30.07.2021 - Antigen receptor allelic exclusion did not arise to avoid autoimmunity but to avoid genome damage
by Jorge Carneiro, Instituto Gulbenkian de Ciência, Portugal
The adaptive immune system of the vertebrates deploys a co-opted transposon machinery, the Rag endonuclease, to generate unlimited diversity by random recombination of the antigen receptor genes. The antigen receptor diversity allows the vertebrate organism to acquire specific immunity to mutating, fast-evolving microorganisms. It has been argued theoretically that specific immunity requires that each lymphocyte bears a unique antigen receptor and that dual receptor lymphocytes would be ambiguous and a potential cause of autoimmune diseases. Since vertebrates are diploid, with maternal and paternal antigen receptor gene alleles, lymphocytes bearing two distinct antigen receptors could arise from independent random recombination of these alleles. Although the vast majority of the lymphocytes show antigen receptor gene allelic exclusion, the conspicuous observation of lymphocytes with two distinct antigen receptors in healthy humans or rodents is puzzling. Using a simple mathematical model of the antigen receptor gene recombination and its potential evolutionary constraints, we demonstrate that allelic exclusion is expected to evolve indirectly from purifying selection against genome damage caused by Rag-mediated illegitimate recombination. This result voids the argument that allelic exclusion is a fundamental property of the adaptive immune system.
This is a joint work of Delphine Pessoa and Jorge Carneiro.