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

Area of Science:

• Immunology
• Genetics

Background:

• Bullous pemphigoid (BP) is an autoimmune blistering disease with complex etiology.
• Understanding the genetic underpinnings of peripheral immunophenotypes in BP is crucial for identifying disease mechanisms.

Purpose of the Study:

• To investigate potential causal relationships between genetically determined peripheral immunophenotypes and the risk of developing bullous pemphigoid (BP).
• To identify specific immune cell signatures associated with BP susceptibility using genetic and transcriptomic data.

Main Methods:

• Utilized two-sample Mendelian randomization (MR) with genome-wide association study (GWAS) data from 731 immunophenotypes and BP.
• Employed single-cell RNA sequencing (scRNA-seq) of expression quantitative trait loci (eQTLs) and flow cytometry in BP-like mice for validation.
• Applied various MR methods (IVW, MR-Egger, etc.) and sensitivity analyses (LOO, MR-PRESSO) to ensure robustness.

Main Results:

• Identified 52 potential immune-related phenotypes associated with BP, with monocyte-related signatures remaining significant after FDR correction.
• Found potential causal associations for monocytic myeloid-derived suppressor cells (M-MDSCs) (OR=1.69), CD16 expression on monocytes (OR=0.83), and CD62L expression on monocytes (OR=0.53).
• scRNA-seq showed CD16 and CD62L upregulation in neutrophils and dendritic cells of BP patients; flow cytometry revealed increased M-MDSCs and decreased CD16 in BP-like mice.

Conclusions:

• M-MDSC absolute count is positively associated with BP risk, while CD62L and CD16 expression on specific monocytes are negatively associated.
• These identified immune signatures may contribute to BP susceptibility and warrant further mechanistic investigation.
• Limited sample size in the GWAS dataset necessitates future studies to elucidate the precise functional mechanisms involved.