Immune cells influence chronic spontaneous urticaria by inflammatory proteins: Mendelian randomization and...

Chronic spontaneous urticaria (CSU) is a histamine-mediated inflammatory skin disease, but key inflammatory proteins remain undefined.

We investigated the causal interrelations and mediators among immune cell signatures, circulating inflammatory proteins, and CSU by Mendelian randomization (MR).

Bidirectional MR and mediation MR analysis were used to identify causal relationships and potential mediators among immune cell signatures, circulating inflammatory proteins, and CSU. The key inflammatory protein was selected to detect its expression levels by real-time reverse transcription-quantitative PCR in clinical samples. Clinical data analysis explored its association with clinical features of CSU. Gene datasets were extracted from the Gene Expression Omnibus (GEO; www.ncbi.nlm.nih.gov/geo) to identify differentially expressed genes related to the key inflammatory proteins. Integrated bioinformatic analysis, including immune infiltration analysis, and functional enrichment analysis, explored the potential mechanism of the key inflammatory proteins in CSU.

IL-10 was protective for CSU, while IL-10RB, SULT1A1, and TGF-α were risk factors. IL-10 partly mediated the effect of CD20⁺ B cells on CSU. IL-10 was elevated in skin of CSU patients but unchanged in blood. CSU patients with high IL-10 levels had higher Urticaria Activity Score 7 scores and elevated IL-17A, TNF-α, and IFN-γ. IL-10 participated in "positive regulation of immune effector processes," "cell activation in immune response," and other immune-related pathways. IL-10 correlated positively with resting mast cells and negatively with naive B cells.

IL-10, IL-10RB, SULT1A1, and TGF-α causally affected CSU. IL-10 exerts protective effects and is linked to inflammatory and immune dysregulation.