It has long been appreciated that disseminated coccidioidomycosis occurs in only a small minority of those at risk. These 2 cases are typical of disseminated disease. In conjunction with our previous report of disseminated coccidioidomycosis in a patient with a dominant IFN-γ receptor mutation, this shows the centrality of the IL-12/IL-23/IFN-γ axis to human control of Coccidioides species.
Early work established that IFN-γ was required for macrophage killing of phagocytosed Coccidioides
species and that this process was potentiated by IL-12 [5
]. Subsequently, IL-12 and IFN-γ responses of human PBMCs stimulated in vitro with coccidioidal antigens were found to distinguish immune (delayed type hypersensitivity–positive) from nonimmune (delayed type hypersensitivity –negative) donors [7
]. Specifically, PBMCs from nonimmune donors with disseminated coccidioidomycosis produced significantly less IFN-γ than did those from healthy immune donors. Furthermore, although IFN-γ production by PBMCs from immune donors could be dramatically increased by IL-12, no increase was seen in patients with disseminated coccidioidomycosis, and this hypo-responsiveness to exogenous IL-12 in nonimmune patients was associated with impaired activation of STAT4 [7
]. These studies unequivocally established IL-12 and IFN-γ as key mediators of cellular immunity to Coccidioides
species, and the cases that we report prove that mutations in the IL-12/IL-23/IFN-γ axis can confer susceptibility to disseminated coccidioidomycosis. It will be interesting to determine whether functional polymorphisms in genes of this axis may account for the ethnocentric vulnerability described in epidemiological studies.
species share the essential property of thermal dimorphism with only a select few other human pathogenic fungi, namely, Histoplasma capsulatum
, Paracoccidioides brasiliensis
, Blastomyces dermatitidis
, Penicillium marneffei
, and Sporothrix schenkii
. Despite differences in phylogeny, biology, and almost certainly in pathogen-associated molecular patterns, human immunological responses converging on the IL-12/IL-23/IFN-γ axis appear to be fundamentally necessary for protection from some of these dimorphic moulds, because mutations in this pathway have also been identified in cases of disseminated histoplasmosis and paracoccidioidomycosis [8
]. Of interest, disseminated coccidioidomycosis and histoplasmosis have been described in patients with autosomal dominant hyper-IgE (Job) syndrome due to mutations in STAT3. Although the mechanism conferring susceptibility remains undefined, STAT3 is critical for IL-23 signaling, and IL-23 may be relevant for synergistic induction of IFN-γ and IL-12 production [10
]. Collectively, these genetic immunodeficiencies illustrate the importance of this axis to control these dimorphic fungi. As a corollary, patients with refractory or disseminated disease with these dimorphic fungi should be evaluated for functional defects in these pathways.
The cases described here are distinct because of their predominant presentations with deep mycoses. Defects in the IL-12/IL-23/IFN-γ axis have been collectively referred to as Mendelian susceptibility to mycobacterial disease (MSMD), based on the seminal discoveries that individuals harboring such mutations were susceptible to these pathogens [11
]. However, the susceptibility phenotype of these genetic disorders continues to expand and now includes thermally dimorphic fungi. In contrast to previous MSMD reports, neither of the patients here has developed mycobacterial infection. Because nontuberculous mycobacteria are thought to be ubiquitous, it is unclear whether this absence represents a regional variation or an effect of this particular mutation predisposing selectively to moulds. The variability in susceptibility to mycobacteria associated with mutations in IL12Rβ1 has been well described [4
], presumably because IL12 is somewhat redundant in protective immunity against mycobacteria. However, the episode of salmonellosis in patient 1 is characteristic of her IL12Rβ1 defect.
Studies of primary immunodeficiencies have defined critical components of natural human immunity to pathogens. Recently, the features of human immunity to fungi have been increasingly characterized. Defects in the phagocyte nicotinamide adenine dinucleotide phosphate oxidase system, which cause chronic granulomatous disease, predispose to infection with Aspergillus
species and other nondimorphic hyalohyphomycetes (eg, Fusarium
species, and Penicillium
species). Impairment of the IL-17/IL-22 axis, seen in STAT3 deficiency and autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy, manifests with mucocutaneous candidiasis [12
]. It is clear from this and previous reports that the IL-12/IL-23/IFN-γ axis is critical to the control of thermally dimorphic fungi [3
]. These primary immunodeficiencies demonstrate that the occurrence of severe fungal disease is not random but can reflect a discrete immune defect. These disorders suggest the immunologic pathways that may be useful to understand susceptibility to invasive fungal disease in at-risk populations.