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

IκB激酶 生发中心 自身免疫 免疫学 生物 突变 癌症研究 常见可变免疫缺陷 B细胞 免疫缺陷 激酶 错义突变 突变体
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
出处
期刊:Science immunology [American Association for the Advancement of Science (AAAS)]
卷期号:6 (63) 被引量:2
标识
DOI:10.1126/sciimmunol.abf6723
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.
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