The protease inhibitor alpha-2-macroglobulin-like-1 is the p170 antigen recognized by paraneoplastic pemphigus autoantibodies in human.
BACKGROUND
Paraneoplastic pemphigus (PNP) is a devastating autoimmune blistering disease, involving mucocutaneous and internal organs, and associated with underlying neoplasms. PNP is characterized by the production of autoantibodies targeting proteins of the plakin and cadherin families involved in maintenance of cell architecture and tissue cohesion. Nevertheless, the identity of an antigen of Mr 170,000 (p170), thought to be critical in PNP pathogenesis, has remained unknown.


RESULTS
Using an immunoprecipitation and mass spectrometry based approach, we identified p170 as alpha-2-macroglobuline-like-1, a broad range protease inhibitor expressed in stratified epithelia and other tissues damaged in the PNP disease course. We demonstrate that 10 PNP sera recognize alpha-2-macroglobuline-like-1 (A2ML1), while none of the control sera obtained from patients with bullous pemphigoid, pemphigus vulgaris, pemphigus foliaceus and normal subjects does.


CONCLUSIONS
Our study unravels a broad range protease inhibitor as a new class of target antigens in a paraneoplastic autoimmune multiorgan syndrome and opens a new challenging investigation avenue for a better understanding of PNP pathogenesis.
Schepens
Isabelle
I
Department of Dermatology, Inselspital, Bern University Hospital and University of Bern, Bern, Switzerland. isabelle.schepens@insel.ch
Jaunin
Fabienne
F
Begre
Nadja
N
Läderach
Ursula
U
Marcus
Katrin
K
Hashimoto
Takashi
T
Favre
Bertrand
B
Borradori
Luca
L
D001323:Autoantibodies / Q000276:immunology*; D001324:Autoantigens / Q000737:chemistry / Q000276:immunology* / Q000378:metabolism; D001327:Autoimmune Diseases / Q000097:blood / Q000276:immunology*; D002460:Cell Line; D003470:Culture Media; D004817:Epidermis / Q000378:metabolism; D005786:Gene Expression Regulation; D006801:Humans; D047468:Immunoprecipitation; D015603:Keratinocytes / Q000166:cytology; D011480:Protease Inhibitors / Q000737:chemistry / Q000276:immunology* / Q000378:metabolism; D017434:Protein Structure, Tertiary; D019163:Reducing Agents / Q000494:pharmacology; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; D014162:Transfection; D000511:alpha-Macroglobulins / Q000737:chemistry / Q000276:immunology* / Q000378:metabolism
C510358:A2ML1 protein, human; D001323:Autoantibodies; D001324:Autoantigens; D003470:Culture Media; D011480:Protease Inhibitors; D019163:Reducing Agents; D000511:alpha-Macroglobulins
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