Why we think the antibody gene CDRH3 region is important in ageing (and in immunity in general)
Firstly, what is the CDRH3 region? CDR3 stands for complementarity determining region 3. A rearranged antibody variable gene (see “how do we get a billion different antibodies”) has four “framework” regions that are important for the structural integrity of the antibody, and three complementarity determining regions that are important in contact between the antigen and antibody. The third one is located where all the different genes of an antibody have been joined together, and because this joining process is not accurate it is a highly variable. CDRH3 means it is the CDR3 from the heavy chain (CDRL3 is the CDR3 of the light chain).
The CDRH3 is thought to be the most important section of the antibody variable region in terms of its contribution to antigen binding. It is so highly variable that it can be used as a fingerprint for the B cell and any of its “family” - as a B cell is activated in response to antigen it starts dividing to make a family of B cells all with the same specificity of B cell receptor for the antigen.
In a normal population of B cells there are millions of different antibody genes – and therefore millions of different CDRH3. In biological populations there is usually a lot of diversity, with a lot of medium sized things and fewer small or large things. It is the same with CDRH3 size. If you plot a graph with the size of CDRH3 region along the bottom axis, and the number of cells that have a CDRH3 of that size on the side axis, you will get a “Gaussian”, or “normal” distribution of sizes:
The average of a CDRH3 distribution is more-or-less where the peak is (strictly speaking the peak of a distribution is called the median).
Memory B cells are populations of cells that have developed in response to challenge, so the ancestors of these cells recognised antigen and proliferated. A population of memory cells therefore represents cells that form a useful response against invading pathogens (while not being harmful to self). A population of naïve B cells is very diverse and has not yet been tested against antigen. There should be very few cells with the potential to react to self. We find that the size of the CDRH3 in a population of memory B cells is smaller than in naïve cells. So cells that have developed under selection pressure to react to foreign and not self tend to favour smaller CDRH3 regions than ones that have not been selected by antigen.
Surprisingly we also found a difference in CDRH3 size between naïve B cells from older individuals than in younger individuals. The older B cell population has slightly larger CDRH3 regions. We do not think this is selection pressure due to foreign antigen as these are naïve B cells. We do not think this is due to the way the antibodies are initially formed as when we look at the very early stages of B cell development, in the bone marrow, there is no difference between the age groups. One possibility might be that there is a difference in selection pressure with respect to eliminating self reactive antibodies. Circumstantial evidence to support this is that older people have higher levels of self reactive antibodies. Our lab continues to investigate this by cloning and expressing antibodies with differently sized CDRH3 regions to look at their binding characteristics against self antigens.
Faculty of Health and Medical Sciences, Duke of Kent Building, University of Surrey,
Guildford, GU2 7XH