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Answer by Tirumalai Kamala:

Typically, B cells need T cell help to switch from making IgM to other antibody isotypes (classes). T cell help consists of a variety of cell-surface and soluble molecules. The process of switching away from IgM is called Class Switch Recombination (CSR). Let’s think of it as a 2-step process.

In the 1st step, engagement of specific T- and B cell-surface molecules starts the generic process. The most important cell-surface molecule in this regard is T cell-specific CD40L, which interacts with CD40 on the B cell surface. Other cell-surface molecules include ICOS, CXCR5, and many others.

The 2nd step of the process provides the specific signal(s) to the B cell directing it to switch to one particular isotype. This is mediated by T cell-specific cytokines, soluble protein molecules, involved in directing CSR away from IgM to another antibody isotype.

Let’s consider mouse models because they have provided us the most comprehensive dataset thus far. Apart from IgM, secreted mouse antibody classes are IgG1, IgG2a, IgG2b, IgG3, IgA, IgE.

Mouse gene knockout studies reveal that particular T cell cytokine(s) are critical as switch factors for a particular mouse antibody isotype.

 

  1. Mouse knockout of cytokine IL-4 (also IL-13): little or no IgG1, no IgE.
  2. Mouse knockout of cytokine IFN-g: little or no IgG2a
  3. Mouse knockout of cytokines IL-6 or TGF-b1: little or no IgA
  4. Mouse knockout of cytokine IL-17A: all isotypes lower but IgG2b most affected.


What do these knockout data imply? If an activated B cell interacts with a T cell making predominantly IFN-g, that B cell will switch from IgM to IgG2a, and so on and so forth.

We know little of switch factor(s) for IgG3.

Biology is rarely simple or linear so it stands to reason that the above schema only applies to classical (or follicular or B1-a) B cells. There are other classes of B cells called Innate B cells (such as B1-b and Marginal Zone B cells), which make low-affinity IgM and can switch to IgA in absence of T cell help, primarily under the influence of abundant gut-associated TGF-b1.

How do B cells determine which antibody class to produce?

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