Regulation of B-cell entry into the cell cycle.

B cells are induced to enter the cell cycle by stimuli including ligation of the B-cell receptor (BCR) complex and Toll-like receptor (TLR) agonists. This review discusses the contribution of several molecules, which act at distinct steps in B-cell activation. The adapter molecule Bam32 (B-lymphocyte adapter of 32 kDa) helps promote BCR-induced cell cycle entry, while the secondary messenger superoxide has the opposite effect. Bam32 and superoxide may fine tune BCR-induced activation by competing for the same limited resources, namely Rac1 and the plasma membrane phospholipid PI(3,4)P(2). The co-receptor CD22 can inhibit BCR-induced proliferation by binding to novel CD22 ligands. Finally, regulators of B-cell survival and death also play roles in B-cell transit through the cell cycle. Caspase 6 negatively regulates CD40- and TLR-dependent G(1) entry, while acting later in the cell cycle to promote S-phase entry. Caspase 6 deficiency predisposes B cells to differentiate rather than proliferate after stimulation. Bim, a pro-apoptotic Bcl-2 family member, exerts a positive regulatory effect on cell cycle entry, which is opposed by Bcl-2. New insights into what regulates B-cell transit through the cell cycle may lead to thoughtful design of highly selective drugs that target pathogenic B cells.

Localization in membrane microdomains of the Ig-alpha/beta component of the BCR expressed by a B lymphoma variant.

The B cell antigen receptor (BCR) composed of the ligand-binding membrane IgM (mIgM) and the signaling component, Ig-alpha/beta, is known to inducibly associate with membrane microdomains rich in cholesterol and sphingolipids, termed lipid rafts. In this study we tested whether the Ig-alpha/beta portion of the BCR has targeting information that allows it to be localized in lipid rafts. In order to do this, we cross-linked the Ig-alpha/beta on the cell surface of the variant B cell line, WEHI 303.1.5, a derivative of the immature murine B cell line WEHI 231 that lacks mu heavy chain and expresses the Ig-alpha/beta on the cell surface by itself. Using two methods to isolate detergent-insoluble, lipid raft-like fractions, we found that Ig-alpha/beta without accompanying mIgM was constitutively located in these raft-like fractions and that the amount was marginally increased after Ig-alpha/beta cross-linking. These results suggest that the Ig-alpha/beta portion of the BCR has the ability to be compartmentalized into raft-like membrane domains even when not associated with mIgM and perhaps this targeting information is normally regulated by the presence of the mIgM portion of the receptor.

A global analysis of Y-chromosomal haplotype diversity for 23 STR loci.

In a worldwide collaborative effort, 19,630 Y-chromosomes were sampled from 129 different populations in 51 countries. These chromosomes were typed for 23 short-tandem repeat (STR) loci (DYS19, DYS389I, DYS389II, DYS390, DYS391, DYS392, DYS393, DYS385ab, DYS437, DYS438, DYS439, DYS448, DYS456, DYS458, DYS635, GATAH4, DYS481, DYS533, DYS549, DYS570, DYS576, and DYS643) and using the PowerPlex Y23 System (PPY23, Promega Corporation, Madison, WI). Locus-specific allelic spectra of these markers were determined and a consistently high level of allelic diversity was observed. A considerable number of null, duplicate and off-ladder alleles were revealed. Standard single-locus and haplotype-based parameters were calculated and compared between subsets of Y-STR markers established for forensic casework. The PPY23 marker set provides substantially stronger discriminatory power than other available kits but at the same time reveals the same general patterns of population structure as other marker sets. A strong correlation was observed between the number of Y-STRs included in a marker set and some of the forensic parameters under study. Interestingly a weak but consistent trend toward smaller genetic distances resulting from larger numbers of markers became apparent.

Dendritic cell-dependent inhibition of B cell proliferation requires CD22.

Recent studies have shown that dendritic cells (DCs) regulate B cell functions. In this study, we report that bone marrow (BM)-derived immature DCs, but not mature DCs, can inhibit BCR-induced proliferation of B cells in a contact-dependent manner. This inhibition is overcome by treatment with BAFF and is dependent on the BCR coreceptor CD22; however, it is not dependent on expression of the CD22 glycan ligand(s) produced by ST6Gal-I sialyltransferase. We found that a second CD22 ligand (CD22L) is expressed on CD11c(+) splenic and BM-derived DCs, which does not contain ST6Gal-I-generated sialic acids and which, unlike the B cell-associated CD22L, is resistant to neuraminidase treatment and sodium metaperiodate oxidation. Examination of splenic and BM B cell subsets in CD22 and ST6Gal-I knockout mice revealed that ST6Gal-I-generated B cell CD22L plays a role in splenic B cell development, whereas the maintenance of long-lived mature BM B cells depends only on CD22 and not on alpha2,6-sialic acids produced by ST6Gal-I. We propose that the two distinct CD22L have different functions. The alpha2,6-sialic acid-containing glycoprotein is important for splenic B cell subset development, whereas the DC-associated ST6Gal-I-independent CD22L may be required for the maintenance of long-lived mature B cells in the BM.