Specific Recognition of Protein Carboxy-Terminal Sequences by Natural IgM Antibodies in Normal Serum

Abstract

Our previous study indicated that normal serum contains complement-fixing natural IgM antibodies reacting with a large variety of randomly generated protein carboxy-termini. Here we show that the "carboxy-terminal" IgM (C-IgM) antibodies specifically react with short peptide sequences located immediately at the protein carboxy-terminus. The specificity of C-IgM-peptide interactions is tentatively defined by three to four amino acid residues. All carboxy-terminal peptides in a large peptide library apparently react with C-IgM antibodies. Immobilized synthetic peptides also react with C-IgM antibodies. No interaction of C-IgM antibodies with internal peptide sequences has been observed. C-IgM antibodies are present in germ-free and in athymic adult rats and are absent in newborn rats. The natural ubiquity of protein carboxy-termini in biological structures suggests that C-IgM could play an important role in antigen clearance and presentation to the immune system. From a practical viewpoint, the recognition of carboxy-terminal peptides by complement-fixing C-IgM antibodies has profound implications for the use of peptide- and protein-derivatized delivery vehicles and artificial materials.

Clearance of Adenovirus by Kupffer Cells Is Mediated by Scavenger Receptors, Natural Antibodies, and Complement

“…Only a single IgM molecule is needed to activate the hemolytic activity of complement, a task that requires roughly 1,000 IgG molecules (11). Natural antibodies and subsequent complement activation cause the lysis or neutralization of many viruses (21,22,38,42,51,52,61). However, we were unable to detect any neutralizing effect of 90% mouse serum on the infectious titer of Ad vectors (our unpublished observations), in agreement with a previous report (2).…”

“…Polyreactive natural IgM antibodies play an important role in the control of viral infections in vivo, where they are a vital innate defense during the early stages of an infection, before the adaptive immune system has mounted an antigen-specific response (8,37,38,69). In addition, natural antibodies are a major obstacle to in vivo gene therapy with retroviruses, bacteriophage, herpes simplex virus type 1, and baculovirus (21,42,51,52,61).…”

In Vivo Selection and Validation of Liver-Specific Ligands Using a New T7 Phage Peptide Display System

“…Thus normal human serum contains a large population of natural IgM antibodies that collectively recognize virtually all randomly generated linear C-terminal peptides (Sokoloff et al 2000;Sokoloff et al 2001;Sokoloff et al 2004). This suggests that linear C-terminal peptides as a group may be difficult to adapt as therapeutic ligands, particularly if present as multiple copies.…”

“…The residual recombination that might produce significant background in liver selections was eliminated by using the "in-house" extract prepared from the "packaging" phage modified by truncating p10 after its Q 343 (VVFQ*). This prevented the recognition of phage by natural IgM (Sokoloff et al 2001), and mutating p17 (K 211 → E), which disrupts the phage liver targeting (Sokoloff et al 2003). With these modifications, any recombination between vector DNA and DNA from the packaging extract would produce long-circulating phage incapable of contributing to selection output (Sokoloff et al 2003).…”

Effects of innate immunity on herpes simplex virus and its ability to kill tumor cells

“…[52][53][54][55] However, experimental evidence suggests that this or a related natural Ig is unlikely to be responsible for the observed effects. 49 Natural IgMs reactive against exposed membrane C-terminal sequences 56 …”