The Secret Lives of Monoclonal B Cells

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The Secret Lives of Monoclonal B Cells

F. Vogt, Jr., Ph.D., and A. , M.D.

It seems that B cells, the lymphocytes responsible for producing antibodies,

are eager to share their secrets. Their revelations were first uncovered

indirectly in serum through reactions with microbes, cells, and toxins;

increases in gamma globulin after immunization; agammaglobulinemia

associated with immune deficiency; and the paraproteins in multiple myeloma

and related disorders that ultimately revealed the structure of

immunoglobulins and prompted the two-gene-one-antibody hypothesis. Further

revelations, often surprising and unique, came from the B cells themselves:

clonal expansion, allelic exclusion, light-chain restriction, somatic

recombination of immunoglobulin V genes, isotype switching, and the

deliberate hypermutation of V genes that leads to high-affinity antibodies.

Exploring the lifestyle of B cells became more intriguing with the

recognition that chronic lymphocytic leukemia (CLL) is generally caused by

an expanding B-cell clone. In this issue of the Journal, Landgren and

associates1 report findings that circulating monoclonal B cells are present

years before diagnosis in virtually all patients with CLL. In this

prospective study, the investigators analyzed 45 samples of cryopreserved

lymphocytes from the blood of cancer-free subjects in whom CLL was

subsequently diagnosed. Monoclonal B cells were detected in each of the 42

samples that had sufficient cells for analysis by flow cytometry. Of these,

17 had been collected at least 3 years and as long as 6 years before the

diagnosis of CLL. Most clones were identifiable by both phenotype and

genotype; impressively, all 25 that had a light-chain restriction specified

in the diagnostic records matched the light chain found in the prediagnostic

cryopreserved sample.

This report is a timely addition to our knowledge of circulating monoclonal

B cells in people without apparent hematologic disease, a condition now

termed monoclonal B-cell lymphocytosis (MBL).2 First reported under various

names and in various clinical settings, MBL was later recognized in familial

CLL kindreds3 and in population-based environmental health studies.4 The

prevalence of MBL is age-related and increases to 5% or more in patients

over the age of 60 years.5,6 Most but not all MBL clones have the low-CD20,

high-CD5 phenotype of classic CLL and often have other markers of CLL, such

as low CD38 and somatically mutated VH genes (which indicate an indolent

clone). Even with a CLL-like phenotype, MBL clones may differ from their

leukemic counterparts. Some findings suggest that kappa-restricted clones

are overrepresented, and VH gene usage in low-count MBL differs from that in

CLL.5 Interestingly, Landgren et al. found multiple cases of biclonal MBL,

whereas biclonal CLL is rare.

http://content.nejm.org/cgi/content/full/360/7/722