Role of Antigen Encounter
Although the nature of antigen and the mechanisms of BCR stimulation in vivo remain largely obscure, evidence suggests that antigen encounter is a crucial event for the onset and progression of B-CLL. Gene expression profiling studies provided the first evidence that B-CLL cells have a phenotype consistent with antigen-experienced, activated B cells. More recent studies have revealed that the BCR signaling pathway signature is upregulated in LN compared with peripheral blood leukemic cells, thus identifying LN as a central site in B-CLL pathogenesis and, within the LN microenvironment, the BCR pathway as the most prominent pathogenetic mechanism in B-CLL. In line with these findings, the LNs of patients with B-CLL are infiltrated with scattered microanatomical structures, known as proliferation centers or pseudofollicles, where B-CLL cells interact with bystander cells (i.e., stromal cells and T cells) and antigens, thus receiving survival and growth signals. These microenvironmental signals complement intrinsic oncogenic lesions thus conferring growth advantage to the malignant clone.[6,30,62] Additional evidence of the importance of antigen in B-CLL comes from the finding that CLL B cells express a restricted IGHV gene repertoire and that expression of IGHV genes in B-CLL is not stochastic.[63–66] Furthermore, CLL B cells that express certain IGHV genes show a preferential use of the complementarity-determining region 3 (CDR3).[63,64] The CDR3 is the most variable region of the Ig heavy chain directly implicated in binding to conventional antigens; therefore, the expression of conserved Ig with restricted CDR3 is indicative that the Ig repertoire in B-CLL cells is highly selected, suggesting that they bind a limited set of antigens relevant to the pathogenesis of B-CLL. Furthermore, the finding that anergized IgM-mediated responses can recover signal capacity in vitro suggest the engagement of putative antigen in vivo. Finally, the correlation with prognosis of several features of the BCR complex (i.e., the number of somatic mutations in the BCR and the expression of ZAP-70) suggests that B-cell selection and BCR stimulation have important roles in disease progression.[2,4,5]
The nature of promoting antigens is still unknown. However, B-CLL cells frequently have polyreactive BCRs, which bind multiple antigens, possible suggesting stimulation by both autoantigens and microbial antigens.
Expert Rev Hematol. 2012;5(3):341-348. © 2012 Expert Reviews Ltd.