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Conformational epitope mapping of desmoglein (Dsg) 3 by using Dsg3/Dsg2 domain-swapped molecules in pemphigus vulgaris and paraneoplastic pemphigus

Other Titles
 보통 천포창과 종양연관성 천포창에서 desmoglein(Dsg)3/Dsg2 영역교환분자를 이용한 Dsg3의 항원기 분석 
Issue Date
2011
Description
Dept. of Medicine/박사
Abstract
Pemphigus vulgaris (PV) is an autoimmune blistering disease caused by autoantibodies against desmoglein (Dsg) 3, a member of the desmosomal cadherin family. These autoantibodies recognize conformation-dependent epitopes on Dsg3. PV can be divided into three clinical subtypes; mucosal, mucocutaneous and cutaneous type. Paraneoplastic pemphigus (PNP) is an autoimmune blistering disease of the skin and mucous membranes associated with underlying neoplasm. It shows more heterogenous and different clinical and histological manifestation compared with PV, and has autoimmune reaction against Dsg 3 as well as plakin family proteins. Characterizing the binding sites of these autoantibodies by epitope mapping is therefore an essential step to understand the pathophysiology of blister formation in pemphigus as well as the basic molecular mechanism of cell-cell adhesion mediated by Dsgs.This study first delineated the epitope profile of PV according to each extracellular (EC) domains of Dsg3 by immunoprecipitation -immunoblotting analysis using the Dsg3/Dsg2 domain swapped molecules that is more biological and appropriate method excluding cross-reactivity which may occur with the previous version using Dsg1 and Dsg3. The result has demonstrated that patients showed heterogenous immunoreactivity to various EC domains of Dsg3. PV autoantibodies react predominantly to EC1 and EC2 domains of amino-terminal which is considered to include a region known to be essential for cell-cell adhesion in cadherins, and relative high frequently to EC4 domain of Dsg3. Moreover these findings were even across activity stages or different clinical subtypes. In PNP, autoimmune response against various EC domains of Dsg3 is more diverse than that in PV, suggesting PNP and PV have different pathophysiologic mechanisms for triggering production of anti-Dsg3 autoantibody. These findings provide new knowledge to elucidate the molecular mechanism of the adhesion function of Dsg3 and the pathophysiologic mechanism of blister formation in pemphigus. Further studies of epitope mapping of Dsg3 using Dsg3/Dsg2 domain swapped molecules on large number of PV or PNP patients are needed to be performed to verify that there are few differences on Dsg3 epitope profiles in different clinical subtypes of PV and epitope spreading is uncommon in PV according to changes of disease activity or phenotype.
URI
http://ir.ymlib.yonsei.ac.kr/handle/22282913/133473
Appears in Collections:
2. 학위논문 > 1. College of Medicine > 박사
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