These issues merit further study. ALE and MA were postgraduate scholars in the Wellcome Trust funded 4-year PhD programme

Molecular Functions in Disease. BWO is supported by Cancer Research UK. The work was additionally supported by a grant from the Arthritis Research Campaign. The authors have no competing conflicts of interest to declare. Figure S1. Detection of cytokine release by cytokine arrays. Figure S2. Expression of integrins on THP-1 and U937 cells. “
“To test whether mechanisms controlling the range of diversity of the developing antibody repertoire in C57BL/6 mice (IgHb) operate similarly to those identified in BALB/c mice (IgHa), we compared learn more the sequences of VH7183-containing H-chain transcripts from sorted adult bone marrow C57BL/6 B-cell subsets with those previously obtained from BALB/c mice. Patterns of VDJ gene segment utilization and CDR-H3 amino acid composition, charge, and average length in C57BL/6 pro-B cells were similar, although not identical, to BALB/c pro-B cells. However, C57BL/6 mature, recirculating B cells failed to demonstrate the reduction in the use of VH81X and the narrowing in the range of variance of CDR-H3 hydrophobicity that characterizes B-cell maturation in BALB/c mice. To further test the ability of the C57BL/6 strain to discard

B cells expressing highly charged CDR-H3s, we introduced a mutant IgHa DH allele CHIR 99021 that forces use of arginine, asparagine, and histidine. Unlike BALB/c mice, C57BL/6 mice congenic for the charged DH maintained normal numbers of mature, recirculating B cells that were enriched for charged CDR-H3s. Together these findings indicate that the mature C57BL/6 B-cell pool permits expression

of immunoglobulins with antigen-binding sites that are typically discarded during late-stage bone marrow B-cell development in BALB/c mice. The ability to create a diverse immunoglobulin repertoire permits the immune system to produce specific responses to a broad range of ancient and novel antigens [1, 2]. Each individual immunoglobulin is produced by a Forskolin molecular weight complex series of V(D)J gene rearrangement events. V(D)J rearrangement is hierarchical, typically beginning with heavy (H) chain DHJH joining followed by VHDJH and then light (L) chain VLJL recombination. B-cell development is marked by passage through successive checkpoints for function. Early checkpoints test the structure of the immunoglobulin products, whereas later ones evaluate antigen-binding properties. The site at which immunoglobulin typically binds antigen is created by the juxtaposition of three hypervariable loops from the H chain and three from the L chain. Of these six loops, termed complementary determining regions [3], the most diverse is CDR-H3 because it is created de novo by V(D)J gene recombination and N addition [1, 2, 4].