Hierarchical contributions of IgM and complement C1q in protection against murine atherosclerosis

Abstract

Natural IgM antibodies and complement C1q have been implicated in atherogenesis through their ability to bind tissue debris such as denatured low‐density lipoprotein (LDL) and apoptotic cells. To investigate their relative contributions, mice deficient in serum IgM (sIgM), C1q or both C1q and sIgM were crossed with LDL receptor deficient mice (Ldlr−/−) and studied at 22 weeks. sIgM.Ldlr−/− mice showed increased lesion size in comparison to Ldlr−/− mice, both en face (~7‐fold, p<0.0001) and at the aortic root (~5‐fold, p<0.0001). Similar findings were noted on a high fat diet with a 98% increase en face (p=0.0009) and a 23% increase in aortic root lesion area (p=0.006) in sIgM.Ldlr−/− mice, and increased smooth muscle cell infiltration (p=0.007). En face and aortic root lesions were substantially larger in sIgM.Ldlr−/− than C1q.Ldlr−/− mice on either diet (all p<0.005), and the effects of combined C1q and serum IgM deficiency were no different to those of sIgM deficiency alone. Thus although IgM antibodies and C1q are both significantly atheroprotective, IgM makes a more prominent contribution. The major mechanism of protection by IgM therefore appears to be independent of classical pathway activation.Funded by the Wellcome Trust and British Heart Foundation