To make better antibodies, don’t forget the cohesin complex!
During the CSR process, AID interacts with cohesins to control the recombination event which leads to the change of immunoglobulin type. This schematic representation shows the proposed model for the function of cohesins.
J Exp Med Nov. 18, 2013
Oct. 22, 2013
Bernardo Reina San Martin's team at the IGBMC has discovered a new player in the production of antibodies. Cohesins, a complex of proteins seems to be crucial for in the process that regulates the synthesis of different classes of immunoglobulins. These results published October 21, 2013 in the Journal of Experimental Medicine (JEM) shed a new light onto a vital mechanism for the immune response.
Every infection triggers the production of antibodies, also called immunoglobulins of specifically fight the offending pathogen. Initially, immunoglobulins circulating in the body are type M (IgM). After meeting with a pathogen, B cells switch the type of immunoglobulins they produce from IgM to A, G, E or D, which have different biological functions and are present in variable quantities in the body. Immunoglobulin type G (IgG), for example, account for 75 % of antibodies in the blood. In tears, saliva and breast milk there are IgA, while IgE are involved in defense against parasites and in allergic reactions.
The production of these different classes of immunoglobulins is regulated by a mechanism of recombination of genes called Class Switch Recombination (CSR). The DNA region which contains the immunoglobulin locus, contains all the genes encoding the different types of immunoglobulins. In its initial conformation, the immunoglobulin locus expresses the type M immunoglobulin. The CSR process brings together two distant DNA elements to close proximity through the formation of a loop, which are then broken and rejoined. The AID protein, a key player in this process, generates errors in some portions of DNA, which causes breaks. After the intervention of a repair system, DNA regions are rejoined, creating the five existing classes of immunoglobulins.
Researchers can trigger the production of immunoglobulin classes in different ways, for example, adding bacterial membrane extract in a cell culture sets off the formation of type 3 IgG. But the underlying biological process regulating the switch from IgM to IgG and in particular, the role played by AID is unknown at this time. Bernardo Reina San Martin’s team at the IGBMC identified a new partner for AID. They show that cohesins interact with AID during CSR and are essential for this process. The researchers became interested in cohesins because of their implication in bringing together DNA molecules in embryonic stem cell. They demonstrate that in their absence, DNA repair following the AID-induced mutations is impaired.
This work demonstrates for the first time the involvement of cohesins in the CSR process. It also leads the way to understand this central mechanism of immunity which when disrupted can lead to the development of lymphoma.