Primary immunodeficiencies suggest redundancy within the human immune system

Area of Science:

• Immunology
• Genetics
• Evolutionary Biology

Background:

• The human immune system is complex, shaped by pathogen evolution, with over 1854 genes involved in immune responses.
• Understanding immune system redundancy and robustness is crucial for diagnosing and treating primary immunodeficiencies (PIDs).

Purpose of the Study:

• To investigate the redundancy of innate immunity pathways by examining monogenic PIDs associated with infections.
• To assess the implications of immune system dispensability for identifying new PIDs and understanding immunotherapy risks.

Main Methods:

• Analysis of mutation frequencies in innate versus adaptive immunity genes in PIDs.
• Review of studies on loss-of-function mutations in pattern-recognition receptor (PRR) pathways.
• Examination of the dispensability of constitutive immune products and innate immune cells.

Main Results:

• Mutations in innate immunity genes are significantly less frequent in PIDs compared to adaptive immunity genes.
• Loss-of-function mutations in PRR pathways rarely lead to infection susceptibility, indicating functional redundancy.
• Certain immune components like secretory IgA and specific innate immune cells are not essential for viability.

Conclusions:

• Innate immunity pathways, especially PRR pathways, exhibit substantial redundancy.
• This redundancy challenges traditional views of immune system essentiality and has implications for PID diagnosis.
• Findings inform the identification of novel PIDs and the assessment of infection risks in targeted immunotherapies.