Arthritis induced by proteoglycan aggrecan G1 domain in BALB/c mice. Evidence for t cell involvement and the immunosuppressive influence of keratan sulfate on recognition of t and b cell epitopes.

Abstract

Our previous work showed that the proteoglycan aggrecan can induce erosive polyarthritis and spondylitis in BALB/c mice, and that the G1 domain of the proteoglycan aggrecan (G1) is the arthritogenic region. In this study, two T cell epitopes residing on G1 within residues 70-84 (peptide G5) and 150-169 (peptide G9) were identified using synthetic peptides and aggrecan-specific T cell lines. Two G1-specific T cell hybridomas exclusively responded to peptide G5. When the G5-specific T cell line was injected intraperitoneally into BALB/c mice, it induced acute inflammatory arthritis in joints, but only in those that had been injected with the epitope recognized by these T cells. Furthermore, we also demonstrate that the keratan sulfate chain(s) (KS) on G1 possess immunosuppressive properties with respect to T and B cell epitope recognition. T cell lines that recognize both G1 and peptide G5 show an increased response to G1 after KS is removed. Antibodies in hyperimmune sera of mice immunized with G1 show increased epitope recognition (quantitative and qualitative) after KS removal before immunization. These studies reveal that a T cell line specific to an epitope on the G1 domain of aggrecan, also recognizing a corresponding mouse G1 epitope, can induce arthritis by adoptive transfer and homing to the intraarticular epitope, thereby implicating T cells in arthritis development caused by immunity to the G1 domain of aggrecan. Moreover, the presence of KS on G1 can inhibit arthritis development by suppressing T and B cell epitope recognition. ( J.

HLA–B27–restricted CD8+ T cell response to cartilage‐derived self peptides in ankylosing spondylitis

“…The G1 domain of the proteoglycan aggrecan has been of special interest in the past, because an animal model resembling AS could be induced by immunization with this protein. However, CD8ϩ T cells do not seem to play a role in this model (25). A T cell response to aggrecan could also be demonstrated in peripheral blood in several rheumatic diseases, including rheumatoid arthritis, osteoarthritis, and AS (26,27).…”

B Cell Clonal Expansion and Somatic Hypermutation of Ig Variable Heavy Chain Genes in the Synovial Membrane of Patients with Osteoarthritis

“…A recent comprehensive proteomic surveillance has revealed that some Ags are recognized predominantly in OA rather than in RA (4). In animal models, immunization with cartilage proteins such as collagen type II, human cartilage glycoprotein-39 (44), cartilage link protein (45), and proteoglycans (46,47) induce destructive arthritis whereas cartilage intermediate layer protein (40) and YKL-39 (42) cause mild synovitis but no cartilage or bone destruction. Whether the immune reaction against these or other cartilage autoantigens play a role in triggering and/or perpetuating synovitis and cartilage damage in OA remains to be demonstrated.…”

HLA-DR1 (DRB1*0101) and DR4 (DRB1*0401) Use the Same Anchor Residues for Binding an Immunodominant Peptide Derived from Human Type II Collagen

“…1-4). Although RA is considered an autoimmune disease of unknown etiology, there has been no shortage of Ags proposed to be initiating or driving the autoimmune response, including viral proteins from CMV and EBV (5,6), autologous proteins expressed in diarthrodial joints such as link and proteoglycan (7)(8)(9), gp39 (10), and type II collagen (CII; Refs. [11][12][13][14].…”