The absence of serum IgM enhances the susceptibility of mice to pulmonary challenge with Cryptococcus neoformans.

The importance of T cell-mediated immunity for resistance to the disease (cryptococcal disease) caused by Cryptococcus neoformans is incontrovertible, but whether Ab immunity also contributes to resistance remains uncertain. To investigate the role of IgM in resistance to C. neoformans, we compared the survival, fungal burden, lung and brain inflammatory responses, and lung phagocytic response of sIgM(-/-) mice, which lack secreted IgM, to that of IgM sufficient C57BL6x129Sv (heretofore, control) mice at different times after intranasal infection with C. neoformans (24067). sIgM(-/-) mice had higher mortality and higher blood and brain CFUs 28 d postinfection, but lung CFUs were comparable. Lungs of control mice manifested exuberant histiocytic inflammation with visible C. neoformans, findings that were not observed in sIgM(-/-) mice, whereas in brain sections, sIgM(-/-) mice had marked inflammation with visible C. neoformans that was not observed in control mice. Cytokine responses were significant for higher levels of lung IL-1beta and IL-12 24 h postinfection in control mice and higher levels of lung and brain IL-17 28 d postinfection in sIgM(-/-) mice. Alveolar macrophage phagocytosis was significantly higher for control than for sIgM(-/-) mice 24 h postinfection; however, phagocytic indices of sIgM(-/-) mice increased after reconstitution of sIgM(-/-) mice with polyclonal IgM. These data establish a previously unrecognized role for IgM in resistance to intranasal infection with C. neoformans in mice and suggest that the mechanism by which it mediates a host benefit is by augmenting Th1 polarization, macrophage recruitment and phagocytosis of C. neoformans.

Improved survival of mice deficient in secretory immunoglobulin M following systemic infection with Cryptococcus neoformans.

Cryptococcus neoformans causes severe, and often fatal, disease (cryptococcosis) in immunocompromised patients, particularly in those with HIV/AIDS. Although resistance to cryptococcosis requires intact T-cell immunity, a possible role for antibody/B cells in protection against natural disease has not been definitively established. Previous studies of the antibody response to the C. neoformans capsular polysaccharide glucuronoxylomannan (GXM) have demonstrated that patients who are at increased risk for cryptococcosis have lower serum levels of GXM-reactive IgM than those who are not at risk, leading to the hypothesis that IgM might contribute to resistance to cryptococcosis. To determine the influence of IgM on susceptibility to systemic cryptococcosis in a murine model, we compared the survival of mice deficient in serum IgM (secretory IgM deficient [sIgM(-/-)]) and C57BL/6 x 129Sv (control) mice after intraperitoneal infection with C. neoformans strain 24067 and analyzed the splenic B- and T-cell subsets by flow cytometry and the serum and splenic cytokine/chemokine and serum antibody profiles of each mouse strain. The results showed that sIgM(-/-) mice survived significantly longer than control mice when challenged with 10(5) CFU of C. neoformans 24067. Naïve sIgM(-/-) mice had higher levels of B-1 (CD5(+)) B cells, proinflammatory mediators (interleukin-6 [IL-6], IL-1beta, MIP-1beta, tumor necrosis factor alpha [TNF-alpha], and gamma interferon [IFN-gamma]), and anti-inflammatory mediators (IL-10 and IL-13) and significantly higher titers of GXM-specific IgG2a 3 weeks postinfection. In addition, CD5(+) splenocytes from both mouse strains had fungicidal activity against C. neoformans. Taken together, these results suggest that the inflammatory milieu in sIgM(-/-) mice might confer enhanced resistance to systemic cryptococcosis, stemming in part from the antifungal activity of B-1 B cells.