Abstract
We have shown previously that collagen V (col(V)) autoimmunity is a consistent feature of atherosclerosis in human coronary artery disease and in the Apoe(-/-) mouse model. We have also shown sensitization of Apoe(-/-) mice with col(V) to markedly increase the atherosclerotic burden, providing evidence of a causative role for col(V) autoimmunity in atherosclerotic pathogenesis. Here we sought to determine whether induction of immune tolerance to col(V) might ameliorate atherosclerosis, providing further evidence for a causal role for col(V) autoimmunity in atherogenesis and providing insights into the potential for immunomodulatory therapeutic interventions. Mucosal inoculation successfully induced immune tolerance to col(V) with an accompanying reduction in plaque burden in Ldlr(-/-) mice on a high-cholesterol diet. The results therefore demonstrate that inoculation with col(V) can successfully ameliorate the atherosclerotic burden, suggesting novel approaches for therapeutic interventions. Surprisingly, tolerance and reduced atherosclerotic burden were both dependent on the recently described IL-35 and not on IL-10, the immunosuppressive cytokine usually studied in the context of induced tolerance and amelioration of atherosclerotic symptoms. In addition to the above, using recombinant protein fragments, we were able to localize two epitopes of the α1(V) chain involved in col(V) autoimmunity in atherosclerotic Ldlr(-/-) mice, suggesting future courses of experimentation for the characterization of such epitopes.
Highlights
Atherosclerosis underlies coronary artery disease (CAD)3 and stroke, major global causes of death [1], and is a chronic inflammatory disease that is modulated by both innate and adaptive immune pathways
Mucosal Administration of ColV Induces Tolerance in LdlrϪ/Ϫ Mice on a Western Diet—In initial experiments to determine whether mucosal administration of colV might induce tolerance to this autoantigen in atherosclerotic mice, 5-week-old LdlrϪ/Ϫ mice on normal chow were treated with small-volume nasal infusions of colV or, as negative controls, PBS or col(I)
Preliminary studies employing Trans Vivo Delayed-type Hypersensitivity (TV-DTH) assays of splenocytes indicated that col(V) autoimmunity becomes consistently detectable in LdlrϪ/Ϫ mice after ϳ12 weeks on the Western diet
Summary
Atherosclerosis underlies coronary artery disease (CAD)3 and stroke, major global causes of death [1], and is a chronic inflammatory disease that is modulated by both innate and adaptive immune pathways. Immune responses to col(V) were blocked more effectively and consistently in TV-DTH assays via co-injection of splenocytes from either PBS- or col(I)treated LdlrϪ/Ϫ mice with neutralizing antibodies to IL-17 (Fig. 2, A and B).
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