Cytokine Profiles from Antigen-Stimulated Whole-Blood Samples among Patients with Pulmonary or Nonmeningeal Disseminated Coccidioidomycosis

Abstract

The outcome of coccidioidomycosis depends on a robust specific cellular immune response. A T-helper type 1 (Th1) cellular immune response has been previously associated with resolution of clinical illness. However, the precise elements of this response and whether cytokines not involved with the Th1 response play a role in coccidioidomycosis are not known. Whole-blood samples were obtained from subjects with active coccidioidomycosis and controls and incubated for 18 h with T27K, a coccidioidal antigen preparation. The supernatant was then assayed for gamma interferon (IFN-␥), interleukin-2 (IL-2), tumor necrosis factor alpha (TNF-␣), IL-4, IL-6, IL-10, and IL-17A. A total of 43 subjects, 16 with acute pneumonia, 9 with pulmonary sequelae of nodules and cavities, and 18 with nonmeningeal disseminated coccidioidomycosis, were studied. Compared to concentrations in healthy immune and nonimmune donors, the median concentration of IL-17A was significantly higher in those with active coccidioidomycosis (for both, P < 0.01). In addition, IL-6 concentrations were higher while IL-2 and IFN-␥ concentrations were significantly lower in those with nonmeningeal disseminated disease diagnosed within 12 months than in those with acute pneumonia (for all, P < 0.05). The cytokine profile among patients with active coccidioidomycosis is distinct in that IL-17A is persistently present. In addition, those with nonmeningeal disseminated disease have an increased inflammatory cytokine response and diminished Th1 responses that modulate over time.

Pathogenesis of Coccidioidomycosis

“…The finding of IL-17 led to a further study in which whole blood samples were obtained from patients with either pulmonary or non-meningeal disseminated coccidioidomycosis and incubated with T27K [31]. In addition to measurement of the release of IL-2, IFN-γ, and TNF-α, a highly sensitive assay for IL-17A was employed.…”

Ex VivoCytokine Release, Determined by a Multiplex Cytokine Assay, in Response to Coccidioidal Antigen Stimulation of Whole Blood among Subjects with Recently Diagnosed Primary Pulmonary Coccidioidomycosis

“…Six inflammatory proteins, GM-CSF, IL-1β, IL-2, IFN-γ, IL-13, and TNF-α, were found to be specifically released ex vivo when whole-blood samples from subjects with recently diagnosed primary pulmonary coccidioidomycosis were incubated with the coccidioidal antigen preparation T27K. While we have previously shown that the T-helper type 1 cytokines IL-2, IFN-γ, and TNF-α are released ex vivo when exposed to coccidioidal antigen ( 5 , 7 , 8 ), the findings for the other cytokines are new and unexpected. We did not find evidence for increased release of IL-6 or IL-17A, as we have previously observed ( 7 ).…”

Immune Response to Coccidioidomycosis and the Development of a Vaccine

“…Humans with a deficiency in CD4 + T cells (i.e., HIV + patients) are at elevated risk of contracting this respiratory disease [ 9 , 69 ]. Whole-blood samples obtained from patients with active coccidioidomycosis produce elevated levels of IL-17A after restimulation with Coccidioides T27K antigen compared to blood samples derived from non-immune donors [ 70 ]. IL-6 concentrations are also higher, while IL-2 and IFN-γ concentrations are significantly lower in those with disseminated coccidioidomycosis diagnosed within 12 months of disease onset relative to those with acute pneumonia.…”

“…IL-6 concentrations are also higher, while IL-2 and IFN-γ concentrations are significantly lower in those with disseminated coccidioidomycosis diagnosed within 12 months of disease onset relative to those with acute pneumonia. These data suggest that patients with disseminated coccidioidomycosis have an increased inflammatory response [ 70 ]. Patients with a homozygous mutation in the β1 subunit of the IL-12 receptor are predisposed to disseminated coccidioidomycosis, indicating that the IL-12/IFN-γ axis of adaptive immunity is essential for the control of Coccidioides infection [ 71 ].…”