Somatic hypermutation of antibody V genes takes place during the foreign antigen driven stages of B cell differentiation in peripheral lymphoid organs. While there has been much speculation concerning the frequency with which this process creates autoreactive antibodies, and the fate of the B cells that express them, little is known regarding how the immune system avoids the generation of autoimmunity during this stage of B cell differentiation. Recent data that we have obtained suggest that the problem is even more difficult than previously thought - many somatically mutated forms of V regions that previously lacked autoreactivity simultaneously gain both higher affinity for the foreign antigen and autoreactivity. However, the B cells that express such antibodies are apparently not selected for entry into the memory B cell compartment, as the antibodies produced by memory B cells display increased affinity only for foreign antigens. The proposed experiments are designed to increase our understanding of both the frequency of somatically mutated V regions that acquired the """"""""dual specificity"""""""" phenotype - for foreign and self antigens- due to somatic hypermutation, and to provide insight into the mechanism(s) involved in preventing such antibodies entering the memory compartment. These experiments will involved a multifaceted approach. The experiments will provide insight into how a state of B cell memory that is highly specific for the eliciting foreign pathogen is formed, and how the normal immune system achieves this state while avoiding the induction of autoimmunity. Knowledge of how the healthy immune system avoids the development of autoimmunity will provide important information applicable to a better understanding of the immune defects leading to autoimmune disease.
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