This study reveals that approximately 20% of patients with disseminated coccidioidomycosis exhibit CD4+ T cell skewing toward a Type-2 phenotype. This immune deviation is closely associated with male sex and can be partially corrected through IL4R-blocking antibody (dupilumab) treatment.
Literature Overview
This paper titled 'Type-2 immune skewing in patients with disseminated coccidioidomycosis', published on medRxiv, reviews the frequency of CD4+ T cell Type-2 skewing in disseminated coccidioidomycosis (DCM) and explores its potential genetic mechanisms. Findings demonstrate significant Type-2 polarization in male patients, which can be partially corrected by IL4R blockade. Whole-genome sequencing identified rare variants in the IL-12-IFN-γ signaling axis, with an IFNGR1 variant confirmed as loss-of-function.
Background Knowledge
Coccidioidomycosis is an infectious disease caused by Coccidioides species (C. immitis and C. posadasii), endemic to arid regions of the southwestern United States. While most infections are asymptomatic or self-limiting respiratory illnesses, approximately 1% progress to disseminated coccidioidomycosis (DCM), which can spread to skin, bones, and the nervous system with 30% mortality within five years. Currently, no reliable laboratory assays or clinical algorithms exist to predict disease progression to dissemination, hindering early intervention. Protective immunity requires robust Type-1 responses, while Type-2 immunity correlates with susceptibility. This study aims to fill critical knowledge gaps by investigating CD4+ T cell Type-2 skewing and its associations with sex, age, and genetic variants to inform clinical strategies.
Research Methods and Experiments
The research team analyzed peripheral blood mononuclear cells from 204 coccidioidomycosis patients, measuring CD4+ T cell cytokine production. Inter-group comparisons were made based on disease severity and demographic characteristics. Whole-genome sequencing was performed on 149 patients to identify rare variants associated with the IL-12-IFN-γ axis.
Key Conclusions and Perspectives
Research Significance and Prospects
Results recommend screening for CD4+ T cell Type-2 polarization in DCM patients, particularly males, and subsequent genetic testing for IL-12-IFN-γ axis defects in skewed cases. This work provides mechanistic evidence supporting IL4R blockade as a therapeutic strategy for refractory cases. Future studies should explore other cytokines (e.g., IL-13, IL-5) in disease progression and develop reliable Coccidioides antigen stimulation reagents to validate findings. Comparative studies in other fungal infection models could determine whether immune polarization represents a universal pathogenic mechanism.
Conclusion
This study identifies CD4+ T cell Type-2 polarization in disseminated coccidioidomycosis (DCM), with marked prevalence in male patients. In vitro experiments confirm IL4R blockade (dupilumab) effectively corrects Th2:Th1 imbalance. Whole-genome sequencing revealed multiple loss-of-function variants in genes like IFNGR1 and IL12RB1. These findings provide novel molecular markers and therapeutic targets for DCM clinical management, supporting development of immunomodulatory strategies. The sex-associated polarization pattern highlights the importance of considering gender and genetic background in patient stratification for precision treatment. This work establishes critical insights into disseminated fungal infection pathogenesis while identifying limitations in antigen stimulation and signaling pathway analyses requiring further investigation.
