Inborn Errors of Immunity and Autoimmune Disease

Area of Science:

• Immunology
• Genetics
• Pediatrics

Background:

• Autoimmunity is common, complicating the identification of rare genetic causes within primary immunodeficiencies.
• Primary immune regulatory disorders represent a specific subgroup of inborn errors of immunity where autoimmunity is a key feature.

Approach:

• This review compares genetic factors in polygenic and monogenic autoimmunity.
• It explores molecular mechanisms, phenotypes, and inheritance patterns of autoimmunity in primary immune regulatory disorders.
• A new framework aids in identifying rare monogenic autoimmunity in children, guiding genomic screening.

Key Points:

• Gain-of-function and non-germline somatic mutations are increasingly recognized in monogenic autoimmunity.
• Clinical and immunological features can suggest single-gene disorders, aiding diagnostic decisions.
• Autoimmunity can mimic other primary immunodeficiencies, including common variable immunodeficiency.

Conclusions:

• Distinguishing rare monogenic autoimmunity from common polygenic forms is essential for accurate diagnosis and management.
• Genomic screening frameworks can improve the identification of primary immune regulatory disorders.
• Understanding the genetic basis of autoimmunity is critical for advancing personalized medicine in immunodeficiency.