%0 Journal Article
%T IgG4-related disease and B-cell malignancy due to an IKZF1 gain-of-function variant.
%A García-Solís B
%A Tapia-Torres M
%A García-Soidán A
%A Hernández-Brito E
%A Martínez-Saavedra MT
%A Lorenzo-Salazar JM
%A García-Hernández S
%A Van Den Rym A
%A Mayani K
%A Govantes-Rodríguez JV
%A Gervais A
%A Bastard P
%A Puel A
%A Casanova JL
%A Flores C
%A Pérez de Diego R
%A Rodríguez-Gallego C
%J J Allergy Clin Immunol
%V 0
%N 0
%D 2024 Apr 4
%M 38579942
%F 14.29
%R 10.1016/j.jaci.2024.03.018
%X <B>BACKGROUND: </B>Monoallelic loss-of-function IKZF1 (IKAROS) variants cause B-cell deficiency or combined immunodeficiency, whereas monoallelic gain-of-function (GOF) IKZF1 variants have recently been reported to cause hypergammaglobulinemia, abnormal plasma cell differentiation, autoimmune and allergic manifestations, and infections.<BR><B>OBJECTIVE: </B>We studied 7 relatives with autoimmune/inflammatory and lymphoproliferative manifestations to identify the immunologic disturbances and the genetic cause of their disease.<BR><B>METHODS: </B>We analyzed biopsy results and performed whole-exome sequencing and immunologic studies.<BR><B>RESULTS: </B>Disease onset occurred at a mean age of 25.2 years (range, 10-64, years). Six patients suffered from autoimmune/inflammatory diseases, 4 had confirmed IG4-related disease (IgG4-RD), and 5 developed B-cell malignancies: lymphoma in 4 and multiple myeloma in the remaining patient. Patients without immunosuppression were not particularly prone to infectious diseases. Three patients suffered from life-threatening coronavirus disease 2019 pneumonia, of whom 1 had autoantibodies neutralizing IFN-α. The recently described IKZF1 GOF p.R183H variant was found in the 5 affected relatives tested and in a 6-year-old asymptomatic girl. Immunologic analysis revealed hypergammaglobulinemia and high frequencies of certain lymphocyte subsets (exhausted B cells, effector memory CD4 T cells, effector memory CD4 T cells that have regained surface expression of CD45RA and CD28-CD57+ CD4+ and CD8+ T cells, TH2, and Tfh2 cells) attesting to immune dysregulation. Partial clinical responses to rituximab and corticosteroids were observed, and treatment with lenalidomide, which promotes IKAROS degradation, was initiated in 3 patients.<BR><B>CONCLUSIONS: </B>Heterozygosity for GOF IKZF1 variants underlies autoimmunity/inflammatory diseases, IgG4-RD, and B-cell malignancies, the onset of which may occur in adulthood. Clinical and immunologic data are similar to those for patients with unexplained IgG4-RD. Patients may therefore benefit from treatments inhibiting pathways displaying IKAROS-mediated overactivity.