Induction of autoimmune arthritis in rats by immunization with homologous rat type II collagen is restricted to the RT1^av1 haplotype

Abstract

Objective. To test for genetic differences in susceptibility to homologous (rat) type I1 collagen-induced arthritis (RII-CIA).Methods. Nine inbred and RT1-congenic rat strains were immunized with native rat type I1 collagen and evaluated for arthritis and IgG anti-RII serum antibody titers.Results. Only RTla"' strains developed a high incidence of severe RII-CIA and high titers of IgG anti-RII serum antibody. Rats having RII-CIAresistant haplotypes, RTI".".' (which are known to develop CIA after immunization with heterologous type I1 collagen), were shown to also be susceptible to passive transfer of CIA with immune serum concentrates. Clinical expression of RII-CIA was down-regulated by non-RT1 genes of BN origin. No strong gender differences in anti-RII autoimmune responses were observed.Conclusion. Arthritogenic, autoimmune reactivity to homologous RII is under strict genetic control but occurs readily in RT1"" rats. Collagen-induced arthritis (CIA) is an experimentally induced model of chronic arthritis that hasFrom The Research Service, Salt Lake City Veteran Affairs Medical Center, and the Division of Rheumatology, University of Utah Medical School, Salt Lake City, Utah.Supported been studied in rats, mice, and primates. Joint inflammation in CIA is due to the generation of collagenreactive T cells and complement-binding, IgG anticollagen antibodies that cross-react with autologous type I1 collagen in joint cartilage (1,2). Several gene products influence the susceptibility of an individual rat to CIA (3-5). Of primary importance are the class I1 molecules that are encoded within the major histocompatibility complex (RTl), and that bind collagen peptides for presentation to T cells by antigen processing cells (5). Equally important are the non-major histocompatibility complex-encoded (non-MHC-encoded), T cell antigen receptor (TCR) molecules, which dictate the strength of interaction between specific T cells and each of the multiple immunogenic peptide fragments of type 11 collagen (6).CIA is commonly induced by immunization with heterologous, native type I1 collagen extracted from the articular cartilage of diverse species including bovine, chick, deer, porcine, and human. The minor, species-specific differences in amino acid sequence that exist among these very conserved molecules are readily detected by the rat immune system and cause an RTl-restricted variability in strain susceptibility to CIA induction by type I1 collagens of different origins (7,8).In this study we analyzed the response of several inbred and RTI-congenic rat strains to immunization with homologous rat type I1 collagen (RII). Of those tested, only one MHC haplotype, RTI"", was associated with a high degree of susceptibility to RII-CIA, although the other haplotypes that were tested are known to promote the induction of CIA by immunization with heterologous type I1 collagens. The results show that MHC-encoded genes determine the

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“…Although these 2 models have many clinical similarities, fundamental differences in their pathophysiology and genetic control are clearly evident and provide an ideal opportunity for defining and comparing the genes that control 2 different mechanisms of arthritis susceptibility. AIA is a particularly informative model because it predominantly involves T cell-mediated mechanisms (1-8), whereas CIA requires both humoral (14)(15)(16)(17)(18)(19)(20) and cellular immunity (21). CIA is characterized by the development of a symmetric erosive polyarthritis in association with the production of anticollagen antibodies (13)(14)(15)(16)(17)(18).…”

“…AIA is a particularly informative model because it predominantly involves T cell-mediated mechanisms (1-8), whereas CIA requires both humoral (14)(15)(16)(17)(18)(19)(20) and cellular immunity (21). CIA is characterized by the development of a symmetric erosive polyarthritis in association with the production of anticollagen antibodies (13)(14)(15)(16)(17)(18). It is an immunologically complex model that requires B cells, T cells, and cytokines of T cell origin to produce arthritis (18,19).…”

“…It is an immunologically complex model that requires B cells, T cells, and cytokines of T cell origin to produce arthritis (18,19). The initial phase of CIA is characterized by the binding of autoantibody to articular cartilage surfaces in association with complement fiuation, release of the chemotractant C5a into the joint space, fibrin deposition, neutrophil invasion, and loss of proteoglycans from joint cartilage (15)(16)(17). The second phase of CIA is characterized by an influx of activated T cells, B cells, and monocytes to produce joint inflammation.…”

“…collagen (CII) (13)(14)(15)(16)(17)(18)(19)(20)(21), respectively. Although these 2 models have many clinical similarities, fundamental differences in their pathophysiology and genetic control are clearly evident.…”

“…Although these 2 models have many clinical similarities, fundamental differences in their pathophysiology and genetic control are clearly evident. AIA is a particularly informative model because it predominantly involves T cell-mediated mechanisms (1)(2)(3)(4)(5)(6)(7)(8), in contrast to CIA, which requires both humoral (14)(15)(16)(17)(18)(19)(20) and cellular immunity (21).…”