Local production of complement proteins in rheumatoid arthritis synovium.
OBJECTIVE
Complement has been repeatedly implicated in the pathogenesis of rheumatoid arthritis (RA) based on studies showing reduced levels of native complement components and increased levels of complement metabolites in plasma, synovial fluid (SF), and synovial tissue (ST) of RA patients. However, there is limited information on local production and activation of key factors of the complement cascade in RA synovium and their potential modulation by novel anticytokine therapies. This study was undertaken to characterize the expression of complement proteins and receptors in RA SF and ST.


METHODS
Using in situ hybridization, immunohistochemistry, and Western blot techniques, we assessed the presence of complement proteins C3, factor B (FB), and C5b-9, as well as the expression of complement receptors C3aR and C5aR in rheumatoid synovium. C3 and FB levels in SF were determined by enzyme-linked immunosorbent assay. Functional assessment was performed by examining the effects of soluble tumor necrosis factor receptor (sTNFR) p55 gene transfer in the SCID mouse model of RA.


RESULTS
Complement proteins and receptors could be localized in all RA synovial specimens, whereas in osteoarthritis (OA) synovium, only a few, single cells expressed complement proteins and receptors. No differences were noted in the concentration of C3 between RA and OA in SF; however, FB levels were markedly reduced in RA versus OA SF. In RA synovium, in contrast to OA synovium, local expression of complement factor and complement receptor messenger RNA was found throughout the various ST compartments, suggesting that activation of the complement cascade occurs in all parts of the rheumatoid synovium. Moreover, C5aR expression was up-regulated following overexpression of sTNFR p55 by adenovirus-based gene transfer.


CONCLUSIONS
In summary, local complement production and activation may play an important role in RA, and specific modulation and inhibition of local complement production could be an attractive therapeutic target for RA.
Neumann
Elena
E
University of Regensburg, Regensburg, Germany.
Barnum
Scott R
SR
Tarner
Ingo H
IH
Echols
Josh
J
Fleck
Martin
M
Judex
Martin
M
Kullmann
Frank
F
Mountz
John D
JD
Schölmerich
Jürgen
J
Gay
Steffen
S
Müller-Ladner
Ulf
U
D000368:Aged; D000818:Animals; D015703:Antigens, CD / Q000235:genetics; D001172:Arthritis, Rheumatoid / Q000276:immunology / Q000503:physiopathology*; D015153:Blotting, Western; D002478:Cells, Cultured; D003167:Complement Activation; D003176:Complement C3 / Q000235:genetics; D011415:Complement Factor B / Q000235:genetics; D015938:Complement Membrane Attack Complex / Q000235:genetics; D003165:Complement System Proteins / Q000235:genetics*; D005260:Female; D005347:Fibroblasts / Q000166:cytology / Q000502:physiology; D015870:Gene Expression / Q000276:immunology; D006801:Humans; D017403:In Situ Hybridization; D008297:Male; D008565:Membrane Proteins; D051379:Mice; D016513:Mice, SCID; D008875:Middle Aged; D012333:RNA, Messenger / Q000032:analysis; D044087:Receptor, Anaphylatoxin C5a; D011951:Receptors, Complement / Q000235:genetics; D013583:Synovial Membrane / Q000166:cytology / Q000276:immunology / Q000503:physiopathology*
D015703:Antigens, CD; D003176:Complement C3; D015938:Complement Membrane Attack Complex; D008565:Membrane Proteins; D012333:RNA, Messenger; D044087:Receptor, Anaphylatoxin C5a; D011951:Receptors, Complement; C085567:complement C3a receptor; D003165:Complement System Proteins; D011415:Complement Factor B