Cohen Barak, E. | Search bioRxiv

bioRxiv2025

TWEAK Signaling Drives the Transition from Psoriasis to Atopic Dermatitis-like Inflammation in Paradoxical Skin Reactions

Targeted biologics have significantly advanced the treatment of inflammatory skin diseases such as psoriasis; however, some patients paradoxically develop eczematous skin reactions during or after anti-TNF, IL-17, or IL-23 therapy. Although these paradoxical reactions resemble atopic dermatitis clinically and histologically, the molecular mechanisms that drive their development are not fully understood. Here, we generated high-resolution cellular and spatial maps of healthy skin, psoriasis, atopic dermatitis, and paradoxical reactions using single-cell RNA sequencing, spatial transcriptomics, immunohistochemistry, and in vitro assays. In paradoxical reactions, we identified a distinct transcriptional landscape characterized by myeloid and T-cell expansion and an altered keratinocyte phenotype shaped by TWEAK signaling. Mechanistically, we showed that TWEAK synergizes with IL-13 to drive the Th2/type I interferon-polarized epithelial program. Notably, anti-TNF therapy induced TWEAK gene expression in myeloid cells, suggesting a compensatory inflammatory circuit. Together, these findings identify the TWEAK-IL-13 axis as a central driver of paradoxical skin reactions and provide a mechanistic framework for how cytokine blockade may rewire cutaneous immune responses. One Sentence Summary The TWEAK-IL-13 signaling axis is a key driver of immune reprogramming underlying paradoxical skin reactions.

immunology↗

bioRxiv2020

Homozygote loss-of-function variants in the human COCH gene underlie hearing loss

Since 1999, the COCH gene encoding cochlin, has been linked to the autosomal dominant non-syndromic hearing loss, DFNA9, with or without vestibular abnormalities. The hearing impairment associated with the variants affecting gene function has been attributed to a dominant-negative effect. Mutant cochlin was seen to accumulate intracellularly, with the formation of aggregates both inside and outside the cells, in contrast to the wild-type cochlin that is normally secreted. While an additional recessive variant in the COCH gene (DFNB110) has recently been reported, the mechanism of the loss-of-function (LOF) effect of the COCH gene product remains unknown. In this study, we used COS7 cell lines to investigate the consequences of a novel homozygous frameshift variant on RNA transcription, and on cochlin translation. Our results indicate a LOF effect of the variant and a major decrease in cochlin translation. This data has a dramatic impact on the accuracy of genetic counseling for both heterozygote and homozygote carriers of LOF variants in COCH.

genetics↗