Loss-of-function mutation in <i>IKZF2</i> leads to immunodeficiency with dysregulated germinal center reactions and reduction of MAIT cells
Iivo Hetemäki, Meri Kaustio, Matias Kinnunen, Nelli Heikkilä, Salla Keskitalo, Kirsten Nowlan, Simo Miettinen, Joona Sarkkinen, Virpi Glumoff, Noora Andersson, K Kettunen, Reetta Vanhanen, Katariina Nurmi, Kari K. Eklund, Johannes Dunkel, Mikko I. Mäyränpää, Heinrich Schlums, T. Petteri Arstila, Kai Kisand, Yenan T. Bryceson, Pärt Peterson, Ulla Otava, Jaana Syrjänen, Janna Saarela, Markku Varjosalo, Eliisa Kekäläinen
Abstract
variant presented with a combined immunodeficiency phenotype characterized by recurrent upper respiratory infections, thrush and mucosal ulcers, and chronic lymphadenopathy. With extensive immunophenotyping, functional assays, and transcriptional analysis, we show that reduced Helios expression was associated with chronic T cell activation and increased production of proinflammatory cytokines both in effector and regulatory T cells. Lymph node histology from patients indicated dysregulated germinal center reactions. Moreover, affected individuals displayed a profound reduction in circulating MAIT cell numbers. In summary, we show that this previously undescribed loss-of-function variant in Helios leads to an immunodeficiency with signs of immune overactivation.