In cis "benign" SOCS1 variants linked to enhanced interferon signaling and autoimmunity

Area of Science:

• Immunology
• Genetics
• Molecular Biology

Background:

• Autoimmune diseases like SLE, immune thrombocytopenia, and autoimmune thyroiditis often have complex genetic underpinnings.
• Suppressor of cytokine signaling 1 (SOCS1) plays a crucial role in regulating cytokine signaling pathways, particularly the JAK-STAT pathway.

Purpose of the Study:

• To investigate the genetic basis of familial autoimmune diseases.
• To characterize the functional impact of novel SOCS1 variants on immune signaling.

Main Methods:

• Whole exome sequencing (WES) to identify genetic variants.
• Functional assays including flow cytometry, immunoblotting, immunoprecipitation, and luciferase reporter assays.
• Gene expression profiling (bulk RNA sequencing) and cytokine analysis (proximity extension assay).

Main Results:

• Two novel, maternally inherited SOCS1 variants (p.Pro50Leu and p.Ala76Gly) were identified in siblings with early-onset SLE and immune thrombocytopenia.
• These variants, individually benign, impaired SOCS1 binding to JAK1 and reduced inhibition of type I interferon (IFN-I) signaling when present together (in cis).
• Increased expression of IFN-I-inducible genes and heightened sensitivity to IFN-I were observed in affected individuals, indicating defective IFN-I regulation.

Conclusions:

• A combination of seemingly benign genetic variants can have significant detrimental effects on immune regulation.
• SOCS1's fine-tuning of IFN-I signaling is critical for preventing autoimmunity.
• This study provides insights into the genetic etiology of complex autoimmune disorders.