The long search for the environmental trigger of the endemic pemphigus foliaceus (EPF,
fogo selvagem) has not yet resulted in any tangible findings. Here, we searched for genetic asso ciations and the differential expression of host genes involved in early viral infections and innate
antiviral defense. Genetic variants could alter the structure, expression sites, or levels of the gene
products, impacting their functions. By analyzing 3063 variants of 166 candidate genes in 227 EPF
patients and 194 controls, we found 12 variants within 11 genes associated with differential suscepti bility (p < 0.005) to EPF. The products of genes TRIM5, TPCN2, EIF4E, EIF4E3, NUP37, NUP50, NUP88,
TPR, USP15, IRF8, and JAK1 are involved in different mechanisms of viral control, for example, the
regulation of viral entry into the host cell or recognition of viral nucleic acids and proteins. Only two
of nine variants were also associated in an independent German cohort of sporadic PF (75 patients,
150 controls), aligning with our hypothesis that antiviral host genes play a major role in EPF due to a
specific virus–human interaction in the endemic region. Moreover, CCL5, P4HB, and APOBEC3G
mRNA levels were increased (p < 0.001) in CD4+ T lymphocytes of EPF patients. Because there is
limited or no evidence that these genes are involved in autoimmunity, their crucial role in antiviral responses and the associations that we observed support the hypothesis of a viral trigger for EPF,
presumably a still unnoticed flavivirus. This work opens new frontiers in searching for the trigger
of EPF, with the potential to advance translational research that aims for disease prevention and
treatment
