Cd5 B Cells And The Possible Role Of Clonal Lymphocytes Of Unknown Significance In

CLL is a disease of CD5+ B cells. CD5 is a highly conserved single-chain 67-kDa transmembrane glycoprotein containing three scavenger receptor cysteine-rich (SRCR) domains. CD5 expression is found on all human T cells, but only on a subset of B cells. Despite its sequence conservation, CD5 expression in T cells and B cells varies widely from species to species; in some, all B cells are CD5 positive. Studies on CD5-deficient mice have shown that CD5 functions as a negative regulator of B-cell receptor-mediated signaling. Murine CD5 + (B1) B cells may represent a distinct lineage of B-cell development, arising early and self-renewing, producing low affinity, polyreactive antibodies that may contribute to the development of autoimmune diseases.12 Whether CD5 expression in human B cells marks a functionally distinct lineage, or whether it reflects its function as an activation antigen, is unclear.

Both CD5+ and CD5~ B cells may be found in the peripheral blood of normal individuals. It seems likely that CLL arises from the former. The evidence for this comes from an intriguing recent finding of clonal CD5 + B cells with the composite immunophenotype typical of CLL (namely CD19+/CD5+/ with low CD20 and CD79b) in the peripheral blood of 3.5% of normal individuals older than 40 years.4 These cells, detected by four-color flow cytometry, were present at low levels (median, 0.013; range, 0.002-1.458 X 109 cells/L), and in most cases, represented only a minority of B cells (median, 11%; range, 3-95%). Clonality was demonstrated using IGH PCR, and sequence analysis showed the presence of mutated IGHV sequences. Moreover, these cells are markedly increased in frequency in first-degree relatives of patients with the familial form of CLL.13

The precise significance of these cells is not clear; in analogy with the situation in myeloma, they have been termed clonal lymphocytes of uncertain significance or "CLUS." Long-term follow-up will be necessary to determine whether the relationship between the low-level "CLL" cells and clinical disease is similar to that seen in MGUS and myeloma. More recently, another study has not only confirmed these findings of low-level CLL-like cells in the peripheral blood of normal individuals, but has also shown the presence of clonal B cells with different immunophenotypes.14 In both studies, the frequency of clonal cells increased with age.

Further study of these populations should allow insights into the pathogenesis of both familial and sporadic forms of CLL.

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