Role of beta 2 integrins in the prevention of apoptosis induction in chronic lymphocytic leukemia B cells

Immunologically committed lymphocytes, especially mature, leukemic B cells, proliferate then accumulate without further cell division in chronic lymph ocytic leukemia patients (CLL), These mature, leukemic B cells often produc e autoantibodies. Under normal circumstances, immunologically committed lym phocytes that are autoreactive are deleted by a programmed cell death mecha nism. In CLL cells, these mechanisms appear to be inhibited; therefore, cel ls accumulate rather than be destroyed. To understand the mechanism by whic h cell survival is selected over death in CLL cells, we studied the role of beta 2 integrins and their ligands in the regulation of apoptosis, CLL cel ls were treated with monoclonal antibodies directed against beta 2 integrin s, Antibodies directed against the I-domain of the alpha chain of CD11b/CD1 8 inhibited apoptosis. The identity of the physiological ligand or counter- receptor for beta 2 integrins that was required for the inhibition of apopt osis induction was sought. The ligand iC3b, but not ICAM-1 or fibrinogen, w as identified as a ligand that could prevent apoptosis of CLL B cells. Free iC3b levels were elevated in CLL patients indicating that this ligand is a vailable in vivo where it may interact with beta 2 integrins on CLL B cells and sustain their viability by preventing activation of the programmed cel l death pathway.