Autoantibodies to Type II Collagen

Abstract

The discovery that immunization of rats with native type II collagen from articular cartilage in incomplete Freund's adjuvant can cause a progressive, inflammatory, erosive arthritis has provided an interesting new animal model of arthritis with features similar to those of human rheumatoid arthritis.1Trentham DE Townes AS Kang AH Autoimmunity to type II collagen: an experimental model of arthritis.J Exp Med. 1977; 146: 857-868Crossref PubMed Scopus (1326) Google Scholar Early studies demonstrated correlation of the immune response to type II collagen with the development of arthritis,2Trentham DE Townes AS Kang AH David JR Humoral and cellular sensitivity to collagen in type II collagen-induced arthritis in rats.J Clin Invest. 1978; 61: 89-96Crossref PubMed Scopus (206) Google Scholar, 3Stuart JM Cremer MA Kang AH Townes AS Collagen-induced arthritis in rats: evaluation of early immunologic events.Arthritis Rheum. 1979; 22: 1344-1351Crossref PubMed Scopus (119) Google Scholar and the autoimmune basis for the disease was further established by demonstrating modification of disease by immune-modulating drugs4Stuart JM Myers LK Townes AS Kang AH Effect of cyclophosphamide, hydrocortisone, and levamisole on collagen-induced arthritis in rats.Arthritis Rheum. 1981; 24: 790-794Crossref PubMed Scopus (31) Google Scholar and by the passive transfer of arthritis with unfractionated immune spleen and lymph node cells.5Trentham DE Dynesius RA David JR Passive transfer by cells of type II collagen-induced arthritis in rats.J Clin Invest. 1978; 62: 359-366Crossref PubMed Scopus (164) Google Scholar Another development of great interest has been the demonstration that susceptibility to type II collagen-induced arthritis is genetically determined by genes that map to the major histocompatibility immune response gene region both in rats6Griffiths MM Eichwald EJ Martin JH Smith CB DeWitt CW Immunogenetic control of experimental type II collagen-induced arthritis. I. Susceptibility and resistance among inbred strains of rats.Arthritis Rheum. 1981; 24: 781-789Crossref PubMed Scopus (140) Google Scholar and in mice.7Wooley PH Luthra HS Stuart JM David CS Type II collagen-induced arthritis in mice. I. Major histocompatibility complex (I region) linkage and antibody correlates.J Exp Med. 1981; 154: 688-700Crossref PubMed Scopus (591) Google Scholar, 8Wooley PH Dillon AM Luthra HS Stuart JM David CS Genetic control of type II collagen-induced arthritis in mice: factors influencing disease susceptibility and evidence for multiple MHC-associated gene control.Transplant Proc. 1983; 15: 180-185Google Scholar In general, arthritis does not develop in inbred strains that are low responders, as measured by antibody specific for homologous type II collagen. Several subsequent studies have further demonstrated the essential role of antibody to type II collagen in the initiation of arthritis in this model. Development of arthritis is altered by depletion of complement after active immunization.9Morgan K Clague RB Shaw MJ Firth SA Twose TM Holt PJL Native type II collagen-induced arthritis in the rat: the effect of complement depletion by cobra venom factor.Arthritis Rheum. 1981; 24: 1356-1362Crossref PubMed Scopus (93) Google Scholar Modification of the immunizing schedule to produce delayed hypersensitivity without antibody response has failed to induce arthritis.10Schoen RT Mehlman H Trentham DE Perry L Greene MI David JR Autoimmunity induced by type II collagen-coupled spleen cells.J Immunol. 1981; 127: 2275-2279PubMed Google Scholar Affinity purified and highly specific antibody to native homologous type II collagen has been shown to induce arthritis in rats11Stuart JM Cremer MA Townes AS Kang AH Type II collagen-induced arthritis in rats: passive transfer with serum and evidence that IgG anticollagen antibodies can cause arthritis.J Exp Med. 1982; 155: 1-16Crossref PubMed Scopus (277) Google Scholar and in mice.12Stuart JM Dixon FJ Serum transfer of collagen-induced arthritis in mice.J Exp Med. 1983; 158: 378-392Crossref PubMed Scopus (337) Google Scholar Specific anticollagen antibody localizes to the surface of articular cartilage13Stuart JM Tomoda K Yoo TJ Townes AS Kang AH Serum transfer of collagen-induced arthritis. II. Identification and localization of autoantibody to type II collagen in donor and recipient rats.Arthritis Rheum. 1983; 26: 1237-1244Crossref PubMed Scopus (82) Google Scholar, 14Kerwar SS Englert ME McReynolds RA Landes MJ Lloyd JM Oronsky AL Wilson FJ Type II collagen-induced arthritis: studies with purified anticollagen immunoglobulin.Arthritis Rheum. 1983; 26: 1120-1131Crossref PubMed Scopus (106) Google Scholar and can be eluted from cartilage of immunized arthritic animals.13Stuart JM Tomoda K Yoo TJ Townes AS Kang AH Serum transfer of collagen-induced arthritis. II. Identification and localization of autoantibody to type II collagen in donor and recipient rats.Arthritis Rheum. 1983; 26: 1237-1244Crossref PubMed Scopus (82) Google Scholar In addition, passive transfer of antibody from arthritic mice of a genetically high-responder susceptible strain promptly induces arthritic inflammation in a low-responder non-susceptible strain.12Stuart JM Dixon FJ Serum transfer of collagen-induced arthritis in mice.J Exp Med. 1983; 158: 378-392Crossref PubMed Scopus (337) Google Scholar Extrapolation of these observations in experimental animals to a meaningful application to human rheumatic disease has been problematic15Trentham DE Collagen arthritis as a relevant model for rheumatoid arthritis: evidence pro and con.Arthritis Rheum. 1982; 25: 911-916Crossref PubMed Scopus (218) Google Scholar but has been given a substantial boost by the report by Wooley and associates in this issue of the Proceedings (pages 737 to 743). These studies show beyond question that anti-type II collagen antibodies from a patient with rapidly progressive seronegative rheumatoid arthritis can passively transfer arthritis to mice in a manner similar to serum from arthritic rodents. Moreover, they demonstrate by inhibition assay that this human antibody shares the same antigenic epitope specificity on type II collagen as autoantibody from arthritic mice. Of more than passing interest also is the fact that this patient has the HLA-DR3 phenotype, which has been linked to a “high-responder” group of rheumatoid patients as measured by titers of antibody to type II collagen.16Dyer PA Clague RB Klouda PT Firth S Harris R Holt PJL HLA antigens in patients with rheumatoid arthritis and antibodies to native type II collagen.Tissue Antigens. 1982; 20: 394-396Crossref PubMed Scopus (25) Google Scholar Thus, several features of this patient seem to parallel important aspects of the animal model of collagen-induced arthritis—for example, a rapidly progressive clinical course with extensive erosions and joint deformity despite the absence of rheumatoid factor, the high titer of autoantibody to type II collagen possibly related to immune response genetic phenotype, the ability of this antibody to induce arthritis on passive transfer, and recognition of a common antigenic epitope on type II collagen comparable to antibody from arthritic rodents. Although these observations suggest a possible pathogenetic role of human autoantibody to type II collagen, a great deal more work is needed to establish the significance of these findings in relationship to the broad group of patients with rheumatoid arthritis, as the authors of this article have carefully pointed out. Previous reports of collagen autoantibodies in rheumatoid arthritis have varied widely in the observed frequency, the quantity of antibody, and the occurrence of these antibodies in diseases other than rheumatoid arthritis.17Andriopoulos NA Mestecky J Miller EJ Bradley EL Antibodies to native and denatured collagens in sera of patients with rheumatoid arthritis.Arthritis Rheum. 1976; 19: 613-617Crossref PubMed Scopus (159) Google Scholar, 18Clague RB Shaw MJ Holt PJL Incidence of serum antibodies to native type I and type II collagens in patients with inflammatory arthritis.Ann Rheum Dis. 1980; 39: 201-206Crossref PubMed Scopus (76) Google Scholar, 19Beard HK Ryvar R Skingle J Greenbury CL Anti-collagen antibodies in sera from rheumatoid arthritis patients.J Clin Pathol. 1980; 33: 1077-1081Crossref PubMed Scopus (32) Google Scholar, 20Trentham DE Kammer GM McCune WJ David JR Autoimmunity to collagen: a shared feature of psoriatic and rheumatoid arthritis.Arthritis Rheum. 1981; 24: 1363-1369Crossref PubMed Scopus (68) Google Scholar, 21Stuart JM Huffstutter EH Townes AS Kang AH 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.Arthritis Rheum. 1983; 26: 832-840Crossref PubMed Scopus (139) Google Scholar Some of these discrepancies have certainly been due to methodologic differences and problems in interpretation of low levels of antibody reactivity. Nevertheless, most investigators in this field would agree with the observation by Wooley and colleagues that patients similar to the one described herein with unequivocally high titers of autoantibody to native type II collagen represent the unusual patient rather than the majority of patients with rheumatoid arthritis.18Clague RB Shaw MJ Holt PJL Incidence of serum antibodies to native type I and type II collagens in patients with inflammatory arthritis.Ann Rheum Dis. 1980; 39: 201-206Crossref PubMed Scopus (76) Google Scholar, 19Beard HK Ryvar R Skingle J Greenbury CL Anti-collagen antibodies in sera from rheumatoid arthritis patients.J Clin Pathol. 1980; 33: 1077-1081Crossref PubMed Scopus (32) Google Scholar, 20Trentham DE Kammer GM McCune WJ David JR Autoimmunity to collagen: a shared feature of psoriatic and rheumatoid arthritis.Arthritis Rheum. 1981; 24: 1363-1369Crossref PubMed Scopus (68) Google Scholar, 21Stuart JM Huffstutter EH Townes AS Kang AH 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.Arthritis Rheum. 1983; 26: 832-840Crossref PubMed Scopus (139) Google Scholar Patients with high levels of autoantibody to type II collagen may thus represent a distinct subgroup of rheumatoid patients. This possibility certainly warrants further attempts to identify such patients and to investigate their background and clinical features carefully in order to determine additional characteristics that may allow them to be distinguished from other patients within the clinical spectrum of rheumatoid arthritis. As is further suggested in the article by Wooley and co-workers in this issue, qualitative differences in autoantibodies to type II collagen may also be important to their pathogenetic significance. Recent data from my laboratory, for example, have suggested that restriction of antibody subclass response with a relative lack of specific antibody of the subclass chiefly responsible for activation of complement may be an important variable in determining susceptibility to collagen-induced arthritis in an antibody-responder but nonarthritic strain of mice.22Watson WC Townes AS Genetic restriction of the lgG2a autoantibody subclass response to collagen II (CII): an hypothesis for resistance to CII autoimmune arthritis in C57BL mice (abstract).Fed Proc. 1984; 43: 3343Google Scholar To localize to the joint cartilage and to activate inflammatory mediators within the joint and synovium, the autoantibody must also be able to gain access to the joint and recognize an antigenic epitope exposed on the surface of the articular cartilage. The autoantibody to type II collagen described in the patient in the report by Wooley and associates certainly seems to meet these criteria. Like arthritogenic antibody from rodents, antibody from this patient reacted across animal species of collagen, and its ability to induce arthritis in mice was clearly demonstrated. In all likelihood, this antibody would also react with human type II collagen, but such reactivity needs to be demonstrated directly in order to implicate the autoantibody in the pathogenesis of arthritis in this patient. Also important is the fact that the antibody from this patient demonstrated inhibition of the binding of rodent arthritogenic antibody to type II collagen in vitro. The reported assay system might prove to be a sensitive and a much simpler way to determine the arthritogenic potential of these antibodies, and it certainly deserves further application in the study of autoantibodies to type II collagen in rheumatoid and other forms of arthritis. The findings of this study do not resolve the uncertainty about the significance of collagen autoantibodies in rheumatic disease. Because of the rarity of patients such as the one described herein with high titers of these antibodies and the lack of correlation with HLA-DR4, it seems doubtful that such antibodies are of primary etiologic importance in most patients with rheumatoid arthritis. This study, however, provides a provocative stimulus to search further for a subgroup of patients in whom collagen autoantibodies may have a primary pathogenetic role. Further investigation with use of the methods described by Wooley and associates may also yield additional evidence in support of a broader role for the participation of autoantibodies to type II collagen in the promotion of arthritic inflammation.