Dysregulation of pre-B cell development by autoantibodies derived from New Zealand Black mice
Date of Award
Doctor of Philosophy (Ph.D.)
Microbiology and Immunology
First Committee Member
Richard L. Riley - Committee Chair
Autoimmune New Zealand Black (NZB) mice exhibit a dramatic age-dependent loss of bone marrow pre-B cells by a mechanism which has not been fully delineated, but may be related to increasing titers of autoantibody in aging NZB mice. In this investigation, we show that there is an extensive loss of B cell precursors in the bone marrow of aged NZB mice. These include precursors which, both by surface phenotype and function, are responsive to IL-7. To determine if antibodies in the repertoire of aged NZB mice contributed to a down-regulation of B lymphopoiesis, sera of NZB mice were assayed for reactivity with B cell precursor cells. NZB sera exhibited an age-related increase in reactivity with pre-B cell lines and inhibited the IL-7 stimulated in vitro proliferation and survival of bone marrow pro-B/pre-B cells. Of three IgM monoclonal antibodies (mAb) produced by fusion of 10 month old NZB splenocytes with SP2/0 cells and selected for reactivity with pre-B cell lines, two mAbs (2F5, 5G9) inhibited bone marrow IL-7 CFU in a concentration dependent manner. The inhibitory mAbs were reactive with a 210kDa protein on the surface of pre-B cell lines and IL-7 expanded pre-B cells. Both the binding of these mAbs and their inhibition of IL-7 CFU were dependent upon expression of the $\lambda$5 surrogate light chain. The inhibition of IL-7 CFU by NZB antibodies was mediated by soluble cofactors ubiquitously produced by adherent bone marrow cells. In summary, these studies suggest that aging NZB mice produce autoantibodies which inhibit pre-B cell expansion. A fraction of these autoantibodies recognize cell surface antigens on IL-7 stimulated pre-B cells and render developing pre-B cells sensitive to negative regulation by cytokines produced by bone marrow adherent cells. These autoantibodies may contribute to the down-regulation of pre-B cell development in vivo seen in aging NZB mice.
Health Sciences, Immunology
Merchant, Melinda S., "Dysregulation of pre-B cell development by autoantibodies derived from New Zealand Black mice" (1996). Dissertations from ProQuest. 3407.