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I know that the$\ C _\mu $ gene appears first in line for class switching and hence the IgM is the default antibody. But what is the rationale for it being so? There must be some advantage (evolutionary?) of having the IgM first in line over the IgG or so on.

The IgM is different from the IgG in being a cluster of five, better agglutination, having more avidity, and more cross reactivity (correct me if any of these is wrong). How do these properties help in containing the infection only for the very first time? Or, why is the IgG is not good for the initial response?

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  • $\begingroup$ The answer is that the Cµ-C∆ locus is expressed in the precursor B-Cells. It is only after the B-cell has produced a functional B-cell receptor and has receive the proper stimulation from cytokines do you get transcription through the other constant chain loci, which then allows class switch recombination to occur. $\endgroup$
    – AMR
    May 21, 2017 at 4:25

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When the Naive B cell gets activated and begins to secrete antibodies the affinity of the antibodies is low, as it hasn't yet gone through several cycles of affinity maturation. The increased avidity of the IgM balances the decreased affinity of these initial antibodies. If IgG were released at this stage, the body would have a much lower immune reaction to the antigen.

However after affinity maturation, the IgG has sufficient avidity and affinity to mount a stronger immune reaction than the initial IgM antibodies. If the body still produced IgM after affinity maturation, there would likely be a significant amount of crosslinking. This could potentially cause aggregates to form in the blood/lymph which could cause occlusions.

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If the affinity of the antigen-binding sites in an IgG and an IgM molecule is the same, the IgM molecule (with 10 binding sites) will have a much greater avidity for a multivalent antigen than an IgG molecule (which has two binding sites). This difference in avidity, often 10^4-fold or more, is important because antibodies produced early in an immune response usually have much lower affinities than those produced later. Because of its high total avidity, IgM—the major Ig class produced early in immune responses—can function effectively even when each of its binding sites has only a low affinity.

Molecular Biology of the Cell

The claim on aggregation after affinity maturation is speculation based on the crosslinking that occurs with IgA antibodies (e.g. Phlegm) when there are only two high-affinity Ig molecules joined together rather than five.

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    $\begingroup$ Thanks! Could you add a reference for your answer. I'd then mark it answered. :) $\endgroup$
    – Polisetty
    May 19, 2017 at 21:52
  • $\begingroup$ I do not really think this answers the question of Why IgM is the default antibody. $\endgroup$
    – AMR
    May 21, 2017 at 4:18
  • $\begingroup$ You are sort of explaining the rational behind Somatic Hypermutation, but not that well... The correct way to answer the question is to leave out the variable chain discussion altogether and explain the myeloid developmental program with regard to the Heavy-Chain Constant region and then discuss Class Switch Recombination in mature B cells. $\endgroup$
    – AMR
    May 21, 2017 at 4:31
  • $\begingroup$ Well, it answers my doubts! I know the heavy chain order in the gene. I wanted to know why it is that way. @AMR $\endgroup$
    – Polisetty
    May 21, 2017 at 5:54
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    $\begingroup$ @Polisetty The avidity / affinity of the variable regions of the light and heavy chains of the immunoglobulin provides no insight into the order of the constant region of the heavy chain. Deficiencies, such as Hyper-IgM syndrome are related to defects in cell signaling. That alone should tell you that the reason for IgM being first is the result of the developmental state of the cell and the signals that it receives, which in turn control the Transcription Factors that bind to the locus and express Cµ instead of the other loci. You can also have SIgM disorders, which you can look up. $\endgroup$
    – AMR
    May 21, 2017 at 18:10

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