Natural Loss-of-Function Mutations in Qa2 and NCF1 Cause the Spread of Mannan-Induced Psoriasis

Area of Science:

• Immunology
• Genetics
• Dermatology

Background:

• Psoriasis predisposition is linked to the PSORS1 locus in the major histocompatibility complex I region.
• This locus encodes nonclassical molecules, including Qa2.
• Natural loss-of-function variants in Qa2 gene clusters are hypothesized to promote psoriasis.

Purpose of the Study:

• To investigate the role of Qa2 gene clusters and Ncf1 mutations in a mouse model of psoriasis.
• To explore the impact of Qa2 deficiency and reactive oxygen species (ROS) on psoriasis development.

Main Methods:

• Development of a mannan-induced psoriasis model in C57BL/6 mice.
• Utilizing mice with natural mutations in Qa2 gene clusters and the Ncf1 gene.
• Assessing the effects of Qa2 deficiency, Ncf1 mutations, and γδ T cell populations on psoriasis severity.

Main Results:

• Complete Qa2 deficiency led to IL-17‒producing γδ T cell and group 3 innate lymphoid cell expansion, causing ear psoriasis.
• A single Qa2 gene copy protected against psoriasis, but this protection was lost with Ncf1 mutation.
• Double defects in Qa2 and Ncf1 caused psoriasis spread from ears to nails, with γδ T cell deficiency reducing nail lesion severity.

Conclusions:

• Ncf1 mutations and Qa2 gene clusters are crucial in the pathogenesis and spread of psoriasis.
• These findings in mice provide insights into the genetic underpinnings of psoriasis, potentially linked to the PSORS1 locus.