IMMUNITY TO THE G1 GLOBULAR DOMAIN OF THE CARTILAGE PROTEOGLYCAN AGGRECAN CAN INDUCE INFLAMMATORY EROSIVE POLYARTHRITIS AND SPONDYLITIS IN BALB C MICE BUT IMMUNITY TO G1 IS INHIBITED BY COVALENTLY BOUND KERATAN SULFATE IN-VITRO AND IN-VIVO/

Earlier work from this laboratory showed that the human proteoglycan a ggrecan from fetal cartilages can induce a CD4(+) T cell-dependent inf lammatory polyarthritis in BALB/c mice when injected after removal of chondroitin sulfate chains. Adult keratan sulfate (KS)-rich aggrecan d oes not possess this property. We found that two CD4(-) T cell hybrido mas (TH5 and TH14) isolated from arthritic mice recognize bovine calf aggrecan and the purified G1 domain of this molecule, which also conta ins a portion of the interglobular domain to which KS is bound. These hybridoma responses to G1 are enhanced by partial removal of KS by the endoglycosidase keratanase or by cyanogen bromide cleavage of core pr otein. KS removal results in increased cellular uptake by antigen-pres enting cells in vitro. After removal of KS by keratanase, G1 alone can induce a severe erosive polyarthritis and spondylitis in BALB/c mice identifying it as an arthritogenic domain of aggrecan. The presence of KS prevents induction of arthritis presumably as a result of an impai red immune response as observed in vitro. These observations not only identify the arthritogenic properties of G1 but they also point to the importance of glycosylation and proteolysis in determining the arthri togenicity of aggrecan and fragments thereof.