A kindred with Mutant IKAROS and autoimmunity

Erika Van Nieuwenhove, Josselyn E. Garcia-Perez, Christine Helsen, Princess D. Rodriguez, Pauline A. van Schouwenburg, James Dooley, Susan Schlenner, Mirjam van der Burg, Els Verhoeyen, Rik Gijsbers, Seth Frietze, Hilde Schjerven, Isabelle Meyts, Frank Claessens, Stephanie Humblet-Baron, Carine Wouters, Adrian Liston
The journal of Allergy and Clinical Immunology

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.

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