作者
Wayne Bainter,Vassilios Lougaris,Jacqueline G. Wallace,Yousef R. Badran,Rodrigo Hoyos-Bachiloglu,Zachary Peters,Hazel Wilkie,Mrinmoy Das,Erin Janssen,Abdallah Beano,Khaoula Ben Farhat,Christy Kam,Luisa Bercich,Paolo Incardona,Vincenzo Villanacci,Maria Pia Bondioni,Antonella Meini,Manuela Baronio,Phammela Abarzua,Silvia Parolini,Giovanna Tabellini,Stefano Maio,Birgitta Schmidt,Jeff Goldsmith,George F. Murphy,Georg A. Holländer,Alessandro Plebani,Janet Chou,Raif S. Geha
摘要
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 VCAM1 expression. Homozygous IKKαY580C/Y580C mutant mice phenocopy the patient findings; lack marginal zone B cells, germinal centers, and antigen-specific T cell response to cutaneous immunization; have impaired Il17a expression; and are susceptible to cutaneous Staphylococcus aureus 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.