Improved Survival of Mice Deficient in Secretory Immunoglobulin M following Systemic Infection with<i>Cryptococcus neoformans</i>

Subramaniam, Krishanthi; Datta, Kausik; Marks, Matthew S.; Pirofski, Liise Anne

doi:10.1128/iai.00506-09

Cited by 17 publications

(24 citation statements)

References 83 publications

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“…Numerous studies have now shown that B cells play a crucial role in protection against experimental cryptococcosis [131–133]. Prior to these reports, very few studies directly examined the role of B cells in host defense against C. neoformans .…”

Section: The Role Of B Cells In Immunity To C Neoformansmentioning

confidence: 99%

Host Immunity to Cryptococcus Neoformans

2015

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Cryptococcosis is caused by the fungal genus Cryptococcus. Cryptococcosis, predominantly meningoencephalitis, emerged with the HIV pandemic, primarily afflicting HIV-infected patients with profound T-cell deficiency. Where in use, combination antiretroviral therapy has markedly reduced the incidence of and risk for disease, but cryptococcosis continues to afflict those without access to therapy, particularly in sub-Saharan Africa and Asia. However, cryptococcosis also occurs in solid organ transplant recipients and patients with other immunodeficiencies as well as those with no known immunodeficiency. This article reviews innate and adaptive immune responses to C. neoformans, with an emphasis on recent studies on the role of B cells, natural IgM and Fc gamma receptor polymorphisms in resistance to cryptococcosis.

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Section: The Role Of B Cells In Immunity To C Neoformansmentioning

confidence: 99%

Host Immunity to Cryptococcus Neoformans

2015

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“…Recently, it was shown that mice that lack IgM, sIgM −/− mice, were more resistant to i.p. infection with C. neoformans than IgM-sufficient mice (22). This finding might appear to be at variance with human data showing that levels of GXM-binding IgM are lower in patients at high risk for CD, namely, HIV-infected patients (12, 23-25), than those at low risk, such as solid organ transplant recipients who subsequently developed CD (13).…”

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confidence: 99%

“…This finding might appear to be at variance with human data showing that levels of GXM-binding IgM are lower in patients at high risk for CD, namely, HIV-infected patients (12, 23-25), than those at low risk, such as solid organ transplant recipients who subsequently developed CD (13). However, given that sIgM −/− mice have an expanded B-1 B cell repertoire (22, 26) and normal levels of IgG2a, which is highly opsonic for C. neoformans , B-1 B cells and/or acquired Ab immunity are likely to protect sIgM −/− mice against i.p. infection (22).…”

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confidence: 99%

The Absence of Serum IgM Enhances the Susceptibility of Mice to Pulmonary Challenge withCryptococcus neoformans

Subramaniam

Datta

Quintero³

et al. 2010

The Journal of Immunology

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102

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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-1β 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.

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“…To test the hypothesis that the inability of B cells to produce IgM would impair anticryptococcal defense, Subramaniam et al [95] used mice genetically altered to lack serum IgM (sIgM −/− mice, secretory IgM-deficient). Surprisingly, these mice proved relatively resistant to a systemic cryptococcal challenge delivered intraperitoneally; this observation also seemed to run counter to human data, in which a lack of GXM-reactive IgM translated to higher risks of cryptococcal disease [50,52], as well as mouse data by different groups, showing that acquired, GXM-reactive IgM confers protection against intraperitoneal cryptococcal infection [35,55,73].…”

Section: Corroboration From Mouse Studiesmentioning

confidence: 99%

“…The B-1a subset of mouse B cells are homologous to the human IgM + memory B cells with protective abilities against encapsulated pathogens [53,96]; sIgM −/− mice have an expanded B-1a B-cell pool localized predominantly in the peritoneal cavity and spleen. Secondly, naive and C. neoformans-challenged sIgM −/− mice had higher levels, respectively, of total and GXM-specific IgG2a, an IgG subtype with known protective effects against C. neoformans (see discussion of [95]). In contrast, when in a subsequent study with the same sIgM −/− model, Subramaniam et al used an intranasal, pulmonary infection model that delivered the cryptococcal inoculum straight to the lungs, these mice succumbed to the infection at a higher rate relative to the IgM-sufficient controls, with higher fungal burdens in the blood and brain [97]; the alveolar macrophages of sIgM −/− mice appeared deficient in phagocytosis of cryptococcal cells, but regained the function when nonspecific polyclonal IgM was administered to the lungs via the same intranasal route.…”

Section: Corroboration From Mouse Studiesmentioning

confidence: 99%

Host Defense Against Cryptococcal Disease: Is There a Role for B Cells and Antibody-Mediated Immunity?

Datta

Subramaniam

2014

Curr Fungal Infect Rep

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The role of B cells and antibody-mediated immunity (AMI) is poorly understood regarding infections with the encapsulated yeast species, Cryptococcus. Human cryptococcal disease, or cryptococcosis, generally occurs in the setting of immune suppression, including deficits of T cells and other components of cell-mediated immunity (CMI), as observed in HIV/AIDS, cancer, solid-organ transplant, and similar conditions. The protective role of CMI is, therefore, well-described in the literature. However, CMI deficiencies alone cannot adequately explain the quantum of cryptococcal disease noted in human and animal populations, and a wealth of clinical and experimental data, mostly spanning the past several decades, has shed light upon a significant role of AMI in anticryptococcal immunity. Recent evidence suggests that rather than functioning discretely, these two host immune compartments work synergistically, with the AMI modulating CMI functions in order to provide a critical balance for host benefit. We describe what is currently known.

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Improved Survival of Mice Deficient in Secretory Immunoglobulin M following Systemic Infection withCryptococcus neoformans

Cited by 17 publications

References 83 publications

Host Immunity to Cryptococcus Neoformans

Host Immunity to Cryptococcus Neoformans

The Absence of Serum IgM Enhances the Susceptibility of Mice to Pulmonary Challenge withCryptococcus neoformans

Host Defense Against Cryptococcal Disease: Is There a Role for B Cells and Antibody-Mediated Immunity?

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