Antibody-producing B lymphocytes are highly regulated by signals received via the B cell antigen receptor (BCR).  Crosslinking of BCR by antigen can trigger the upregulation of membrane molecules which facilitate productive encounters with antigen-specific T cells, as well as trigger B cell clonal expansion, anergy, and apoptosis.  The factors controlling these diverse functional outcomes are not fully understood but are of upmost importance in determining whether autoreactive B cells in the mature B cell repertoire become pathologically relevant.

Our research group investigates how the physicochemical nature of antigen : BCR engagement, i.e. affinity, antigenic valency, and presence of accessory ligands, influences the induction of various activation phenomena and programmed cell death in human B lymphocytes.  A set of model "antigens", i.e. murine anti-human IgM monoclonal Abs with differing binding site affinity and experimentally-manipulated valencies, has been a powerful tool in such studies.  We have found that diverse B cell activation phenomena have differing BCR binding thresholds for induction.  B cells proceed through the cell cycle to an extent dependent upon the affinity and valency of the BCR-binding ligand, and suboptimal engagements which fail to permit protracted (serial) BCR signaling in G1 appear to channel at least some activated B cells into apoptosis rather than S phase.   The antigen concentration and affinity thresholds for BCR-triggered B cell S phase entry are significantly lowered when antigens co-engage BCR and the complement-binding CD21:CD19 receptor complex in the presence of IL-4.  This suggests that antigens with bound complement fragments (C3d) trigger proliferation in a larger proportion of the B cell repertoire (see figure).  Current investigations on how BCR : CD21 co-ligation affects other BCR-triggered activation phenomena may elucidate why in vivo B cell responses to T cell-dependent antigens are highly dependent upon complement and the CD21:CD19 complex.  Insights into how cytokines and/or accessory molecules lower the binding thresholds for antigen-induced B cell activation should help in developing therapeutic strategies to block B cell activation in autoimmune disease.

Representative Publications:

1. Mongini PKA, Vilensky, MA, Highet PF, and Inman JK.  The affinity threshold for human B cell activation via the antigen receptor complex is reduced upon co-ligation of the antigen receptor with CD21 (CR2).  J. Immunol.  159: 3782-3791 (1997).

2. Mongini, PKA, Vilensky, MA, Highet PF, and Inman JK.  Membrane IgM-stimulated human B lymphocytes succumb to activation-related apoptosis at a G₁®S transition: Influence of ligand affinity and valency.  Cell. Immunology 188: 137-150 (1988).

3. Mongini, PKA, Liu Q, Vilensky, MA, Highet PF, and Inman JK.  Evidence for an upper affinity threshold for anti-IgM-induced apoptosis in a human B-cell lymphoma.  Blood 92: 3756-3771 (1998)

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