A kindred with mutant IKAROS and autoimmunity

• Published in: Journal of allergy and clinical immunology Vol. 142; no. 2; pp. 699 - 702.e12
• Main Authors: Van Nieuwenhove, Erika, Garcia-Perez, Josselyn E., Helsen, Christine, Rodriguez, Princess D., van Schouwenburg, Pauline A., Dooley, James, Schlenner, Susan, van der Burg, Mirjam, Verhoeyen, Els, Gijsbers, Rik, Frietze, Seth, Schjerven, Hilde, Meyts, Isabelle, Claessens, Frank, Humblet-Baron, Stephanie, Wouters, Carine, Liston, Adrian
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.08.2018; Elsevier Limited; Elsevier
• Subjects: Age; Animals; Antibodies, Antinuclear - metabolism; Anticoagulants; Autoimmunity; Autoimmunity - genetics; B-Lymphocytes - pathology; Bacteriology; Cell Differentiation - genetics; Child; Deoxyribonucleic acid; DNA; Female; Gene expression; Gene Frequency; Genetic testing; Hepatitis; Humans; Ikaros protein; Ikaros Transcription Factor - genetics; Immunoglobulins; Immunology; Life Sciences; Lupus; Lupus Coagulation Inhibitor - metabolism; Lupus Erythematosus, Systemic - diagnosis; Lupus Erythematosus, Systemic - genetics; Lymphocytes; Mice; Microbiology and Parasitology; Mutation; Mutation - genetics; NIH 3T3 Cells; Pedigree; Polymorphism, Genetic; Sialic Acid Binding Ig-like Lectin 2 - metabolism; Systemic lupus erythematosus; Transgenic animals; Virology
• ISSN: 0091-6749; 1097-6825
• DOI: 10.1016/j.jaci.2018.04.008

IKAROS (encoded by IKZF1) is an important hematopoietic transcription factor critical for early B cell differentiation, with major defects known to lead to low B cell numbers and hypogammaglobulinemia. More perplexing is the link between IKZF1 variants and autoimmunity, including polymorphisms associated with susceptibility to SLE, and recently, rare variants driving monogenic autoimmunity. We identified a novel p.L188V mutation in IKZF1 in the index patient and her father and found this mutation to lead to loss of DNA binding. Peripheral B cells lacking a full complement of IKAROS function show upregulation of molecules accentuating B cell activation, while CD22, a key negative feedback circuit, is suppressed. The resulting hyperresponsiveness of peripheral B cells, in combination with elevated follicular helper T cell (Tfh) numbers, provides a putative mechanistic explanation for the association of IKZF1 variants with the emergence of autoimmune manifestations in this kindred. Mutation in IKZF1 , a hematopoietic transcription factor, gives rise to autoimmunity in a novel kindred. Our study identifies a link between mutant IKAROS and decreased CD22 expression driving the hyperresponsive B cell phenotype.