Mendelian Randomization and Experimental Validation Identify Key Immune Signatures in Bullous Pemphigoid

This study aims to investigate the potential causal relationships between genetically determined peripheral immunophenotypes and bullous pemphigoid (BP).

Leveraging publicly available genetic data from GWAS of 731 immunophenotypes and BP, we assessed potential associations between immunophenotypes and BP risk using Mendelian randomization (MR) and scRNA-seq of eQTLs analysis. The IVW method with FDR-adjusted q-values was the primary tool for estimating causal effects, supplemented by MR-Egger, weighted mode, weighted median, and simple mode for further investigation. LOO analysis, MR-PRESSO, and MR pleiotropy residual sum were used to ensure result robustness, exclude horizontal pleiotropy outliers, and assess heterogeneity. Single-cell sequencing data were used to explore transcriptional correlates of the MR-identified signatures, and flow cytometry was used to examine their changes in the circulation of BP-like mice.

Two-sample MR identified 52 potential immune-related phenotypes associated with BP, of which monocyte-related signatures remained significant after false discovery rate (FDR) correction. Monocytic myeloid-derived suppressor cells (M-MDSCs), CD16 (FcγRIII) on CD14-CD16 + monocytes, and CD62L on monocytes were identified as having a potential causal association with BP, (M-MDSCs: OR=1.69, 95% CI=1.35-2.13, q=0.002; CD16: OR=0.83, 95% CI =0.75-0.92, q=0.038; CD62L: OR=0.53, 95% CI=0.39-0.72, q=0.011). scRNA-seq revealed that CD16 and CD62L expression was significantly upregulated in neutrophils and dendritic cells of BP patients; furthermore, Functional enrichment analysis showed these immune cells are involved in pathogen recognition and inflammatory response. In BP-like mice, flow cytometry detected an increase in M-MDSCs and a decrease in CD16 (FcγRIII) on CD14-CD16+ monocytes in the circulation; CD62L was not assessed in the murine model.

These findings suggest that M-MDSC absolute count is positively associated with BP risk, while CD62L expression on monocytes and CD16 expression on CD14-CD16+ monocytes are negatively associated. These immune signatures are potential contributors to BP susceptibility that require further mechanistic validation. However, the BP case cohort included in the GWAS dataset had a limited sample size; future mechanistic studies are needed to elucidate their specific underlying functional mechanisms.