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Antibody-mediated immunity is highly protective against disease. The majority of current vaccines confer protection through humoral immunity, but there is high variability in responsiveness across populations. Identifying immune mechanisms that mediate low antibody responsiveness may provide potential strategies to boost vaccine efficacy. Here, we report diverse antibody responsiveness to unadjuvanted as well as adjuvanted immunization in substrains of BALB/c mice, resulting in high and low antibody response phenotypes. Furthermore, these antibody phenotypes were not affected by changes in environmental factors such as the gut microbiota composition. Antigen-specific B cells following immunization had a marked difference in capability to class switch, resulting in perturbed IgG isotype antibody production. In vitro, a B-cell intrinsic defect in the regulation of class-switch recombination was identified in mice with low IgG antibody production. Whole genome sequencing identified polymorphisms associated with the magnitude of antibody produced, and we propose candidate genes that may regulate isotype class-switching capability. This study highlights that mice sourced from different vendors can have significantly altered humoral immune response profiles, and provides a resource to interrogate genetic regulators of antibody responsiveness. Together these results further our understanding of immune heterogeneity and suggest additional research on the genetic influences of adjuvanted vaccine strategies is warranted for enhancing vaccine efficacy., (© 2018 Malaghan Institute of Medical Research Immunology & Cell Biology published by John Wiley & Sons Australia, Ltd on behalf of Australasian Society for Immunology Inc.)

Liver fibrosis is a progressive pathological process involving inflammation and extracellular matrix deposition. Dipeptidyl peptidase 4 (DPP4), also known as CD26, is a cell surface glycoprotein and serine protease. DPP4 binds to fibronectin, can inactivate specific chemokines, incretin hormone and neuropeptides, and influences cell adhesion and migration. Such properties suggest a pro-fibrotic role for this peptidase but this hypothesis needs in vivo examination. Experimental liver injury was induced with carbon tetrachloride (CCl 4 ) in DPP4 gene knockout (gko) mice. DPP4 gko had less liver fibrosis and inflammation and fewer B cell clusters than wild type mice in the fibrosis model. DPP4 inhibitor-treated mice also developed less liver fibrosis. DNA microarray and PCR showed that many immunoglobulin (Ig) genes and some metabolism-associated transcripts were differentially expressed in the gko strain compared with wild type. CCl 4 -treated DPP4 gko livers had more IgM + and IgG + intrahepatic lymphocytes, and fewer CD4 + , IgD + and CD21 + intrahepatic lymphocytes. These data suggest that DPP4 is pro-fibrotic in CCl 4 -induced liver fibrosis and that the mechanisms of DPP4 pro-fibrotic action include energy metabolism, B cells, NK cells and CD4 + cells.

Following antigen encounter, immunoglobulin genes are diversified by somatic hypermutation. The mechanism by which this mutational process preferentially targets immunoglobulin genes is not known, but is likely linked to transcription. However, transcription is not sufficient to ensure mutability. Here, by polymerase chain reaction amplification of bisulfite-modified DNA, the pattern of demethylation within the Igkappa mutation domain is analysed and transgenes are used to identify an association between demethylation and mutability. In mice carrying an Igkappa transgene that is well transcribed but only poorly targeted for hypermutation, the mutated transgene copies have been demethylated within the mutation domain, whereas the methylated copies remain unmutated. Thus, the hypermutation mechanism only acts on immunoglobulin gene targets that are demethylated as well as transcribed, although transcription and demethylation do not themselves guarantee mutability.

A truncated T cell receptor (TCR) V beta 8.2 polypeptide expressed on the surface of a precursor lymphoid cell line and on a subset of mesenteric lymph node cells has previously been shown to be encoded by transcripts from unrearranged V beta 8 genes. Germline V beta 8 transcription has now been demonstrated in multiple lymphoid and non-lymphoid tissues in mice of varying ages and in cultured cell lines by reverse transcription-polymerase chain reaction (RT-PCR). Significant levels of V beta 8 germline transcription were found in thymus, spleen, liver and bone marrow and in all lymphoid cell lines studied. Germline V beta 8 transcription in the liver dropped as mice aged, and increased in the bone marrow. Germline V beta 8 transcription was also detectable in thymus, spleen, liver and bone marrow of RAG-1-/- mice. This indicated that it is not dependent upon the presence of mature lymphoid cells, nor necessarily related to V(D)J rearrangement events. Semi-quantitative polymerase chain reaction (PCR) and hybridization with oligonucleotides specific for V beta 8.1, 8.2 and 8.3 showed that the V beta 8.2 gene produced at least 90% of all the germline V beta 8 transcripts in all of the tissues examined. The significance of these results in lymphoid cell development and for models of the regulation of V(D)J rearrangement are discussed.