Cloning of novel soluble gp130 and detection of its neutralizing autoantibodies in rheumatoid arthritis

In an attempt to isolate disease-associated autoantigens in rheumatoid arth ritis (RA), we cloned a new autoantigen named gp130-RAPS, which is a novel soluble form of the IL-6 signal-transducing molecule gp130. gp130-RAPS is a 50-kDa protein translated from alternatively spliced mRNA and has a trunca ted form of gp130 with a unique sequence, Asn-Ile-Ala-Ser-Phe (NIASF), in i ts COOH-terminus. We observed serum antibodies to this NIASF sequence frequ ently in patients with RA, but not in those with other systemic rheumatic d iseases or in healthy subjects. In RA, detection of those antibodies was si gnificantly associated with disease activity indices such as serum C-reacti ve protein (CRP) levels, erythrocyte sedimentation rate, brood platelet cou nts, and serum IL-6 concentration. In vitro experiments revealed that gp130 -RAPS inhibited IL-6 activity, and this inhibition was neutralized by antib odies to the COOH-terminus of gp130-RAPS derived from patients with RA. Thu s, autoantibody to gp130-RAPS may play an important role in the progression of RA by promoting IL-6 activity. Inspection of autoantibodies to gp130-RA PS may become a practical clinical test for RA. gp130-RAPS and its autoanti body provide a new clue to the complicated pathogenesis of RA.