The stress protein BiP is overexpressed and is a major B and T cell target in rheumatoid arthritis.
OBJECTIVE
The ubiquitously expressed intracellular protein formerly designated p68 has been identified as autoantigen at both the antibody and the T cell level in rheumatoid arthritis (RA).


METHODS
We used 2 independent approaches, Edman degradation and matrix-assisted laser desorption ionization-time-of-flight mass spectrometry, to characterize p68, and we compared its features with those of the endoplasmic reticulum stress protein BiP.


RESULTS
In synovial sections from RA patients, BiP was highly overexpressed as compared with control sections. Under in vitro stress conditions, BiP was found to translocate to the nucleus and the cell surface. BiP-specific autoantibodies were present in 63% of 400 RA patients, in 7% of 200 patients with other rheumatic diseases, and in none of the healthy subjects. Thus, BiP-specific autoantibodies represent a new diagnostic marker in RA. Furthermore, we found that BiP-specific T cell reactivity was altered in RA. In healthy individuals and patients with other rheumatic diseases, BiP-reactive T cells were undetectable. In RA, overt T cell reactivity to BiP was observed or could be induced by specifically blocking antigen presentation to potentially regulatory T cells.


CONCLUSIONS
Since overexpression of BiP has been shown to decrease the sensitivity of cells to killing by cytotoxic T cells, BiP overexpression and BiP-specific autoimmunity may be involved in the pathogenesis of RA.
Bläss
S
S
Department of Rheumatology and Clinical Immunology, Charité University Hospital, Berlin, Germany.
Union
A
A
Raymackers
J
J
Schumann
F
F
Ungethüm
U
U
Müller-Steinbach
S
S
De Keyser
F
F
Engel
J M
JM
Burmester
G R
GR
D001172:Arthritis, Rheumatoid / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D001402:B-Lymphocytes / Q000378:metabolism*; D002352:Carrier Proteins / Q000737:chemistry / Q000378:metabolism*; D000091342:Endoplasmic Reticulum Chaperone BiP; D005260:Female; D019084:Fluorescent Antibody Technique, Indirect; D006360:Heat-Shock Proteins / Q000378:metabolism*; D006801:Humans; D008297:Male; D018832:Molecular Chaperones / Q000737:chemistry / Q000378:metabolism*; D010446:Peptide Fragments / Q000032:analysis; D010449:Peptide Mapping; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; D013583:Synovial Membrane / Q000378:metabolism / Q000473:pathology; D013601:T-Lymphocytes / Q000378:metabolism*
D002352:Carrier Proteins; D000091342:Endoplasmic Reticulum Chaperone BiP; D006360:Heat-Shock Proteins; D018832:Molecular Chaperones; D010446:Peptide Fragments