Methyl-CpG binding domain protein-1 polymorphisms impact immune homeostatic levels of IgG

Abstract

Abstract Host immunity plays a key role in protection against infection, however, there is significant individual-to-individual variation in the induction and quality of immune response that is driven in part by genetic factors. A growing body of evidence suggests that variation in immune status prior to specific insult may influence subsequent response to vaccination or pathogen challenge. Therefore, understanding the variation in immune status prior to specific insult is necessary for assessing variability in immune response to vaccination or pathogen challenge. The Collaborative Cross (CC) mouse population is a genetically diverse population that was designed to mimic the genetic and phenotypic diversity that is observed in humans and allows us to investigate mechanistically the contribution of genetics to complex phenotypes. Consequently, we asked whether there was variation in antibody levels in 57 CC strains prior to pathogen challenge and if that variation was associated with specific genetic factors. To assess this, we measured antibody levels for IgM, total IgG, IgG1, IgG2a, IgG2b, and IgG2c by ELISA and mapped quantitative trait loci (QTL) associated with variation in antibody concentrations. We observed substantial variation in all antibody isotypes measured. We also identified a suggestive (p=0.1) QTL on chromosome 18. Allele effects show that the C57Bl/6J allele at the locus of interest is linked to higher levels of total IgG. Subsequent analysis of genes under the QTL identified Methyl-CpG binding domain protein-1 (Mbd1) as the most promising candidate gene associated with total IgG variation. Ongoing studies are evaluating the role of Mbd1 in the regulation of total IgG production.