Irf4 is a positional and functional candidate gene for the control of serum IgM levels in the mouse

Abstract

Natural IgM are involved in numerous immunological functions but the genetic factors that control the homeostasis of its secretion and upholding remain unknown. Prompted by the finding that C57BL/6 mice had significantly lower serum levels of IgM when compared with BALB/c mice, we performed a genome-wide screen and found that the level of serum IgM was controlled by a QTL on chromosome 13 reaching the highest level of association at marker D13Mit266 (LOD score¼3.54). This locus was named IgMSC1 and covered a region encompassing the interferon-regulatory factor 4 gene (Irf4). The number of splenic mature B cells in C57BL/6 did not differ from BALB/c mice but we found that low serum levels of IgM in C57BL/6 mice correlated with lower frequency of IgM-secreting cells in the spleen and in the peritoneal cavity. These results suggested that C57BL/6 mice have lower efficiency in late B-cell maturation, a process that is highly impaired in Irf4 knockout mice. In fact, we also found reduced Irf4 gene expression in B cells of C57BL/6 mice. Thus, we propose Irf4 as a candidate for the IgMSC1 locus, which controls IgM homeostatic levels at the level of B-cell terminal differentiation

Impact of Natural IgM Concentration on Gene Therapy with Adenovirus Type 5 Vectors

“…We failed to detect any influence of the Igh-6 locus on the IgM concentration (Fig. 2F), in agreement with a prior study of the genetic control of IgM concentrations (16). Our results therefore suggest that the IgM concentration and the Igh-6 locus may independently influence liver transduction.…”

“…Amounts of natural antibody differ among individual mice and between mouse strains (9,16). Although the presence of natural antibodies clearly inhibits Ad5 liver transduction (9,10), the impact of natural antibody concentrations is unclear.…”

Manipulation of the glycan‐specific natural antibody repertoire for immunotherapy

“…It is clear that the nAb‐secreting plasma cell pool size is tightly controlled most likely by intrinsic homeostatic mechanisms because mice reared in the absence of antigenic stimulation (i.e., under germ‐free conditions receiving an chemically defined diet) demonstrate normal levels of IgM antibodies relative to conventionally raised counterparts, whereas other isotypes such as IgG and IgA are greatly decreased . However, numerous experimental observations demonstrate that the timing of exogenous antigen exposure during neonatal and perinatal B cell lymphopoiesis can drastically alter the clonal representation of antigen‐specific B cells in the adult mouse repertoire .…”

Perivascular Adipose Tissue Harbors Atheroprotective IgM-Producing B Cells

“…B-2 cells are abundant in secondary lymphoid organs (SLOs), play a major role in adaptive immune responses and are thought to promote atherosclerosis. In contrast, B-1 cells, the major source for natural IgM secretion in the body (Corte-Real et al, 2009 ; Holodick et al, 2010 ; Choi et al, 2012 ), produce IgM to OSE on OxLDL and provide innate immune protection from diet-induced atherosclerosis in mice (Kyaw et al, 2011 ; Rosenfeld et al, 2015 ).…”