Department of Medicine, University of Arizona, SAVAHCS. Tucson, AZ, 85723 USA
There are many similarities between coccidioidomycosis and paracoccidioidomyco.sis. Both are caused by soil-dwelling dimorphic fungi endemic only to the Western Hemisphere. Symptomatic disease in both is more common in men than women. Both are controlled in the human host by a robust cellular immune response. However, they differ in their precise geographical distribution and in their clinical presentations. Coccidioidomycosis is recognized as a major fungal infection in the southwest United States and northern Mexico. However, there are pockets of endemicity in Central and South America, including northeast Brazil and north-central Argentina. Among those infected, 60% are completely asymptomatic and the other 40% have a disease that most frequently resembles a community-acquired bacterial pneumonia that resolves without therapy. However, approximately 5% have persistent illness, either as a chronic pulmonary infection or as disseminated beyond the thoracic cavity. Sites of dissemination are most commonly the skin, joints, soft tissues and méninges. Risks for dissemination include underlying immunosuppression, such as seen in patients with HIV infection and transplantation recipients. Certain racial groups also appear to be at risk and older age predisposes to symptomatic disease. My laboratory has been interested in the human cellular immune response to coccidioidomycosis for several years. Previously, we have shown that the lack of lymphocyte response among donors with active coccidioidomycosis is correlated with severity of disease. We have been able to overcome this nnergy in vitro by incubating cells with autologous mature dendritic cells loaded with coccidioidal antigen. We have also been able to describe immunological events within human coccidioidal granulomata and have demonstrated clusters of lymphocytes that contain principally B cells and CD4+ T cells. These clusters contain relatively more interleukin-10 (IL-10) than interferon-gamma (IFN-γ) and may serve as sites of immune down-regulation. More recently, we have described specific elements that appear important in this response. Specifically, mRNA for IL-12 receptor β2 (ILI2Rp2) and activated intranuclear STAT-4 are upregulated in response to the coccidioidal antigen T27K in cells from immune donors but not from non-immune donors. On the other hand, IL12RP1 is increased in both immune and non-immune donors. In addition, the monomer IL-12p40 is increased in cells from immune donors after incubation with coccidioidal antigen but the heterodimer IL-12p70 is not detectable. We now also have evidence that the innate immune system, including the mannose receptor (MR) and TollLike Receptor-2 (TLR-2) play a role in recognition of coccidioidal antigens by human peripheral blood mononuclear cells from immune donors. We have demonstrated that the release of IFN-γ and IL-2 are both diminished in cells from immune donors co-incubated with coccidioidal antigen and the inhibitor of MR, mannan. In addition, the release of the cytokine TNF-(X is decreased by immune cells incubated with coccidioidal antigen coincubated with antibody directed against TLR-2 but not TLR-4. These insights should be useful in better understanding the human immune response to coccidioidomycosis and may hold the key to future therapies.
Financial Support: Merit Review Award from the Department of Veterans Affairs and NIAID grant IPOIAI61310-01 from the National Institutes of Health.
Copyright Instituto de Medicina Tropical de Sao Paulo Oct 2005
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