Pemphigus vulgaris and foliaceus are disfiguring and potentially life-threatening autoimmune blistering diseases affecting skin and mucous membranes that are mediated by autoantibodies against keratinocyte cell adhesion molecules called desmogleins. The pathogenic antibodies directly cause blister formation by interfering with cell adhesion. Normal individuals do not produce autoantibodies (i.e. are """"""""tolerant"""""""" to molecules normally present and exposed in their bodies). Pemphigus occurs because B cells, which produce antibodies, lose tolerance to desmogleins permitting them to produce anti-desmoglein antibodies that cause disease. We will address a basic issue pertaining to the pathophysiology of pemphigus, namely, whether a onetime trigger in each patient causes one set of oligoclonal B cells that have lost tolerance to desmogleins, and autoantibodies throughout the course of disease are derived from this parental set of non-tolerant B cells. Alternatively, do patients with disease have a propensity for developing loss of B cell tolerance to desmogleins with multiple clonally unrelated anti- desmoglein antibodies derived from continually evolving sets of parental non-tolerant B cells? We will address these questions by using antibody phage display, a method to clone monoclonal antibodies from patients so that the DNA encoding each antibody can be sequenced, allowing genetic characterization of each cloned antibody to determine its parental B cell clonal origin. We will longitudinally clone and genetically characterize monoclonal antibodies from pemphigus patients when active and with relapse after a clinical remission. We will determine if patients in long term remission after rituximab, a therapy that destroys B cells temporarily, but in whom the B cells repopulate, still have any anti-desmoglein B cell clones. These studies will determine if individual pemphigus patients maintain the same clonally-related anti-desmoglein B cell clones throughout disease or if relapse results in anti-desmoglein B cells unrelated to the original clones. These findings have important implications for pathophysiology and therapy;in the former case an initial insult may result in a few anti-desmoglein B cell clones that have escaped from tolerance and, if eliminated (e.g. by rituximab), may cure disease, whereas in the later case patients would have a propensity to lose tolerance, a condition much more difficult to understand and treat. Finally, we will determine if rituximab therapy does eliminate all detectable anti-desmoglein B cell clones or, on the other hand, somehow allows their regulation so they do not produce pathogenic antibodies. These studies will elucidate the pathophysiology of the autoimmune response in pemphigus with implications for therapy.

Public Health Relevance

Pemphigus is a disfiguring and potentially fatal blistering autoimmune disease. This project will clone the autoantibodies from these patients to determine if autoimmunity is triggered by a onetime insult or is caused by a basic defect in the patient's ability to regulate their immune system that causes continually evolving sets of autoantibodies. If the former, then therapies that destroy the B cells causing the abnormal antibodies could cure disease.

National Institute of Health (NIH)
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Research Project (R01)
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Arthritis, Connective Tissue and Skin Study Section (ACTS)
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Cibotti, Ricardo
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University of Pennsylvania
Schools of Medicine
United States
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Emtenani, S; Yuan, H; Lin, C et al. (2018) Normal human skin is superior to monkey esophagus substrate for detection of circulating BP180-NC16A-specific immunoglobulin G antibodies in bullous pemphigoid. Br J Dermatol :
Yoshida, Kenji; Ishii, Ken; Shimizu, Atsushi et al. (2017) Non-pathogenic pemphigus foliaceus (PF) IgG acts synergistically with a directly pathogenic PF IgG to increase blistering by p38MAPK-dependent desmoglein 1 clustering. J Dermatol Sci 85:197-207
Chen, Jing; Zheng, Qi; Hammers, Christoph M et al. (2017) Proteomic Analysis of Pemphigus Autoantibodies Indicates a Larger, More Diverse, and More Dynamic Repertoire than Determined by B Cell Genetics. Cell Rep 18:237-247
Hammers, Christoph M; Stanley, John R (2016) Mechanisms of Disease: Pemphigus and Bullous Pemphigoid. Annu Rev Pathol 11:175-97
Hammers, Christoph M; Chen, Jing; Lin, Chenyan et al. (2015) Persistence of anti-desmoglein 3 IgG(+) B-cell clones in pemphigus patients over years. J Invest Dermatol 135:742-749
Hammers, Christoph M; Stanley, John R (2014) Antibody phage display: technique and applications. J Invest Dermatol 134:1-5
Hammers, Christoph M; Stanley, John R (2013) Desmoglein-1, differentiation, and disease. J Clin Invest 123:1419-22
Toumi, Amina; Saleh, Marwah Adly; Yamagami, Jun et al. (2013) Autoimmune reactivity against precursor form of desmoglein 1 in healthy Tunisians in the area of endemic pemphigus foliaceus. J Dermatol Sci 70:19-25
Kouno, Michiyoshi; Lin, Chenyan; Schechter, Norman M et al. (2013) Targeted delivery of tumor necrosis factor-related apoptosis-inducing ligand to keratinocytes with a pemphigus mAb. J Invest Dermatol 133:2212-20
Lunardon, Luisa; Tsai, Kathleen J; Propert, Kathleen J et al. (2012) Adjuvant rituximab therapy of pemphigus: a single-center experience with 31 patients. Arch Dermatol 148:1031-6

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