Genetic Associations and Differential mRNA Expression Levels of Host Genes Suggest a Viral Trigger for Endemic Pemphigus Foliaceus

Abstract

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 associations 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 susceptibility (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.

Genetic Association and Differential RNA Expression of Histone (De)Acetylation-Related Genes in Pemphigus Foliaceus—A Possible Epigenetic Effect in the Autoimmune Response

“…Total RNA was extracted from CD4 + T lymphocytes isolated from peripheral blood samples from four patients (three females and one male), before the start of oral corticosteroid treatment, who constantly presented new skin lesions and whose mean age was 36 years, as well as from five controls (four females and one male) from EPF-endemic regions, whose mean age was 39.6 years. The selection process of CD4 + T cells has been previously described by Bumiller-Bini Hoch et al [18].…”

“…Genotype data were available from a previous study using microarray hybridization (CoreExome-24, version 1.1, Illumina, San Diego, CA, USA) [19]. The genomic positions of 144 genes, encoding HATs (12) and HDACs (18) and members of histone acetylation Figure 1. Flowchart of the study samples.…”

“…Genotype data were available from a previous study using microarray hybridization (CoreExome-24, version 1.1, Illumina, San Diego, CA, USA) [19]. The genomic positions of 144 genes, encoding HATs (12) and HDACs (18) and members of histone acetylation (59) and deacetylation (55) complexes, were identified, considering 1000 base pairs downstream and upstream from the sequence for the longest transcript, according to the human genome version GRC37/hg19 (NCBI gene) [20] (Table S1). A total of 2486 SNPs located in these gene sequences were extracted from DNA microarray data of EPF samples.…”

Viral Diseases in Dermatology

“…In this context, the editors of the journal Viruses decided to create a Special Issue, entitled “Viral Diseases in Dermatology”. It encompasses six articles that cover various aspects of viral skin diseases [ 1 , 2 , 3 , 4 , 5 , 6 ].…”

“…This Special Issue sheds light on various aspects of viral diseases in dermatology, including, but not limited to, pathophysiology and treatment. To be brief, the key published articles in this Special Issue addressed the following topics: skin herpes viruses and their manifestations as well as management [ 1 , 2 ]; viral triggers for endemic pemphigus foliaceus [ 3 ]; and the etiological characterization of skin warts [ 4 ]. Additionally, the mechanisms and management of skin lesions in COVID-19 were highlighted in two articles [ 5 , 6 ].…”