Biallelic loss-of-function mutation in NIK causes a primary immunodeficiency with multifaceted aberrant lymphoid...

Area of Science:

• Immunology
• Genetics
• Molecular Biology

Background:

• Primary immunodeficiency disorders (PIDs) are crucial for identifying genes involved in human immunity.
• Recurrent infections suggest underlying genetic defects in immune system regulation.

Purpose of the Study:

• To identify the genetic cause of recurrent bacterial, viral, and Cryptosporidium infections in patients.
• To elucidate the role of the identified gene, MAP3K14 (NIK), in human immune responses.

Main Methods:

• Genetic analysis to identify mutations in patients with PIDs.
• In silico prediction and functional assays to assess kinase activity of mutant NIK.
• Flow cytometry and immunological assays to analyze immune cell populations and functions (B cells, T cells, NK cells).

Main Results:

• A biallelic mutation in the MAP3K14 gene encoding NIK was identified.
• Loss of NIK kinase activity resulted in defective canonical and non-canonical NF-κB signaling.
• Patients exhibited B-cell lymphopenia, reduced memory B cells, hypogammaglobulinemia, impaired ICOSL expression, perturbed T cells, and decreased NK cell function.

Conclusions:

• NIK plays a non-redundant role in human immune responses.
• Loss-of-function mutations in NIK cause multiple defects in lymphoid immunity.
• Understanding NIK's function is critical for diagnosing and potentially treating specific PIDs.