부산대학교 도서관

Variation in immune homeostasis, the state in which the immune system is maintained in the absence of stimulation, is highly variable across populations. This variation is attributed to both genetic and environmental factors. However, the identity and function of specific regulators have been difficult to identify in humans. We evaluated homeostatic antibody levels in the serum of the Collaborative Cross (CC) mouse genetic reference population. We found heritable variation in all antibody isotypes and subtypes measured. We identified 4 quantitative trait loci (QTL) associated with 3 IgG subtypes: IgG1, IgG2b, and IgG2c. While 3 of these QTL map to genome regions of known immunological significance (major histocompatibility and immunoglobulin heavy chain locus), Qih1 (associated with variation in IgG1) mapped to a novel locus on Chromosome 18. We further associated this locus with B cell proportions in the spleen and identify Methyl-CpG binding domain protein 1 under this locus as a novel regulator of homeostatic IgG1 levels in the serum and marginal zone B cells (MZB) in the spleen, consistent with a role in MZB differentiation to antibody secreting cells. Author summary: The baseline immune state is highly variable across populations, which is a function of both environmental and genetics factors. Here, we have used the Collaborative Cross, a genetically diverse mouse population, to study the role of genetic variation on baseline serum antibody concentrations. We identified several regions of the genome that were associated with variation in serum concentrations of multiple antibody subtypes. Most of which are in regions of the genome that have been shown previously to impact immune responses. We also identified a novel region of the genome associated with variation in IgG1 and further identify Methyl-CpG binding domain protein 1 (MBD1) as a regulator of both baseline IgG1 and B cell homeostasis. Given that MBD1 is an epigenetic regulator of differentiation in other contexts, further studies of MBD1 in B cell homeostasis may define previously unknown pathways involved in marginal zone B cell differentiation. [ABSTRACT FROM AUTHOR]