The adaptor protein CIKS/ACT1 is necessary for collagen-induced arthritis, and it contributes to the production of collagen-specific antibody.
OBJECTIVE
CIKS/ACT1 is an adaptor molecule that is necessary for signaling by members of the interleukin-17 cytokine family. The aim of this study was to determine whether this adaptor is required for the initiation of collagen-induced arthritis (CIA). If it is required, then CIKS-mediated signaling could be a potential target for therapeutic intervention in patients with rheumatoid arthritis (RA).


METHODS
CIA model studies were performed with CIKS-deficient and CIKS-sufficient mice on an otherwise wild-type (WT) C57BL/6 background or on a C57BL/6 background lacking Fcγ receptor IIb (FcγRIIb). In addition, collagen antibody-induced arthritis (CAIA) studies were performed in WT and CIKS-deficient mice. Pathologic changes of arthritis were evaluated by visual inspection of the paws, by histochemical analysis of tissue sections, and by measurements of collagen-specific antibodies.


RESULTS
Pathologic changes of CIA were readily induced in WT mice, with exacerbation of the changes in FcγRIIb-deficient mice. In contrast, CIKS-deficient mice were protected from all aspects of CIA pathology, even on an FcγRIIb-deficient background. The absence of CIKS completely prevented neutrophil infiltration into joints, bone erosion, and cartilage damage; furthermore, the production of type II collagen (CII)-specific antibodies was reduced. In contrast to the CIA model, CIKS-deficient mice in the CAIA model remained susceptible to arthritis.


CONCLUSIONS
CIKS-mediated signaling is necessary for the pathogenesis of CIA, but not CAIA. These findings suggest critical functions of CIKS during the development of arthritis in the CIA model, including in the formation of CII antibodies, and they mark the CIKS adaptor as a potential therapeutic target in RA.
Pisitkun
Prapaporn
P
National Institute of Allergy and Infectious Diseases, NIH, Bethesda, Maryland 20892-1876, USA.
Claudio
Estefania
E
Ren
Nina
N
Wang
Hongshan
H
Siebenlist
Ulrich
U
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D000818:Animals; D001169:Arthritis, Experimental / Q000209:etiology / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D024043:Collagen Type II / Q000276:immunology* / Q000378:metabolism; D016207:Cytokines / Q000276:immunology / Q000378:metabolism; D005434:Flow Cytometry; D007596:Joints / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D020556:Neutrophil Infiltration / Q000276:immunology; D015398:Signal Transduction
D048868:Adaptor Proteins, Signal Transducing; D024043:Collagen Type II; D016207:Cytokines; C515963:Traf3ip2 protein, mouse