title: 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 score=3.54). 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.
authors.affiliation: Instituto Gulbenkian de Ciência, Oeiras, Portugal.
authors.forename: J
authors.initials: J
authors.lastname: Côrte-Real
authors.forename: J
authors.initials: J
authors.lastname: Rodo
authors.forename: P
authors.initials: P
authors.lastname: Almeida
authors.forename: J
authors.initials: J
authors.lastname: Garcia
authors.forename: A
authors.initials: A
authors.lastname: Coutinho
authors.forename: J
authors.initials: J
authors.lastname: Demengeot
authors.forename: C
authors.initials: C
authors.lastname: Penha-Gonçalves
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D033481:Chromosomes, Mammalian; D005819:Genetic Markers; D006706:Homeostasis; D007075:Immunoglobulin M / Q000097:blood* / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D050835:Interferon Regulatory Factors / Q000235:genetics* / Q000276:immunology / Q000378:metabolism*; D008126:Lod Score; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D010529:Peritoneal Cavity / Q000166:cytology; D040641:Quantitative Trait Loci; D013154:Spleen / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D000099218:Interferon Regulatory Factor-4
chemical_list: D005819:Genetic Markers; D007075:Immunoglobulin M; D050835:Interferon Regulatory Factors; D000099218:Interferon Regulatory Factor-4