Functional autoantibodies against serpin E2 in rheumatoid arthritis.
OBJECTIVE
To search for novel autoantibodies in patients with rheumatoid arthritis (RA) in an effort to better understand the processes of joint destruction in this disease.


METHODS
Using a modified SEREX technique and complementary DNA derived from RA synovium, serpin E2 was identified as a novel autoantigen and was analyzed by immunohistochemistry. Levels of anti-serpin E2 autoantibodies in serum and synovial fluid from patients with RA, osteoarthritis (OA), psoriatic arthritis, and ankylosing spondylitis, and/or from healthy individuals were assessed by enzyme-linked immunosorbent assay. Since serpin E2 is an inhibitor of serine proteases, we studied the inhibitory activity of serpin E2 toward its target, urokinase plasminogen activator (uPA), in vitro in the presence of isolated anti-serpin E2 autoantibodies and in vivo using the uPA activity assay.


RESULTS
We identified autoantibodies against serpin E2 by the SEREX technique. Serpin E2 was overexpressed in RA synovial tissues as compared with OA synovial tissues. Significantly higher levels of anti-serpin E2 autoantibodies were present in samples of synovial fluid (28%) and serum (22%) from RA patients as compared with OA patients (0 and 6%, respectively) or with healthy individuals (6% of sera). Most importantly, anti-serpin E2 autoantibodies isolated from RA sera reversed the inhibitory activity of serpin E2 by 70%. Furthermore, the levels of anti-serpin E2 autoantibodies correlated with the uPA activity in vivo.


CONCLUSIONS
This study characterizes a functional property of a novel autoantibody in RA. Since anti-serpin E2 autoantibodies interfere with the inhibitory activity of serpin E2 toward serine proteases, they might facilitate the joint destruction in RA.
Maciejewska-Rodrigues
H
H
University Hospital, University of Zurich, Zurich, Switzerland.
Al-Shamisi
M
M
Hemmatazad
H
H
Ospelt
C
C
Bouton
M C
MC
Jäger
D
D
Cope
A P
AP
Charles
P
P
Plant
D
D
Distler
J H W
JH
Gay
R E
RE
Michel
B A
BA
Knuth
A
A
Neidhart
M
M
Gay
S
S
Jüngel
A
A
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015535:Arthritis, Psoriatic / Q000097:blood / Q000276:immunology; D001172:Arthritis, Rheumatoid / Q000097:blood / Q000276:immunology*; D001323:Autoantibodies / Q000097:blood*; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D008297:Male; D008875:Middle Aged; D020411:Oligonucleotide Array Sequence Analysis; D010003:Osteoarthritis / Q000097:blood / Q000276:immunology; D011994:Recombinant Proteins / Q000276:immunology; D015843:Serpins / Q000276:immunology*; D013167:Spondylitis, Ankylosing / Q000097:blood / Q000276:immunology; D013582:Synovial Fluid / Q000276:immunology / Q000378:metabolism; D013583:Synovial Membrane / Q000378:metabolism / Q000473:pathology; D014568:Urokinase-Type Plasminogen Activator / Q000037:antagonists & inhibitors; D055815:Young Adult
D001323:Autoantibodies; D011994:Recombinant Proteins; D015843:Serpins; D014568:Urokinase-Type Plasminogen Activator