B Cells in Inflamed Lymph Nodes: A Link between Inflammation and Autoimmunity

TNF-α transgenic (TNFtg) mice develop a spontaneous inflammatory joint disease resembling rheumatoid arthritis (RA) in patients. Bin cells phenotypically defined as CD23+CD21highCD1d high B cells have been shown to accumulate in the lymph nodes (LNs) that drain inflamed tissues of TNFtg mice and are involved in the significant histological and functional LN alterations that accompany disease exacerbation. Work presented in this thesis characterizes the origin and potential function of Bin cells. Via adoptive transfer of sorted GFP+ follicular B (FoB) cells we show that Bin cells can be generated from circulating FoB that preferentially home to the inflamed LNs of TNFtg mice and rapidly change their phenotype in the node proinflammatory environment. Remarkably, we found the Bin phenotype in WT lymph nodes after challenge with a T-dependent antigen (Ag) in adjuvant. Interestingly Bin cells display a germinal center phenotype at higher rates compared to FoB cells. Moreover, Ag-free adjuvant can induce Bin phenotype in draining LN of wild type mice, indicating that Bin induction is not dependent on exogenous Ag. Furthermore, we show that Bin cells can capture and process Ag-immune complexes in a CD21-dependent manner more efficiently than FoB cells, and express higher levels of MHC-II, CD80 and CD86. In addition, we show that Bin cells are more potent than FoB cells in providing co-stimulation to antigen-specific CD4+T cells and eliciting cytokine production. Collectively, we propose that Bin cells: i) are a polyclonal population of B cells which derive from circulating FoB cells early in inflammation, and ii) play a role in facilitating T cell response during acute infections by promiscuous Ag presentation to T cells, thus increasing the chance of Ag-specific T cells meeting their cognate Ag before development of Ag-specific B cell clones. In cases of chronic inflammation such as in inflamed LNs of TNFtg mice, continuous presence of factor(s) responsible for induction of Bin phenotype results in persistence of Bin cells and their accumulation in inflamed LNs. The unusual accumulation of these cells may contribute to disruption of lymph node structure and further draining malfunction, as well as tolerance breakdown, leading to exacerbation of the disease. The work presented here provides new insights into pathogenesis of the autoimmune diseases and the development of new preventive and therapeutic strategies.