Predicting the outcome of infectious diseases: variability among inbred mice as a new and powerful tool for biomarker discovery.

Individuals respond differently to infectious diseases. Even among inbred mice that are presumed to be genetically identical, the response to a microbial pathogen is variable, which is generally thought to reflect experimental inconsistencies, technical errors, and stochastic processes. Here we describe the remarkable observation that the variability of Helicobacter pylori colonization density in the stomachs of experimentally infected C57BL/6J mice is tightly correlated with weight loss and viral load after a challenge with influenza virus, though H. pylori infection per se does not affect influenza and vice versa. Since these two infectious agents are found in different tissue compartments and are detected using unrelated methods, the correlation in microbial burden must represent a biological measure of disease susceptibility among genetically nearly identical individuals and not technical or stochastic factors. We hypothesize that inbred mice represent a powerful new tool for the identification of biomarkers to predict the outcome of infectious diseases.

B-1 cells in the bone marrow are a significant source of natural IgM.

Natural IgM antibodies secreted in the absence of antigenic challenge are important contributors to antimicrobial immunity and tissue homeostasis. Early studies identified BM and, to a lesser extent the spleen, as main tissue sources of this spontaneously secreted IgM. However, the responsible B-cell subset has never been identified. Using multicolor flow cytometry, cell sorting and chimeric mice in which B-1 and B-2 cells and their secreted antibodies are distinguished by their Ig-allotype, we unequivocally identify the natural IgM-secreting cells in spleen and, for the first time, in the BM as IgM(+) IgD(lo/-) CD19(hi) CD43(+) CD5(+/-) B-1 cells. The newly identified population of BM B-1 cells shows many of the phenotypic characteristics of splenic B-1 cells but is distinct from B-1 cells in the peritoneal cavity, which generate at best very small amounts of IgM. Antibody-secreting spleen and BM B-1 cells are distinct also from terminally differentiated plasma cells generated from antigen-induced conventional B cells, as they express high levels of surface IgM and CD19 and lack expression of CD138. Overall, these data identify populations of non-terminally differentiated B-1 cells in spleen and BM as the most significant producers of natural IgM.

B7-1/2 (CD80/CD86) direct signaling to B cells enhances IgG secretion.

B cell responses are regulated by Ag recognition, costimulatory signals provided by interaction with helper T cells, and by innate signals. We recently provided evidence for a link between the effects of innate and costimulatory signals on B cells during influenza virus infection, by demonstrating that most B cells in the regional lymph nodes of the respiratory tract enhance surface expression of the costimulator B7-2 (CD86) within 24-48 h following infection via a type I IFNR-dependent mechanisms, a finding we are confirming here. While the role of B7-1/2 for helper T cell activation is well documented, its role in direct B cell regulation is poorly understood. Here, our in vivo studies with mixed bone marrow irradiation chimeric mice, lacking B7-1/2 only on B cells, demonstrated that B7-1/2 expression is crucial for induction of maximal local, but to a lesser extent systemic, IgG Ab responses following influenza virus infection. In contrast to mice that completely lack B7-1/2 expression, loss of B7-1/2 on B cells alone did not significantly affect germinal center formation or the extent of CD4(+) T cell activation and IFN-gamma secretion. Instead, our in vitro studies identify a dramatic effect of B7-2 engagement on IgG, but not IgM secretion by already class-switched B cells. Concomitantly, B7-2 engagement induced expression of X-box binding protein 1 (XBP-1) and spliced XBP1, evidence for increased protein synthesis by these cells. Taken together, these results identify direct signaling through B7-1/2 as a potent regulator of IgG secretion by previously activated B cells.

Infant cross-fostering between Japanese (Macaca fuscata) and rhesus macaques (M. mulatta).

Cross-fostering of infant rhesus macaques between unrelated females has become a routine management strategy at the California Primate Research Center. In order to study the effect of environmental factors on vocal development, we extended this procedure to offspring exchange between two different macaque species living in small social groups. A total of four neonatal Japanese and rhesus monkeys were fostered onto mothers of the other species. Six attempts were required, for an overall success rate of 67%. However, two of the adoptions involved the same foster mother, and both rejections occurred with the same female. The cross-fostered individuals gained weight normally in the first year of life and did not require any hospital treatment. These results indicate that raising nonhuman primate infants with members of a different species can be a viable means of altering species-typical experience without sacrificing essential aspects of maternal care, socialization, and psychological well-being.