Contrary to earlier beliefs, that cells of the immune system which recognized self were eliminated early in their development, we now know that many circulating immune cells do in fact recognize self-antigens to some degree, although various mechanisms appear to moderate/prevent autoimmune complications. This phenomenon of self-tolerance is known as anergy. We have developed a mouse model to investigate how autoimmune disaster is avoided when challenged with a foreign antigen that “looks” like self. Murine B-cells which express an antibody specific for hen egg white lysozyme (HEL) are introduced into mice which are otherwise genetically equivalent, apart from also constitutively expressing a modified form of HEL (so as to lessen the affinity), as a self-antigen. The recipient mice are further challenged by injection with an antigen similar to HEL, in this case the lysozyme purified from duck eggs (DEL), which has 20 amino acid changes over 129 positions. Hence, the mice are at an immunological crossroad – they need to respond to the foreign antigen whilst not triggering autoimmunity. Blood samples are taken over time and the B-cells sequenced to catalogue mutations which accrue in this specific B-cell line during the immune response. Remarkably we have identified mutations that, simultaneously, lower affinity for self (HEL), whilst increase affinity for non-self (DEL). In order to obtain a structural understanding of the mutations observed we have solved the crystal structure of DEL, as well as complexes between DEL and the antibody variants, and compare them to known structures of the antibody-HEL complex.