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Research Interests:Genetic and functional characterization of human anti-desmoglein B cell repertoiresPrecision cellular immunotherapies for pemphigus and other autoantibody-mediated diseasesKey words: autoimmunity, human immunology, CAR T cells, cell therapy, precision medicine, cell adhesion, dermatology, skin, B cellDescription 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, but that divergent evolution limits the onset of autoimmunity after infection. Further studies have uncovered the developmental pathways and lineage relationships of IgG and IgA B cells in pemphigus, indicating that the IgG4 B cells that are predominant in active disease are clonally distinct from the shared lineages found within the IgG1-IgA1-IgA2 axis. Ongoing projects aim to better understand the features of the autoimmune response in pemphigus, including 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 autoreactive 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 (CAR) T cells, which have led to lasting remissions of B cell-mediated cancers, for precision cellular immunotherapy of B cell-mediated autoimmune diseases such as 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 published initial proof-of-concept for the CAAR approach as well as the definitive preclinical studies that enabled an Investigational New Drug application for DSG3-CAART, which is now in a phase 1 trial to determine safety and preliminary efficacy of this approach. In addition, we are extending the CAAR concept to other B cell-mediated diseases, such as MuSK myasthenia gravis, and applying the technology to the treatment of dogs with cancer and autoimmune conditions.Lab personnel:Burcin Altun, PhD, senior research investigatorInsuk Choe, JD, program coordinatorEun Jung Choi, MS, lab manager and research specialistChristoph Ellebrecht, MD, instructorEmma Goodman, graduate studentCasey Lee, MD-PhD graduate studentBritt Levy, DVM, postdoctoral fellowSilvio Manfredo-Vieira, PhD, senior research investigatorXuming Mao, MD, PhD, senior research investigatorDamian Maseda, PhD, senior research investigatorSangwook Oh, PhD, senior research investigatorPatricia Tsao MD, PhD, senior research investigatorLab alumni (current position):Preety M. Sharma, PhD (Research Scientist, Columbia University)Takeru Funakoshi, MD, PhD (Dermatology faculty, Keio University, Japan)Luisa Lunardon, MD (Dermatology, University of Milan, Italy)Arielle Nagler, MD (Assistant Professor and Medical Director, New York University)Sara Berg, MD (Dermatology, Lahey Hospital and Medical Center, Tufts University School of Medicine)Courtney Rubin, MD (Dermatology Brigham and Women's Hospital)Michael Jeffrey Cho, PhD (Senior Manager, Oncology Analytics, GlaxoSmithKline)Eric Mukherjee, MD, PhD (Dermatology residency, Vanderbilt University)Nina Ran, MD, MTR (Dermatology resident, University of Pennsylvania)Adam Alghalith (UCLA/Caltech MSTP)Carolyn Kushner, MD (Dermatology resident, New York University)Napatra Tovanabutra, MD (Dermatology, Chiang Mai University, Thailand)Jinmin Lee, PhD (Senior Scientist, Cabaletta Bio)Daniel Lundgren (NIH Oxford-Cambridge Scholars Program)Other Penn Appointments:Director, Penn Clinical Autoimmunity Center of ExcellenceCore Director, Penn Skin Biology and Diseases Resource-based CenterAssociate Director, Medical Scientist Training ProgramCo-Director, Dermatology Research Residency ProgramFaculty Advisor, Association for Women Student MD-PhDs (AWSM)Immunology Graduate GroupCell and Molecular Biology Graduate Group
Lee J, Lundgren DK, Mao X, Manfredo-Vieira S, Nunez-Cruz S, Williams EF, Assenmacher CA, Radaelli E, Oh S, Wang B, Ellebrecht CT, Fraietta JA, Milone MC, Payne AS: Antigen specific B-cell depletion for precision therapy of mucosal pemphigus vulgaris J Clin Invest : 2020.
Maehara T, Kaneko N, Perugino CA, Mattoo H, Kers J, Allard-Chamard H, Mahajan VS, Liu H, Murphy SJ, Ghebremichael M, Fox DA, Payne AS, Lafyatis R, Stone JH, Khanna D, Pillai S: Cytotoxic CD4+ T lymphocytes may induce endothelial cell apoptosis in systemic sclerosis J Clin Invest 130 (5): 2451-2464,2020.
Kushner CJ, Wang S, Tovanabutra N, Tsai DE, Werth VP, Payne AS: Factors associated with complete remission after rituximab therapy for pemphigus JAMA Dermatol 155 (12): 1404-09,2019.
Cho A, Caldara AL, Ran NA, Menne Z, Kauffman RC, Affer M, Llovet A, Norwood C, Scanlan A, Mantus G, Bradley B, Zimmer S, Schmidt T, Hertl M, Payne AS, Feldman R, Kowalczyk AP, Wrammert J: Single-cell analysis suggests that ongoing affinity maturation drives the emergence of pemphigus vulgaris autoimmune disease Cell Rep 28 (4): 909-922,2019.
Ellebrecht CT, Lundgren DK, Payne AS: On the mark: genetically engineered immunotherapies for autoimmunity Curr Opin Immunol 61 : 69-73,2019.
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.
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, 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.
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