Incidence and specificity of antibodies to types I, II, III, IV, and V collagen in rheumatoid arthritis and other rheumatic diseases as measured by ¹²⁵i‐radioimmunoassay

Abstract

Antibodies to human native and denatured types I, 11, 111, IV, and V collagens were measured using Iz5I-radioimmunoassay. Mean levels of binding by sera from 30 rheumatoid arthritis patients were significantly higher than those from 20 normal subjects against all of the collagens tested. The relative antibody concentration was higher in synovial fluid than in simultaneously obtained serum. Many patients with gout or various other rheumatic diseases also had detectable anticollagen antibodies. With a few notable exceptions, the majority of the reactivity detected in all patient groups was directed against covalent structural determinants present on all of the denatured collagens, suggesting a secondary reaction to tissue injury.A potential role for collagen autoimmunity in the pathogenesis of rheumatoid arthritis (RA) was suggested by Steffen in 1970 (1). Subsequently, several reports of antibodies to collagen in human sera and synovial fluid have appeared describing a variety of methods and reaching varied conclusions (2-6). Some authors have found frequent collagen reactivity in RA sera o r synovial fluid (2,5), while others have concluded that anomalous reactions could account. for the majority of reactivity (7-9). In addition, antibodies to collagen have been found in other diseases (10-12), raising some question as to the pathologic significance of antibodies to collagen in RA if they were present.Recently it was discovered that immunization of rats or mice with native type I1 collagen results in the development of an inflammatory polyarthritis (13). Arthritis was associated with both cellular and humora1 immunity to type I1 collagen (14). Because of this discovery, there has been renewed interest in the role of collagen autoimmunity in human arthritis. We have recently shown that type I1 collagen-induced arthritis in rats can be passively transferred with serum and that purified IgG anticollagen antibodies are capable of inducing arthritis in non-immunized rats ( I 5). During the course of our studies of collagen-induced arthritis in rats, we used a sensitive radioimmunoassay to detect antibodies to collagen (16). We now report on the application of that method in human arthritis.

Collagen antibodies in rheumatoid arthritis. SIgnificance of antibodies to denatured collagen and their association with HLA‐DR4

“…Since Steffen and Timpl (1) showed, in 1963, that the antibodies to homogenates of joint capsule cartilage from RA patients were reactive with collagen, many studies have confirmed that sera from patients with RA have antibodies to a variety of collagens (1)(2)(3)(4)(5)(6)(7)(8)(9). When tested, these antibodies have been found at higher titer in patients' synovial fluid as well (9-1 1).…”

“…These antibodies have been demonstrated to react to some degree with all types of collagen tested (9), but major interest has centered on type I collagen, which is found predominantly in skin, bone, vessels, and at joint surfaces, and type I1 collagen, which is found in hyaline cartilage. Antibodies have been shown to react with native collagens (M), denatured collagens (2), or both native and denatured collagens (3,8,9,11).…”

“…However, with the ' introduction of radioimmunoassays to detect collagen antibodies, reactivity has been detected in almost all sera tested, from patients and controls (4,8,9,11). The significance of this reactivity has not been certain.…”

“…Inhibition studies have shown that sera containing high levels of reactivity to collagen contain specifically reactive antibodies (2,3,9), but RA patient sera exhibiting reactivity that is within the range of the control group have not been tested, and much of the reactivity, particularly to denatured collagen, could have been the result of nonspecific binding of IgG, rheumatoid factor, or immune complexes. However, this is unlikely since levels of reactivity to denatured collagen in our study showed no correlation with levels of rheumatoid factor or immune complexes, and sera from patients with primary Sjogren's syndrome with marked hypergammaglobulinemia and high levels of rheumatoid factor showed low reactivity.…”

“…Studies conducted during the past several years have demonstrated the presence of antibodies to collagen in the serum (1)(2)(3)(4)(5)(6)(7)(8)(9) and synovial fluid (9-1 1) of patients with rheumatoid arthritis (RA), although it has not been possible to relate the presence or titer of collagen antibody to the course or severity of the disease. These studies have used a variety of collagen types as antigen, and often no distinction has been made between antibodies to native collagen and antibodies to denatured collagen.…”