A study of the mechanism of B cell autoimmunity and of somatic hypermutation
In healthy individuals, the immune system protects the host by reacting to foreign antigens while at the same time remains tolerant to self antigens. Although certain forms of self-recognition may be a normal part of the development and physiological functioning of the immune system, the abnormal immune response to the self results in autoimmune diseases. The defect(s) in autoimmune diseases is complicated. Both T cells and B cells, as well as other components of the immune system, can contribute to the development of autoimmune diseases. For most of these diseases, the nature of the primary defect(s) is unknown. One important manifestation of autoimmune disease is the production of autoantibodies. Therefore the knowledge of the origin of disease-associated autoantibodies constitutes a crucial step towards the understanding of autoimmune diseases. In order to understand the mechanism of the disease-associated autoantibody production, we studied the autoantibodies derived from an autoimmune MRL/lpr mouse. We analyzed the V region mRNA sequences of these antibodies, and used the sequence information to determine the clonality, the evidence for antigen selection and the V gene usage of the disease-associated autoantibody response. Features of the disease-associated autoantibody response were compared to those of the natural autoantibody response. The relationship between the autoantibody response and the rest of the spleen activated B cell repertoire in the same mouse was also analyzed. Our results demonstrate that the disease-associated autoantibody response is antigen-driven, and that self-antigen(s) is most likely the stimulating antigen(s). The availability of expanded hybridoma clones presented us a good opportunity to study the somatic hypermutation. Our study provides direct evidence for single point mutations as the major form of somatic hypermutation. Mutations occur over many cell divisions and are distributed randomly throughout the V region. We confirmed the hypothesis that the somatic hypermutation can stop during the antibody response. We show that mutation-stopping and the isotype-switching are independent processes. We found evidence indicating that, in addition to trans-acting element(s), cis-acting element(s) may also be involved in the mutational process. Lastly, the effect of the somatic hypermutation on B cell clonal expansion was studied by computer simulation of the hybridoma data.
Shan, Hua, "A study of the mechanism of B cell autoimmunity and of somatic hypermutation" (1991). Dissertations available from ProQuest. AAI9200389.