Human germline biallelic loss-of-function OSMR variants cause severe allergic disease

Area of Science:

• Immunology
• Genetics
• Dermatology

Background:

• Oncostatin M receptor beta (OSMRβ) is a cell surface receptor crucial for human immunity.
• It belongs to the IL-6 superfamily and binds OSM and IL-31.

Purpose of the Study:

• To investigate the role of OSMR in severe allergic diseases.
• To identify genetic variants in OSMR associated with specific clinical phenotypes.

Main Methods:

• Identified probands with biallelic damaging variants in the OSMR gene.
• Assessed OSMRβ expression on cell surfaces.
• Measured OSM-mediated STAT activation (STAT1, STAT3, STAT5).
• Analyzed transcriptional changes in primary dermal fibroblasts.
• Utilized lentiviral transduction to rescue WT-OSMR function.

Main Results:

• Patients presented with severe, early-onset atopic dermatitis, eosinophilia, and elevated IgE.
• Patient-derived OSMRβ variants showed impaired cell surface expression.
• OSMR variants significantly reduced OSM-mediated STAT activation.
• Defective OSMR function led to loss of interferon and inflammatory signatures in fibroblasts.
• Lentiviral transduction of WT-OSMR rescued these cellular defects.

Conclusions:

• Human germline biallelic loss-of-function OSMR variants cause severe allergic disease.
• This discovery defines a novel primary atopic disorder.
• Facilitates recognition of additional affected individuals and disease characterization.