Combined immunodeficiency with autoimmunity caused by a homozygous missense mutation in inhibitor of nuclear factor κB kinase alpha (IKKα)

• Published in: Science immunology 2021-09, Vol.6 (63), p.eabf6723-eabf6723
• Main Authors: Bainter, Wayne, Lougaris, Vassilios, Wallace, Jacqueline G, Badran, Yousef, Hoyos-Bachiloglu, Rodrigo, Peters, Zachary, Wilkie, Hazel, Das, Mrinmoy, Janssen, Erin, Beano, Abdallah, Farhat, Khaoula Ben, Kam, Christy, Bercich, Luisa, Incardona, Paolo, Villanacci, Vincenzo, Bondioni, Maria Pia, Meini, Antonella, Baronio, Manuela, Abarzua, Phammela, Parolini, Silvia, Tabellini, Giovanna, Maio, Stefano, Schmidt, Birgitta, Goldsmith, Jeffrey D, Murphy, George, Hollander, Georg, Plebani, Alessandro, Chou, Janet, Geha, Raif S
• Format: Article
• Language: English
• Subjects: Animals; Autoimmunity - immunology; HEK293 Cells; Humans; I-kappa B Kinase - genetics; I-kappa B Kinase - immunology; Mice; Mice, Inbred C57BL; Mice, Transgenic; Mutation, Missense - genetics; Mutation, Missense - immunology
• ISSN: 2470-9468; 2470-9468
• DOI: 10.1126/sciimmunol.abf6723

Inhibitor of nuclear factor kappa B kinase alpha (IKKα) is critical for p100/NF-κB2 phosphorylation and processing into p52 and activation of the noncanonical NF-κB pathway. A patient with recurrent infections, skeletal abnormalities, absent secondary lymphoid structures, reduced B cell numbers, hypogammaglobulinemia, and lymphocytic infiltration of intestine and liver was found to have a homozygous p.Y580C mutation in the helix-loop-helix domain of IKKα. The mutation preserves IKKα kinase activity but abolishes the interaction of IKKα with its activator NF-κB–inducing kinase and impairs lymphotoxin-β–driven p100/NF-κB2 processing and expression. Homozygous IKKα mutant mice phenocopy the patient findings; lack marginal zone B cells, germinal centers, and antigen-specific T cell response to cutaneous immunization; have impaired expression; and are susceptible to cutaneous infection. In addition, these mice demonstrate a severe reduction in medullary thymic epithelial cells, impaired thymocyte negative selection, a restricted TCRVβ repertoire, a selective expansion of potentially autoreactive T cell clones, a decreased frequency of regulatory T cells, and infiltration of liver, pancreas, and lung by activated T cells coinciding with organ damage. Hence, this study identifies IKKα deficiency as a previously undescribed cause of primary immunodeficiency with associated autoimmunity.