(30 lines maximum): Pemphigus is a group of potentially fatal blistering diseases characterized by autoantibodies against desmoglein (Dsg) cell adhesion proteins. Current therapy requires general immune suppression, which risks fatal infection and secondary cancers. A major frontier for autoimmunity research is to target only disease- causing antibodies. Our overall aim is to better define this pathogenic antibody population in pemphigus, with the long term goal of designing rational, targeted therapies. We have pioneered the use of antibody cloning technology in pemphigus to identify features of variable and constant regions of patient autoantibodies that cause disease. We have identified a pattern of variable region gene usage for pathogenic autoantibodies, which is shared even among different patients. Having defined a subset of anti-Dsg variable regions sufficient for skin blistering, we are now uniquely situated to address the role of the antibody constant region (Fc) in pemphigus pathogenesis. We hypothesize that IgG4, IgA and IgE are the critical pathogenic isotypes in pemphigus, accounting for the full clinical and histologic spectrum of disease. Anti-Dsg IgG1 is found in patients in remission and their healthy relatives, while patients with active disease exhibit IgG4 autoantibodies. In IgA pemphigus, neutrophilic skin abscesses are caused by anti-Dsg IgA binding to leukocyte Fc receptors, and anti-Dsg IgE may cause eosinophilic forms of pemphigus by analogy. Because chronic antigen stimulation promotes class switching from IgG1 to IgG4, IgA, and IgE, these isotypes may serve as clinical markers to distinguish disease-specific antibodies from the other IgG subclasses that are more important for providing immunity from infection.
In Aim 1 we will clone IgG1 and IgG4 anti-Dsg monoclonal antibodies (mAbs) from pemphigus patients to determine whether pathogenic antibodies are found in IgG1, IgG4, or both isotypes. If found in both IgG1 and IgG4, we will determine whether anti-Dsg IgG4 result from class switching from IgG1 or arise from separate B cell populations, lending insight into mechanisms of IgG4 class switching in pemphigus.
In Aims 2 and 3 we will clone anti-Dsg IgA and IgE mAbs from patients with neutrophilic and eosinophilic forms of pemphigus, respectively. We will evaluate whether anti-Dsg IgA and IgE reproduce inflammatory blistering disease in mice humanized for the relevant Fc receptor and demonstrate the Fc-dependence of blistering and/or inflammation by treating mice with inhibitors of Fc effector function. By systematically characterizing the pathogenicity of the variable and constant regions of pemphigus mAb isotypes, we can define which structural features cause disease. These studies will create a rational framework for predicting the response of different forms of pemphigus to therapy, describe novel mouse models for evaluating Fc-mediated disease, and may identify novel therapeutic strategies, such as isotype-specific targeting. As similar isotype profiles occur in pemphigoid, epidermolysis bullosa acquisita, and other chronic autoimmune conditions, our studies may have therapeutic relevance for a broad range of autoantibody-mediated diseases.

Public Health Relevance

(3 sentences): We propose to use antibody cloning technology as a novel approach to identify features within patient autoantibodies that cause pemphigus, a potentially fatal autoimmune blistering skin disorder. We hypothesize that IgG4, IgA, and IgE are the critical pathogenic antibody isotypes in pemphigus, and as such may serve as clinical markers to distinguish disease-specific antibodies from the other IgG subclasses that are important for providing immunity from infection. Our studies will create a rational framework for predicting the response of different forms of pemphigus to therapy, describe novel mouse models for evaluating disease, and may suggest novel and potentially safer therapeutic strategies, such as isotype-specific targeting.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR057001-05
Application #
8651422
Study Section
Arthritis, Connective Tissue and Skin Study Section (ACTS)
Program Officer
Cibotti, Ricardo
Project Start
2010-04-01
Project End
2015-03-31
Budget Start
2014-04-01
Budget End
2015-03-31
Support Year
5
Fiscal Year
2014
Total Cost
$345,273
Indirect Cost
$127,008
Name
University of Pennsylvania
Department
Dermatology
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Ellebrecht, Christoph T; Mukherjee, Eric M; Zheng, Qi et al. (2018) Autoreactive IgG and IgA B Cells Evolve through Distinct Subclass Switch Pathways in the Autoimmune Disease Pemphigus Vulgaris. Cell Rep 24:2370-2380
Kasperkiewicz, Michael; Ellebrecht, Christoph T; Takahashi, Hayato et al. (2017) Pemphigus. Nat Rev Dis Primers 3:17026
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
Ellebrecht, Christoph T; Bhoj, Vijay G; Nace, Arben et al. (2016) Reengineering chimeric antigen receptor T cells for targeted therapy of autoimmune disease. Science 353:179-84
Lo, Agnes S; Mao, Xuming; Mukherjee, Eric M et al. (2016) Pathogenicity and Epitope Characteristics Do Not Differ in IgG Subclass-Switched Anti-Desmoglein 3 IgG1 and IgG4 Autoantibodies in Pemphigus Vulgaris. PLoS One 11:e0156800
Ellebrecht, Christoph T; Choi, Eun J; Allman, David M et al. (2014) Subcutaneous veltuzumab, a humanized anti-CD20 antibody, in the treatment of refractory pemphigus vulgaris. JAMA Dermatol 150:1331-5
Cho, Michael Jeffrey; Lo, Agnes S Y; Mao, Xuming et al. (2014) Shared VH1-46 gene usage by pemphigus vulgaris autoantibodies indicates common humoral immune responses among patients. Nat Commun 5:4167
Ellebrecht, Christoph T; Payne, Aimee S (2014) Plakophilins, desmogleins, and pemphigus: the tail wagging the dog. J Invest Dermatol 134:874-876
Mao, Xuming; Li, Hong; Sano, Yasuyo et al. (2014) MAPKAP kinase 2 (MK2)-dependent and -independent models of blister formation in pemphigus vulgaris. J Invest Dermatol 134:68-76
Baratta, Andrea; Camarillo, Diana; Papa, Christine et al. (2013) Pediatric pemphigus vulgaris: durable treatment responses achieved with prednisone and mycophenolate mofetil (MMF). Pediatr Dermatol 30:240-4

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