Natural Antibody and Complement Mediate Neutralization of Influenza Virus in the Absence of Prior Immunity

Abstract

Early control of virus replication by the innate immune response is essential to allow time for the generation of a more effective adaptive immune response. As an important component of innate immunity, complement has been shown to be necessary for protection against numerous microbial infections. This study was undertaken to investigate the role of complement in neutralizing influenza virus. Results demonstrated that the classical pathway of complement mediated serum neutralization of influenza virus. Although nonimmune serum neutralized influenza virus, the mechanism of virus neutralization (VN) required antibody, as sera from RAG1-deficient mice lacked VN activity; moreover, purified natural immunoglobulin M (IgM) restored VN activity to antibody-deficient sera. The mechanism of VN by natural IgM and complement was associated with virion aggregation and coating of the viral hemagglutinin receptor; however, viral lysis did not significantly contribute to VN. Additionally, reconstitution of RAG1-deficient mice with natural IgM resulted in delayed morbidity during influenza virus infection. Collectively, these results provide evidence that natural IgM and the early components of the classical pathway of complement work in concert to neutralize influenza virus and that this interaction may have a significant impact on the course of influenza viral pneumonia.

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However, we were unable to detect any neutralizing effect of 90% mouse serum on the infectious titer of Ad vectors (our unpublished observations), in agreement with a previous report (2).…”

“…Similar findings have previously been made with a number of other viruses (21,22,37,61). Although the monomeric affinity of natural IgM tends to be much lower than that of affinity-matured antigen-specific IgG antibodies, the avidity of IgM can be very high when bound to repetitive antigens (such as viral capsids), because IgM is a pentamer or a hexamer that contains 10 or 12 Fabs (69).…”

Innate Immunity Mediates Follicular Transport of Particulate but Not Soluble Protein Antigen

“…We provide evidence that the reason for the much more efficient transport of viral particles lies in the presence of natural Abs. Unspecific nIgM Abs present in serum of naive animals have been shown to bind a number of pathogens (36)(37)(38)43). They represent an innate defense mechanism and play an important role in protection from viral and bacterial infection.…”

“…In the absence of specific immunity, the classical pathway can be activated by so-called natural IgM (nIgM) Abs that are produced without previous exposure to foreign Ag. Several reports have shown that sera from naive mice contain low-affinity nIgM Abs that bind to viruses and bacteria and are important for neutralizing these pathogens (36)(37)(38)(39). The reduced Ag deposition in C1q-deficient mice suggested that nIgM may also play a role in Ag transport.…”

A revival for immunoglobulin therapy in septic shock?

“…Natural IgM antibodies are constitutively secreted by B1 cells. Several elegant animal models have demonstrated the protective role of natural IgM against numerous viral, bacterial, and parasitic infections (Influenza, Pseudomonas aeruginosa, Plasmodium falciparum) and a worse outcome of patients with IgM deficiency [5][6][7]. IgM has an important role in the classical pathway of complement activation when complexed with antigens and its pentameric structure favors agglutination of the invading organism and its neutralization.…”