Immunoglobulins may have been developed in evolution to provide specificity for clearing body waste in the first animals with three germ layers. Tissue homeostasis in vertebrates comprises clearance of proteins released from lysed cells, elimination of altered plasma proteins, of senescent and apoptotic cells. Rather specific IgM and IgG naturally occurring antibodies (NAbs) to cytoplasmic and cytoskeletal proteins bind to proteins released from lysing cells and the IgG NAbs are slightly upregulated upon demand. Some of these NAbs along with complement have devastating effects when massive amounts of intracellular proteins are released during an infarct or an ischemia/reperfusion experiment. IgM NAbs to neoepitopes on plasma proteins/lipids help clear denatured proteins and are protective. IgG NAbs to an exposed protein, band 3 from red blood cells, bind to oligomerized band 3 and due to an affinity for C3 within their framework preferentially form C3b2-IgG complexes from nascent C3b. Thus, anti-band 3 NAbs gain potency by using avidity and generating a potent precursor of the amplifying C3 convertase. IgM NAbs to neoepitopes, which are generated by oxidized lipids forming Schiff bases with proteins, are protective and help clear this waste in atherosclerosis, but IgG antibodies (NAbs?) of the same specificity promote disease.