IgG4-related disease and B-cell malignancy due to an IKZF1 gain-of-function variant - 26/04/24
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Graphical abstract |
Abstract |
Background |
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.
Objective |
We studied 7 relatives with autoimmune/inflammatory and lymphoproliferative manifestations to identify the immunologic disturbances and the genetic cause of their disease.
Methods |
We analyzed biopsy results and performed whole-exome sequencing and immunologic studies.
Results |
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.
Conclusions |
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.
Le texte complet de cet article est disponible en PDF.Key words : Primary immunodeficiency, inborn errors of immunity, IKAROS, IKZF1, gain-of-function, IgG4-related disease, lymphoma, multiple myeloma, allergy
Abbreviations used : COVID-19, CTL, GOF, IEI, IgG4-RD, IKZF1/IKZF3, ITP, MM, PC, TEM, TEMRA, Tfh
Plan
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