Follicular lymphoma and the immune system: from pathogenesis to antibody therapy.

Follicular lymphoma (FL) is a B-cell tumor arising in germinal centers and retaining features of its normal B-cell counterpart. Lymphomagenesis appears stepwise from the t(14;18) translocation, through FL-like cells, to FL in situ, then to overt FL. Surface Ig is mandatory and carries a striking V-region modification because of introduction of glycan addition sites during somatic mutation. These are positively selected and acquire unusual high mannoses, which interact with lectins. The Ig-associated mannoses appear essential for FL, providing a disease- specific target for antibody attack. Antibody therapy is currently focused on anti-CD20 (rituximab), which appears to rely predominantly on the Fcγ module recruiting suitably activated macrophages. Immunogloblulin and, to some extent, CD20, can each escape antibody attack in vitro by modulation, but this is difficult to demonstrate clinically. Instead, studies of anti-CD20 therapy of FL suggest that effector modulation, similar to that seen in the suppression of autoimmune inflammation by infusions of normal human IgG, may be important. Both antigenic and effector modulations might be minimized by repeated small doses of more potent antibodies. Clearly, mechanisms of attack vary with the malignancy, the target molecule, and the antibody design, offering opportunities for optimizing this promising strategy.