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Role of autoantibody isotype in pemphigus pathogenesis

自身抗体同种型在天疱疮发病机制中的作用

基本信息

批准号：
8651422
负责人：
Aimee S Payne
金额：
$ 34.53万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-04-01 至 2016-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8651422
关键词：
Abscess Accounting Address Antibodies Antigens Autoantibodies Autoimmune Process Autoimmunity B-Lymphocytes Binding Bulla Bullous Pemphigoid Cell Adhesion Molecules Cells Chemotaxis Chronic Chronic Disease Clinical Clinical Markers Cloning Dapsone Defect Dependence Disease Disease remission Epidermolysis Bullosa Acquisita Exhibits Fc Receptor Fc(alpha) receptor Goals Histologic Human IgE IgE Receptors IgG1 IgG4 Immune Immunity Immunoglobulin A Immunoglobulin Class Switching Immunoglobulin Constant Region Immunoglobulin G Immunoglobulin Variable Region Immunosuppression Infection Inflammation Inflammatory Lesion Leukocytes Link Mediating Monoclonal Antibodies Mus Neonatal Pathogenesis Pathogenicity Patients Pattern Pemphigus Pemphigus Vulgaris Phage Display Population Relative (related person)Research Risk Role Second Primary Cancers Skin Technology Therapeutic Transgenic Mice anti-IgA anti-IgE design desmoglein eosinophil eosinophilic inflammation frontier inhibitor/antagonist insight mouse model neutrophil novel novel strategies novel therapeutics omalizumab response skin abscess skin disorder variable region gene

项目摘要

Project summary (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.

项目总结（最多30行）：