Mice selected for the maximum acute inflammatory reaction (AIRmax) are highly susceptible to pristane-induced arthritis (PIA), whereas mice selected for the minimum response (AIRmin) are resistant. These lines show distinct patterns of leukocyte infiltration and R and S allele frequency disequilibrium of the solute carrier family 11a member 1 (Slc11a1) gene. In order to study the interactions of the Slc11a1 R and S alleles with the inflammation modulating Quantitative Trait Loci (QTL) during PIA development, homozygous AIRmax RR , AIRmax SS , AIRmin RR and AIRmin SS lines were produced by genotype-assisted breedings. These mice received two intraperitoneal injections of 0.5 ml pristane at 60-day intervals, and the subsequent development of arthritis was assessed for 210 days. Cytokine-secreting cell profiles were investigated using enzyme-linked immunospot. Arthritis incidence in AIRmax RR mice reached 29%, whereas PIA incidence in AIRmax SS mice was 70% by day 180. AIRmin RR mice were resistant, whereas 13.3% of AIRmin SS mice became arthritic. The presence of the defective S allele also increased arthritis severity, although acute inflammation was higher in mice bearing the R allele. A predominant Th0/Th2-type response in Slc11a1 SS mice was observed. These results indicate that Slc11a1 is a strong candidate for the QTL modulating acute inflammation and for PIA.

Natural IgM has a wide range of actions in the immune system. Here we demonstrate that mice lacking serum IgM have an expansion in splenic marginal zone B cells with a proportionately smaller reduction in follicular B cells. The increase in the marginal zone-follicular B cell ratio (and an expansion in peritoneal B1a cells) is fully reversed by administration of polyclonal IgM, but not by two IgM monoclonals. Mice engineered to have a secreted oligoclonal IgM repertoire with an endogenous membrane IgM also exhibited a similar expansion of marginal zone B cells. We propose that natural IgM, by virtue of its polyreactivity, enhances Ag-driven signaling through the B cell receptor and promotes the formation of follicular B cells. These results demonstrate that natural IgM regulates the selection of B lymphocyte subsets.

B cell survival has a central role in maintaining immune responses to foreign organisms while curbing autoimmunity. In this study, we show that mature B cell survival is impaired and B cell turnover is accelerated in the spleen of mice lacking secreted IgM. Although in vitro responses to BCR cross-linking were normal, there was a marked reduction in basal ERK and global tyrosine phosphorylation in splenic B cells from serum IgM-deficient mice, suggesting diminished interaction with cognate Ag in vivo. The provision of BAFF either in vitro or in vivo reversed the increase in B cell apoptosis, demonstrating that other survival signals can compensate for the loss of secreted IgM in the spleen. In striking contrast to the splenic compartment, peritoneal B cell survival was enhanced in secreted IgM-deficient mice, despite a similar reduction in basal BCR signaling compared with wild type mice. These results suggest that secreted IgM acts as an adjuvant, boosting BCR signals to maintain survival and maintenance of mature splenic B cells while increasing B cell apoptosis in the peritoneum. BAFF administration mitigated the consequences of secreted IgM deficiency on B cell survival in the spleen but not in the peritoneum. This work provides new insight into the regulation of B cell signaling and homeostasis in different peripheral compartments by secreted IgM.

No abstract