Why you may not want to loose IgM

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Immunoglobulin G is the main type of antibody that is produced against infection, but these arrive from cells that originally make IgM. This through a process of class switching were by the constant genes that code for IgM or replaced by IgG constant genes were as the target binding variable region genes are maintained. The memory B cell that makes these come from unswitched cells that make IgD. As the cells mature IgD is lost as is IgM and they become IgG positive and gain CD27. However some memory B cells do not class switch and stay as an IgM memory cell and CD27 positive. In this study they looked at the COVID virus neutralizing potential from antibodies that remained as an IgM or those that class switched to IgG from people infected and recovered from COVID-19. They could then regress the IgG back to IgM antibodies using genetic engineering of the antibody genes. What they found was that the IgM which have the equivalent of 5 IgG molecules was better at neutralizing a variety of SARS-COv-2 virus substrains than the IgG like molecules

Humoral immunity (i.e. antibody responses) to SARS-CoV-2 can be supplemented with polyclonal (lots of different antibodies to the same target) sera from convalescent donors or an engineered monoclonal antibody (mAb) product (one antibody type per target). While pentameric IgM antibodies are responsible for much of convalescent sera’s neutralizing capacity, all available mAbs are based on the monomeric IgG antibody subtype. We now show that IgM mAbs derived from immune memory B cell receptors are potent neutralizers of SARS-CoV-2. IgM mAbs outperformed clonally identical IgG antibodies across a range of affinities and SARS-CoV-2 receptor-binding domain epitopes. Strikingly, efficacy against SARS-CoV-2 viral variants was retained for IgM but not for clonally identical IgG. To investigate the biological role for IgM memory in SARS-CoV-2, we also generated IgM mAbs from antigen-experienced IgM+ memory B cells in convalescent donors, identifying a potent neutralizing antibody. Our results highlight the therapeutic potential of IgM mAbs and inform our understanding of the role for IgM memory against a rapidly mutating pathogen.

Why could this be important?

Hypogammaglobulinemia (low antibody levels) is potentially a risk fact for severe infection, so the suggestion that MS drugs that dont reduce IgG levels is something beneficial.

For most people it probably isn’t a problem and even when IgG levels drop it is relatively limite. So the argument is made that IgG gammaglobulinemia is not a big problem in perhps for perhaps for people taking B cell depleting antibodies it could be an issue in relation to COVID-19. This is because the level of IgM in the blood drops by about 25% in the first few months of treatment and maybe drops by about 50% within a few years of treatment. If IgM is good at giving us protection then it could be of significance. However, the clinical outcome for most suggests tht it is not a major issue.

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