The role of serum IgM and memory IgM B cells in resistance and susceptibility to Cryptococcus neoformans

Abstract

Cryptococcus neoformans (CN) is a facultative, intracellular fungal pathogen that is the causative agent of cryptococcosis, a life-threatening infection which predominantly affects immunocompromised individuals. Notably, the patient groups most susceptible to cryptococcal disease (CD) are those with defects in both cellular and humoral immunity including those with: HIV infection, solid organ transplants receiving immunosuppressive therapy, common variable immunodeficiency (CVID), X-linked hyper IgM syndrome (XHIM), sarcoidosis, chronic leukemias and lymphomas and those receiving corticosteroid therapy.;The study was comprised of two HIV-infected cohorts. Cohort 1 included 59 HIV-infected individuals with and without a history of CD and 20 HIV-negative subjects. Within cohort 1, the HIV-infected population consisted of: 29 subjects with (HIV+CN+) and 30 subjects without a history of CD (HIV+CN-). We determined the level of memory B cells, total immunoglobulin and Ab to GXM for each group. Our results showed that the HIV+CN+ group had significantly lower levels of memory IgM B cells than HIV+CN- and HIV- subjects. Moreover, in both univariate and multivariate logistic regression models, memory IgM B cell expression was a strong predictor of CD status while controlling for age, sex, race and HIV viral load. Similar to the Ugandan cohort, CN disease status was not associated with differences in total immunoglobulin level or levels of IgG or IgA to GXM. However, HIV+CN+ subjects had significantly lower levels of IgM to GXM than HIV+CN- subjects. These findings suggested that reduced memory IgM B cell expression could be a risk factor for the development of CD, but since we studied a post-disease cohort, we could not determine whether or not the loss of memory IgM B cells was a pre- or post-disease event.;In view of our finding that B cells, rather than Ab levels were associated with CN disease status, we were interested in determining the role that memory IgM B cells play in the host response to CN. Memory IgM B cells produce naturally-occurring IgM that is thought to augment resistance to several pathogens including S. pneumoniae and West Nile Virus in mice. Based on available data, we evaluated the contribution of serum IgM to resistance to CN by comparing the survival of mice deficient in secretory IgM (sIgM-/-) to wildtype mice after intraperitoneal challenge with a lethal dose of CN. Our hypothesis was that the absence of serum IgM would be associated with enhanced lethality after infection with CN. Surprisingly, we found that sIgM-/- mice survived significantly longer than wildtype mice and had significantly lower levels of serum GXM after infection. sIgM-/- mice also had higher levels of B-1 B cells, a subset that is considered to be to the mouse homolog of human memory IgM B cells and mounted a robust serum inflammatory response. There was no significant differences in splenic CD4 or CD8 T cells and mononuclear cells between the sIgM-/- and wildtype mice. Taken together, these results suggested that B-1 B cells may confer a survival advantage to mice with systemic CN infection by modulating the inflammatory response. (Abstract shortened by UMI.).