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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR052672-07
Application #
8294628
Study Section
Arthritis, Connective Tissue and Skin Study Section (ACTS)
Program Officer
Cibotti, Ricardo
Project Start
2005-07-01
Project End
2016-06-30
Budget Start
2012-07-01
Budget End
2013-06-30
Support Year
7
Fiscal Year
2012
Total Cost
$360,000
Indirect Cost
$135,000
Name
University of Pennsylvania
Department
Dermatology
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
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 135:742-9
Hammers, Christoph M; Stanley, John R (2014) Antibody phage display: technique and applications. J Invest Dermatol 134:e17
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
Amagai, Masayuki; Stanley, John R (2012) Desmoglein as a target in skin disease and beyond. J Invest Dermatol 132:776-84
Yamagami, Jun; Payne, Aimee S; Kacir, Stephen et al. (2010) Homologous regions of autoantibody heavy chain complementarity-determining region 3 (H-CDR3) in patients with pemphigus cause pathogenicity. J Clin Invest 120:4111-7
Yokouchi, Mariko; Saleh, Marwah Adly; Kuroda, Keiko et al. (2009) Pathogenic epitopes of autoantibodies in pemphigus reside in the amino-terminal adhesive region of desmogleins which are unmasked by proteolytic processing of prosequence. J Invest Dermatol 129:2156-66
Stanley, John R; Ishii, Ken; Siegel, Don L et al. (2009) Update on the cloning of monoclonal anti-desmoglein antibodies from human pemphigus patients: implications for targeted therapy. Vet Dermatol 20:327-30
Yamagami, Jun; Kacir, Stephen; Ishii, Ken et al. (2009) Antibodies to the desmoglein 1 precursor proprotein but not to the mature cell surface protein cloned from individuals without pemphigus. J Immunol 183:5615-21

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