As part of the immune system anitbodies recognise and neutralise invading pathogens. The different antibody classes are defined by the different heavy chains they carry within their antibody structure, where each class of antibody exerts distinct effector functions that allow them to penetrate different tissues within the body and recruit a particular diverse set of effector cells of the immune system.
Antibody-producing B cells can switch the class of immunoglobulin they produce through a process of inducible genomic rearrangement called class-switch recombination. This genetic recombination can occur in two orientations- if the correct rearrangement occurs a productive gene encoding a new immunoglobulin class results, the other orientation prevents immunoglobulin production. Theoretically, these two events have an equal probability of occurring, resulting in a failure rate of 50%, which would limit the efficiency of antibody responses. However, new research shows that the immune system is far more effective than mere chance, with a success rate of 90% in favour of functional rearrangements in class-switching.
The first class of immunoglobulin produced as part of an immune response is IgM. The ? heavy chain within these molecules is what denotes them as IgM. As the immune response progresses the immunoglobulins produced by B cells change from predominantly IgM to IgG, IgE or IgA classes dependent upon the type of infection. Each of IgG, IgE and IgA consist of their own heavy chain types, ?, ? or ? respectively, denoting their class and each class is associated with a different function; IgG immunoglobulins are effective against bacterial or viral infections, IgA immunoglobulins are the primary effectors of the mucosal immune system and IgE immunoglobulins are effective against certain parasites and often associated with allergies and asthma.
The genes encoding the constant regions of each class of heavy chain immunoglobulin are all preceded by a distinct repetitive switch sequence- S?, S?, S? and S?. During class-switching, the enzyme activation-induced deaminase creates DNA strand breaks at the S? and another S region. These DNA strands are then repaired by non-homologous end joining to give an orientation that, in 90% of the cases, gives rise to a new constant region in the place of the IgM immunoglobulin class while the intervening sequence is circularised and excised, or in just 10% of the cases, inactivates the antibody gene through its incorporation in an inverted orientation.
Knockout cells for the DNA-repair factor ATM kinase, which coordinates the response to activation-induced deaminase DNA breaks, showed a reduced orientation bias in immunoglobulin class-switching. Additionally, the expression of the DNA-binding proteins H2AX, Rif-1 and 53BP-1 that prevent broken DNA strands from being resected, thereby promoting non-homologous end joining, was shown to positively influence the orientation bias in immunoglobulin class-switching. The study authors propose that inhibiting end resection accentuates an intrinsic predisposition of class-switch recombination to proceed in a specific orientation. The preferred orientation of these recombination events are dictated by the topology of the heavy chain gene elements and allow non-homologous end joining to repair breaks that are not correctly paired and could join in either orientation.
The only other known example of orientation-biased DNA recombination is VDJ recombination, which also functions within B cells to vary the antibody sequence to achieve antigen recognition. The mechanisms underlying these processes are poorly understood, yet it seems that they have both evolved to be as effective as possible to ensure the production of antibodies and provide an effective immune response.