Indeed the mature recirculating B-cell pool in C57BL/6 mice appeared to be retaining both highly hydrophobic and highly charged CDR-H3 sequences. We have previously shown that selection against these types
of sequences can be thwarted, to a certain extent, by forcing increased bone marrow production of charged or hydrophobic CDR-H3s [20]. In BALB/c mice, late selective steps appear to ameliorate the effect of the change in the repertoire by reducing the number of B cells that have reached the final maturation step in the bone marrow. This clearly does not occur in C57BL/6 mice, as evidenced by significant increase in hydrophobic CDR-H3-bearing sequences selleck in fraction F B cells as well as the inability of C57BL/6 IgHa.ΔD-iD mice to reduce the numbers of fraction F B cells with highly charged, arginine-enriched CDR-H3s when compared with BALB/c IgHa.ΔD-iD mice and wild-type controls (Fig. 8 and 9). This apparent inability to efficiently perform late-stage somatic, clonal selection against “disfavored” sequence occurs in parallel with the apparent inability of C57BL/6 wild-type mice to reduce the use of the VH81X gene segment in the transition from fraction E to fraction F. Differences in mechanism could include differences in receptor editing in fraction E, or differences in the consequences of antigen receptor
influenced signaling after exposure to antigen in the periphery. These and other mechanisms are currently being studied in our laboratory. Whether or not the MK-1775 supplier difference in the outcome of late-stage selection is contributing to the increased propensity of C57BL/6 to produce potentially pathogenic auto-reactive antibodies [26] is unclear. However, as analogous to the comparison of the
auto-immune prone C57BL/6 strain to the auto-immune resistant BALB/c strain, previous studies comparing MRL mice to their sister, autoimmune-resistant C3H strain have demonstrated a similar lack of control in the auto-immune prone MRL strain [27]. In either case, it appears that while the Ribose-5-phosphate isomerase C57BL/6 VH7183 repertoire contains reduced diversity of CDR-H1 and CDR-H2 due to decreased numbers of functional VH gene segments, there is increased diversity of CDR-H3 due to altered patterns of somatic selection. This appears to permit mature, recirculating C57BL/6 B cells to create a subset of antibodies within their repertoire with antigen-binding sites that are considerably less common, and potentially even nonexistent, in mature, recirculating BALB/c B cells. The role of these differences in creating a propensity for self-reactivity or other alterations in the immune response is a focus of ongoing investigations in our laboratory. We obtained bone marrow from C57BL/6 mice with either a wild-type or ΔD-iD [19] DH locus.
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