research thesis student
Michael Stephens, MS2 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 R. Nagler, MD (Dermatology faculty, New York University)
Michael Jeffrey Cho, PhD (Healthcare consultant)
Sara A. Farber, MD (Dermatology resident, University of Pennsylvania)
Courtney B. Rubin, MD (Medicine Intern)
Other Penn Appointments:
Associate Director, Medical Scientist Training Program
Immunology Graduate Group
Cell and Molecular Biology Graduate Group
Institute for Translational Medicine and Therapeutics
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 : 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): 1065-73,2016.
Cho MJ, Ellebrecht CT, Payne AS: The dual nature of interleukin 10 in pemphigus vulgaris Cytokine 73 : 335-341,2015.
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.
Ellebrecht CT, Choi EJ, Allman DM, Tsai DE, Wegener WA, Goldenberg DM, Payne AS: 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, Payne AS.: 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, Payne AS.: Enrichment of total serum IgG4 in pemphigus patients Br.J.Dermatol. 167 : 1245-1253,2012.
Lunardon L, Payne AS.: Inhibitory human anti-chimeric antibodies to rituximab in a pemphigus patient J.Allerg.Clin.Immunol. 130 : 800-803,2012.
Lunardon L, Tsai KJ, Propert KJ, Fett N, Stanley JR, Werth VP, Tsai DE, Payne AS.: Adjuvant rituximab therapy of pemphigus: a single center experience with 31 patients. Arch.Dermatol. 148 (9): 1031-1036,2012.
Murrell DF, Dick S, Ahmed AR, Amagai M, Barnadas MA, Borradori L, Bystryn JC, Cianchini G, Diaz L, Fivenson D, Goldsmith L, Hall R, Harman K, Hashimoto T, Hertl M, Hunzelmann N, Iranzo P, Joly P, Jonkman M, Kitajima Y, Korman N, Martin LK, Mimouni D, Payne AS, Rubenstein D, Shimizu H, Sinha A, Sirois D, Zillikens D, Werth VP: Consensus statement on definitions of disease endpoints and therapeutic response for pemphigus Journal of the American Academy of Dermatology 58 : 1043-1046,2008.
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