PubMed2003
Many cartilage matrix proteins or domains such as collagen types II, IX, and XI, GP39, AG1, VG1, and LP are potential antigens that might induce polyarthritis in susceptible animals (Table 1). Ordinarily, spondylitis is not a feature of polyarthritis induced with collagen types II, IX, and XI, GP39, cartilage matrix protein (matrilin-1) and cartilage LP. It seems that only the proteoglycans aggrecan and versican are capable of inducing sacroiliitis and spondylitis. Both molecules are structural proteins in intervertebral discs. Moreover, the arthritogenic or spondylitogenic epitopes of both molecules have been localized to the homologous N-terminal G1 globular domains. This region of versican and aggrecan is highly conserved, with 52% identity of amino acids. The homology is seen exclusively in the G1 domain and is concentrated between residues 115 and 332 (AG1 numbering) near the natural cleavage DIPEN site of aggrecan [84, 85]. Extra-articular pathology is often seen in rheumatic diseases, especially in AS. Other tissues, such as the sclera of the eye [86] and the media of the arteries [86, 87], also contain type II collagen, AG1, VG1, and LP, and versican is present in the central and peripheral nervous systems. Thus, there is the potential for an immune response against cartilage G1 and LP to be directed against related structures in extra-articular tissues. The presence of versican in the tendon and trochlea of the human superior oblique muscle might account for the occurrence of transient attacks of acquired Brown syndrome in patients with juvenile and adult forms of chronic RA [88]. Thus, it will be interesting to determine whether or not extra-articular expression of these cartilage proteins is closely related to extra-articular pathogenic expression in rheumatic diseases. Uveitis develops in VG1-immunized BALB/c mice, which is not seen in AG1-, and LP-treated animals. There is evidence that aggrecan and LP are also localized at these sites in the eye, but only immunity to versican can induce uveitis. In sacroiliitis and enthesitis of AS patients, the inflammation is associated with chondrometaplasia. In versican-induced sacroiliitis, replacement of cartilage by bone is seen with relatively little inflammation, somewhat resembling the situation in AS (Fig. 2). Versican can also stimulate chondrocyte proliferation [43]. Three conserved domains of human cartilage matrix molecules, namely VG1, AG1, and LP, show considerable homology [77, 79, 80, 89], and each is capable of inducing a unique inflammatory arthritis in BALB/c mice, with VG1 inducing only spondylitis [65], LP inducing peripheral arthritis with no spondylitis [90], and AG1 inducing axial and peripheral arthritis [66, 91]. It remains a mystery why such similar molecules cause different pathology in different target tissues. The exact immunopathogenic mechanisms deserve further study.