IgD class switching: Identification of a novel recombination site in neoplastic and normal B cells

Abstract

IgD on normal B lymphocytes usually is co-expressed with IgM. A minority of normal plasma cells and rare B cell malignancies express exclusively IgD (IgM-IgD+). The low frequency has been explained by the lack of a recognizable switch region within the C mu-C delta intron. We analyzed four cases of IgM-IgD+ hairy cell leukemia (HCL) by Southern (DNA) blot analysis and identified two cases with a recombinatorial event within the C mu-C delta intron and deletion of C mu. DNA sequence analysis of junctional regions showed that S mu or the immediate upstream region was used as a donor site and that the C mu-C delta intronic sigma delta region was used as acceptor site. Using polymerase chain reaction, we subsequently analyzed whether similar S mu-sigma delta recombinations occur in normal tonsils containing IgM-IgD+ plasma cells. Multiple products with a size range of 200-800 base pairs were detected in all four individuals, suggesting clustering of acceptor sites within sigma delta. Sequence analysis of three cloned products showed S mu-sigma delta recombinations similar those observed in HCL. The sigma delta region contains a relatively high content of pentameric repeats with an extremely G-rich area and appears to function as a vestigial switch recombination site in normal and neoplastic IgM-IgD+ B cells.

Regional induction of adhesion molecules and chemokine receptors explains disparate homing of human B cells to systemic and mucosal effector sites: dispersion from tonsils

“…12,14 Nevertheless, we were able to identify the actual marker cells and/or their IgD ϩ PC progeny in peripheral blood and various tissues, although at different levels ( Figure 1B). The C deletion was revealed not only in recurrent tonsillitis specimens as previously reported 12,14 but also in hyperplastic adenoids and, at somewhat lower levels, in normal NALT biopsies from children down to the age of 1 to 2 years as well as in lymph nodes, bone marrow, and Peyer patches ( Figures 1B and 2, left). It was interesting to note that the 3 positive Peyer patches were from the upper age range (20-39 years), while no age dependency was indicated for the other lymphoid tissues (data not shown).…”

“…13 Tonsillar germinal centers (GCs) have been determined to generate 2% to 5% sIgD ϩ IgM Ϫ CD38 ϩ centroblasts as a result of nonclassical Ig heavy-chain constant (C H )-gene switching; this process involves deletion of the C-gene segment, variably including the switch (S) region, thereby principally prohibiting further downstream class switch. 12,14 By a specifically designed nested polymerase chain reaction (PCR) method performed on extracted DNA, we were able to show that the sIgD ϩ IgM Ϫ CD38 ϩ subset enters peripheral blood, and we could identify these plasmablasts and/or their IgD ϩ PC progeny at distant tissue sites. The IgD ϩ PCs showed a mucosal phenotype by expressing J chain, and we believe that we have established a marker to track the general homing pattern of mucosal B cells activated in human NALT, including the sIgA ϩ plasmablasts Supported by the University of Oslo, the Research Council of Norway, the Norwegian Cancer Society, and Anders Jahre's Fund.…”

Artiodactyl IgD: The Missing Link

“…Due to the absence of an authentic S␦ region, B cells expressing exclusively IgD (IgM Ϫ IgD ϩ ) are extremely rare in humans and are almost absent in mice (34). Homologous recombination mediated by two 442-bp repeats localized upstream of the S and within the C-C␦ intron, or nonhomologous recombination between S and ␦ regions has been suggested as the molecular basis for generating these rare IgM Ϫ IgD ϩ cells (35,36). To date, the cow is the only species in which a true S␦ region has been demonstrated.…”

Identification of Two IgD+ B Cell Populations in Channel Catfish,Ictalurus punctatus

“…Also, 90% of human IgM 2 /IgD + cells express Igl L chains, and studies of the expressed V repertoires showed that the VH and VL chain regions of these B cells are highly mutated in the complementary determining region, as well as in the framework region (35)(36)(37)(38)(39). Notably, in 2009, our collaborators (40) demonstrated that human IgM 2 /IgD + plasmablasts are produced from upper respiratory B cells that undergo class-switch recombination using the previously identified cryptic-switch region found between Cm and Cd (41,42). These IgM 2 /IgD + plasmablasts secrete IgD, which, in turn, is bound to basophils through a calciummobilizing receptor and upon IgD cross-linking, the cells release antimicrobial peptides, such as cathleicidin and pentraxin-3, proinflammatory cytokines IL-1, IL-4, and B cell-activating factor of TNF family (40).…”