Deletion of the gene encoding CD59a in mice increases disease severity in a murine model of rheumatoid arthritis

Abstract

Objective. To investigate the roles of CD59a in the protection of joint tissue in the context of murine antigen-induced arthritis (AIA).Methods. AIA was triggered in CD59a-deficient (CD59a ؊/؊ ) mice and in CD59a-sufficient (CD59a ؉/؉ ) controls; the course and severity of disease were compared between groups. The effects on arthritis of restoring CD59 to the joint in CD59a ؊/؊ mice by use of a membrane-targeted recombinant CD59 were also explored.Results. Disease, as assessed clinically by measurement of joint swelling on day 1 (P < 0.0001), day 2 (P < 0.01), and day 7 (P < 0.02) and histologically from indicators of joint damage on day 21 (P < 0.02), was significantly enhanced in CD59a ؊/؊ mice compared with CD59a؉/؉ wild-type controls. Membrane attack complex (MAC) deposition in the arthritic joints of CD59a ؊/؊ mice was also increased compared with that in the joints of CD59a ؉/؉ controls. Restitution of CD59 activity in joints of CD59a ؊/؊ mice was attempted with soluble recombinant rat CD59 (sCD59) or with a novel membrane-targeted rat CD59 derivative (sCD59-APT542). Strong immunohistochemical staining of the synovial membrane and subsynovial tissue was apparent in sCD59-APT542-injected joints, but not in joints injected with untargeted sCD59. Intraarticular administration of sCD59-APT542 markedly ameliorated disease severity in CD59a ؊/؊ mice, knee swelling was significantly reduced over the time course of the disease, and joint damage, assessed histologically, was significantly milder on day 21 (P < 0.05).Conclusion. These data firmly implicate the MAC of complement as a major effector of joint damage in the murine AIA model of rheumatoid arthritis (RA), and they provide a rationale for the inhibition of MAC assembly as a therapeutic strategy for RA.

Backcross and Partial Advanced Intercross Analysis of Nonobese Diabetic Gene-Mediated Effects on Collagen-Induced Arthritis Reveals an Interactive Effect by Two Major Loci

“…For example, opsonization with C3b is the main mechanism by which complement contributes to phagocytosis of pathogenic microorganisms. The hypothesis that C5a and/or MAC are main contributors to the disease is further supported by beneficial effects of oral C5aR antagonist in treatment of arthritis in rat (38) as well as increased arthritis severity in mice lacking the MAC inhibitor, CD59 (39). Interestingly, in the PAI experiment, the level of complement activity was up-regulated at day 70, which is consistent with the fact that several complement factors are acute phase proteins up-regulated upon inflammation.…”

Leucocyte complement receptor 1 (CR1/CD35) transcript and its correlation with the clinical disease activity in rheumatoid arthritis patients

“…The complement system contributes significantly to the pathogenesis of RA and other autoimmune diseases [11,12]. Under normal physiological conditions, tissues in the body are protected from complement-mediated damage by expression of multiple complement regulatory proteins that co-operate to inhibit complement activation on selftissues [13].…”

“…In the patients' synovial fluid, decreased levels of native complement components and increased levels of activation products have been detected [11]. Furthermore, deposition of activated complement components has been demonstrated in synovial tissue [12]. Various studies on animal models of autoimmune diseases have demonstrated that membrane-bound complement regulatory proteins may critically determine the sensitivity of the host tissues to complement injury in autoimmune and inflammatory disorders [3].…”

PRELP Protein Inhibits the Formation of the Complement Membrane Attack Complex

“…*, p Ͻ 0.05; **, p Ͻ 0.01; ***, p Ͻ 0.001. ns, not significant. been shown to contribute to the pathology of the disease in mice models, as CD59a Ϫ/Ϫ mice develop a more severe arthritis than their wild type counterparts in an antigen-induced arthritis model (23). Furthermore, a membrane-targeted rat CD59 derivative (sCD59-APT542) was shown to decrease disease severity in the same arthritis model in rats (23,24).…”

“…been shown to contribute to the pathology of the disease in mice models, as CD59a Ϫ/Ϫ mice develop a more severe arthritis than their wild type counterparts in an antigen-induced arthritis model (23). Furthermore, a membrane-targeted rat CD59 derivative (sCD59-APT542) was shown to decrease disease severity in the same arthritis model in rats (23,24). Increasing our knowledge on mechanisms of complement regulation within the joints is essential for future development of specific complement inhibitors or inhibitors of the factors causing local complement activation suitable for human use with minimal systemic effects.…”