title: Anti-α-2-macroglobulin-like-1 autoantibodies are detected frequently and may be pathogenic in paraneoplastic pemphigus.
abstract: Paraneoplastic pemphigus (PNP) shows autoantibodies mainly to plakin and desmosomal cadherin family proteins. We have recently identified alpha-2-macroglobulin-like-1 (A2ML1), a broad range protease inhibitor, as a unique PNP antigen. In this study, we tested a large number of PNP sera by various methods. Forty (69.0%) of 58 PNP sera recognized A2ML1 recombinant protein expressed in COS7 cells by immunofluorescence (IF) and/or immunoprecipitation (IP)/immunoblotting (IB). IP/IB showed higher sensitivity than IF. In addition, 22 (37.9%) PNP sera reacted with A2ML1 by IB of cultured normal human keratinocytes (NHKs) under non-reducing conditions. Statistical analyses using various clinical and immunological data showed that the presence of anti-A2ML1 autoantibodies was associated with early disease onset and absence of ocular lesions. Next, to investigate the pathogenic role of anti-A2ML1 antibody, we performed additional functional studies. Addition of anti-A2ML1 polyclonal antibody to culture media decreased NHK cell adhesion examined by dissociation assay, and increased plasmin activity detected by casein zymography, suggesting that anti-A2ML1 antibody may decrease NHK cell adhesion through plasmin activation by inhibition of A2ML1. This study demonstrates that autoantibodies to A2ML1 are frequently and specifically detected and may have a pathogenic role in PNP.
authors: Department of Dermatology, Kurume University School of Medicine, and Kurume University Institute of Cutaneous Cell Biology, Kurume, Japan.
authors: Sanae
authors: S
authors: Numata
authors: Kwesi
authors: K
authors: Teye
authors: Daisuke
authors: D
authors: Tsuruta
authors: Ryosuke
authors: R
authors: Sogame
authors: Norito
authors: N
authors: Ishii
authors: Hiroshi
authors: H
authors: Koga
authors: Yohei
authors: Y
authors: Natsuaki
authors: Atsunari
authors: A
authors: Tsuchisaka
authors: Takahiro
authors: T
authors: Hamada
authors: Tadashi
authors: T
authors: Karashima
authors: Takekuni
authors: T
authors: Nakama
authors: Minao
authors: M
authors: Furumura
authors: Chika
authors: C
authors: Ohata
authors: Tamihiro
authors: T
authors: Kawakami
authors: Isabelle
authors: I
authors: Schepens
authors: Luca
authors: L
authors: Borradori
authors: Takashi
authors: T
authors: Hashimoto
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000818:Animals; D001323:Autoantibodies / Q000097:blood / Q000494:pharmacology / Q000502:physiology*; D019556:COS Cells; D002448:Cell Adhesion / Q000187:drug effects; D002478:Cells, Cultured; D002648:Child; D002522:Chlorocebus aethiops; D004195:Disease Models, Animal; D005341:Fibrinolysin / Q000378:metabolism; D005455:Fluorescent Antibody Technique; D006801:Humans; D047468:Immunoprecipitation; D015603:Keratinocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008875:Middle Aged; D010257:Paraneoplastic Syndromes / Q000209:etiology* / Q000503:physiopathology*; D010392:Pemphigus / Q000209:etiology* / Q000503:physiopathology*; D051381:Rats; D014162:Transfection; D055815:Young Adult; D000511:alpha-Macroglobulins / Q000235:genetics / Q000276:immunology*
chemical_list: D001323:Autoantibodies; D000511:alpha-Macroglobulins; D005341:Fibrinolysin