Production of class switched antibody secreting cells and antibody is inversely correlated with expression of the adaptor protein HSH2 (IRM8P.712)

Abstract Control and HSH2 transgenic (HSH2-Tg) mice were compared to mice that express approximately 1/6th the normal level of HSH2 (HSH2-Lo) to determine if there is an inverse relationship between HSH2 expression and class switched antibody (Ab) production. In contrast to HSH2-Tg mice, HSH2-Lo mice have normal serum Ig titers for IgG1 and IgG2b and elevated titers of IgG3. HSH2-Lo mice also exhibit enhanced production of IgG1, and IgG2b, or IgG3 in response to challenge with either TD or TI Ag, respectively. Stimulation of B cells isolated from HSH2-Lo mice with anti-CD40 and IL-4 results in the production of significantly more antibody secreting cells (ASC) that produce IgG1 and IgE versus control B cells, whereas HSH2-Tg B cells produce significantly fewer class switched ASCs. Although HSH2 expression is associated with a modest effect on class switch recombination, changes in class switched ASC production are most closely linked to alterations in terminal differentiation of GC B cells into plasma cells. Terminal differentiation of class switched B cells from HSH2-Lo mice is significantly increased following in vitro stimulation, resulting in enhanced production of class switched ASCs compared to control B cells. Conversely, class switched B cells generated from HSH2-Tg mice exhibit a significant decrease in differentiation into ASCs in vitro. Thus, differential expression of HSH2 in the B lineage regulates multiple steps associated with the generation of class switched ASCs.