Unmutated Immunoglobulin M Can Protect Mice from Death by Influenza Virus Infection

Abstract

To elucidate the role of class switch recombination (CSR) and somatic hypermutation (SHM) in virus infection, we have investigated the influence of the primary and secondary infections of influenza virus on mice deficient of activation-induced cytidine deaminase (AID), which is absolutely required for CSR and SHM. In the primary infection, AID deficiency caused no significant difference in mortality but did cause difference in morbidity. In the secondary infection with a lethal dose of influenza virus, both AID−/− and AID+/− mice survived completely. However, AID−/− mice could not completely block replication of the virus and their body weights decreased severely whereas AID+/− mice showed almost complete prevention from the reinfection. Depletion of CD8+ T cells by administration of an anti-CD8 monoclonal antibody caused slightly severer body weight loss but did not alter the survival rate of AID−/− mice in secondary infection. These results indicate that unmutated immunoglobulin (Ig)M alone is capable of protecting mice from death upon primary and secondary infections. Because the titers of virus-neutralizing antibodies were comparable between AID−/− and AID+/− mice at the time of the secondary infection, a defect of AID−/− mice in protection of morbidity might be due to the absence of either other Ig classes such as IgG, high affinity antibodies with SHM, or both.

Antibodies to myelin oligodendrocyte glycoprotein are not involved in the severity of chronic non-remitting experimental autoimmune encephalomyelitis

“…We chose AID −/− by three reasons to examine whether an MOG antibody, in particular about MOG IgG antibody, contributed to the onset of EAE equally. First, AID is involved in regulation or catalysis of the DNA/RNA modification step of both class switching recombination and somatic hypermutation, subsequently AID −/− do not produce IgG and IgA, and IgM synthesized by AID −/− is low affinity antibody, indicating that the Ag-specific IgM may not act sufficiently [25,40]. Second, there is not manifestation of AID expression in T cells and AID may not contribute T cell function.…”

Histone Deacetylase Inhibitors Upregulate B Cell microRNAs That Silence AID and Blimp-1 Expression for Epigenetic Modulation of Antibody and Autoantibody Responses

“…In addition, in both normal and autoimmune mice, HDI treatment allowed for some residual AID expression, which resulted in a significant reduction but not ablation of secondary antibody isotypes. These can, even at low titers, mediate a protective anti-microbial immunity, as suggested by the apparently normal risk of infections in Aicda +/– mice with reduced AID levels (65). Thus, in normal and autoimmune mice, HDI dampen the antibody or autoantibody response by efficiently inhibiting CSR, SHM and plasma cell differentiation, while leaving an intact or even increased IgM pool as well as residual IgG and IgA levels that may be sufficient for immune protection.…”

Influenza Virus-Specific Neutralizing IgM Antibodies Persist for a Lifetime

“…They demonstrated that unmutated IgM antibodies were sufficient to protect from death against both primary and secondary infections with A/PR/8/34 albeit with higher morbidity. Although high-affinity IgG clearly plays an important role in influenza immunity, the level of protection provided by IgM was remarkable in AID-deficient mice (21). IgM antibodies have also been shown to play an important role in host defense against other viral infections.…”