Antibodies to the endoplasmic reticulum-resident chaperones calnexin, BiP and Grp94 in patients with rheumatoid arthritis and systemic lupus erythematosus.
OBJECTIVE
To investigate the presence of autoantibodies against mammalian chaperones of the endoplasmic reticulum (ER) in patients with RA and other immune-mediated diseases.


METHODS
Sera from healthy donors, from early RA patients with two follow-up samples, patients with SLE, SSc and IBD were collected and analysed for anti-ER chaperone antibodies. Detection of serum IgG antibodies against immunoglobulin heavy chain binding protein (BiP), glucose-regulated protein 94 (Grp94) and calnexin was carried out using ELISA. The specificity of sera positive for individual ER chaperones was confirmed by immunoblotting. Statistical analysis was performed using Welch's t-test, Mann-Whitney U-test, partial correlation and Pearson's correlation.


RESULTS
In patients with RA and SLE, autoantibody titres against BiP, Grp94 and calnexin were significantly higher than those in healthy controls. These autoantibodies were detectable in patients with early RA and titres remained stable for at least 6-12 months. Also several SSc and IBD patients exhibited autoantibodies against these ER chaperones; however, titres and frequencies were lower than in RA or SLE patients. Furthermore, anti-calnexin antibodies correlated significantly with the presence of BiP and Grp94 autoantibodies in patients with RA and SLE.


CONCLUSIONS
Calnexin and Grp94 were identified as novel autoantigens in RA and calnexin in SLE. Since calnexin, Grp94 and BiP are ER-resident proteins of eukaryotic cells, our data suggest that autoantibody generation against ER chaperones is independent of initial exposure to the corresponding bacterial chaperones; rather, ER chaperones may represent genuine autoantigens.
Weber
Christian K
CK
IZKF Research Group 2, Nikolaus Fiebiger Centre of Molecular Medicine, Department of Internal Medicine 3 and Institute for Clinical Immunology, Friedrich-Alexander-University Erlangen-Nuremberg, 91054 Erlangen, Germany.
Haslbeck
Martin
M
Englbrecht
Matthias
M
Sehnert
Bettina
B
Mielenz
Dirk
D
Graef
Daniela
D
Distler
Jörg H
JH
Mueller
Ruediger B
RB
Burkhardt
Harald
H
Schett
Georg
G
Voll
Reinhard E
RE
Fürnrohr
Barbara G
BG
D000328:Adult; D000368:Aged; D001172:Arthritis, Rheumatoid / Q000276:immunology* / Q000378:metabolism; D001323:Autoantibodies / Q000276:immunology / Q000378:metabolism; D037281:Calnexin / Q000276:immunology* / Q000378:metabolism; D016022:Case-Control Studies; D004721:Endoplasmic Reticulum / Q000276:immunology / Q000378:metabolism; D000091342:Endoplasmic Reticulum Chaperone BiP; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D018840:HSP70 Heat-Shock Proteins / Q000276:immunology* / Q000378:metabolism; D006360:Heat-Shock Proteins / Q000276:immunology; D006801:Humans; D008180:Lupus Erythematosus, Systemic / Q000276:immunology* / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins / Q000276:immunology* / Q000378:metabolism; D008875:Middle Aged; D018832:Molecular Chaperones / Q000276:immunology* / Q000378:metabolism
D001323:Autoantibodies; D000091342:Endoplasmic Reticulum Chaperone BiP; D018840:HSP70 Heat-Shock Proteins; D006360:Heat-Shock Proteins; D008565:Membrane Proteins; D018832:Molecular Chaperones; C018551:glucose-regulated proteins; D037281:Calnexin