The goal of this project is to determine whether Ly-1 B cells differ fundamentally from other B cells in being incapable of high-rate somatic mutation of their assembled Ig V genes. Mutation will be sought in Ly-1 B cell lymphomas, in expanded populations of Ly-1 B cells in very old normal mice and in younger congenitally autoimmune mice. The project rests on four cardinal observations. First, Ly-1 B cells of normal young adult mice produce antibodies reactive with a range of self antigens; antibodies reactive with these same antigens are elevated in congenitally autoimmune mice. Second, the V gene assemblies expressed by Ly-1 B cells of normal young adult mice reveal the features of an antigen-driven primary response, but no evidence of the somatic mutation associated with a secondary response. Third, expanded clones of Ly-1 B cells develop in normal mice only in old age, but in autoimmune mice they appear in young adults. Fourth and finally, autoantibodies produced by mice with active autoimmune disease are products of a typical secondary response; they are produced by dominant clones of B cells whose assembled Ig V genes have been modified by multiple somatic mutations. The investigators will attempt to reconcile these potentially anomalous results. They will treat mice bearing lethal transplants of Ly-1 B cell lymphomas that express fully sequenced Ig genes (IgM, IgG or IgA) with subcurative doses of monoclonal anti-Id directed against """"""""private"""""""" idiotopes and analyze the expressed Ig genes of late-arising recurrent tumors for evidence of somatic mutation. Dr. Haughton and coworkers will monitor the response to phosphatidyl choline (PtC) as an index of the immunobiology of Ly-1 B cells, using fluorescein-loaded synthetic liposomes and flow cytometry to detect the B cells and solid phase binding to detect the antibody. They will make hybridomas from clones of PtC binding Ly-1 B cells in the peritoneums of old normal and young autoimmune mice and sequence the expressed immunoglobulin gene assemblies, seeking evidence of somatic mutation. The investigators will explore the use of allotype-chimeric mice, derived from congenitally autoimmune (1pr) or immunodeficient (xid) strains to analyze the involvement of Ly-1 B cells in the generation of pathogenic autoantibody. Results will be useful in understanding the immunobiology of normal Ly-1 B cells, the possible involvement of Ly-1 B cells in autoimmune disease and in designing a strategy for specific immunotherapy of B cell malignancy.
| Phillips-Quagliata, J M; Faria, A M; Han, J et al. (2001) IgG2a and igA co-expression by the natural autoantibody-producing murine B lymphoma T560. Autoimmunity 33:181-97 |
| Phillips-Quagliata, J M; Faria, A M; Han, J et al. (1999) The IgG2a/IgA produced by the murine T560 B lymphoma that arose during a graft-versus-host reaction is polyreactive and somatically mutated. Autoimmunity 29:215-33 |
| Whitmore, A C; Haughton, G; Arnold, L W (1996) Phenotype of B cells responding to the thymus-independent type-2 antigen polyvinyl pyrrolidinone. Int Immunol 8:533-42 |
| Arnold, L W; Spencer, D H; Clarke, S H et al. (1993) Mechanisms that limit the diversity of antibody: three sequentially acting mechanisms that favor the spontaneous production of germline encoded anti-phosphatidyl choline. Int Immunol 5:1365-73 |
| Haughton, G; Arnold, L W; Whitmore, A C et al. (1993) B-1 cells are made, not born. Immunol Today 14:84-7;discussion 87-91 |
