Immunoglobulin G4-related disease and B-cell malignancy due to an IKZF1 gain-of-function variant.

in The Journal of allergy and clinical immunology by Blanca García-Solís, María Tapia-Torres, Ana García-Soidán, Elisa Hernández-Brito, María Teresa Martínez-Saavedra, José M Lorenzo Salazar, Sonia García-Hernández, Ana Van Den Rym, Karan Mayani Mayani, José Vicente Govantes-Rodríguez, Adrian Gervais, Paul Bastard, Anne Puel, Jean-Laurent Casanova, Carlos Flores, Rebeca Pérez de Diego, Carlos Rodríguez-Gallego

TLDR

  • The study found that certain genetic changes in a protein called IKZF1 can cause autoimmune/inflammatory diseases, IgG4-RD, and B-cell malignancies. The study also found that treatments that target the overactivity of this protein may be helpful for patients with these conditions.

Abstract

Monoallelic loss-of-function IKZF1 (IKAROS) variants cause B-cell deficiency or combined immunodeficiency, whereas monoallelic gain-of-function IKZF1 variants have recently been reported to cause hypergammaglobulinemia, abnormal plasma cell differentiation, autoimmune and allergic manifestations, and infections. We studied seven relatives with autoimmune/inflammatory diseases and lymphoproliferative diseases. We analysed biopsy results and performed whole-exome sequencing and immunological studies. Disease onset occurred at a mean age of 25.2 years (range: 10-64, years). Six patients suffered from autoimmune/inflammatory diseases, four had confirmed immunoglobulin G4-related disease (IgG4-RD), and five developed B-cell malignancies: lymphoma in four and multiple myeloma in the remaining patient. Patients without immunosuppression were not particularly prone to infectious diseases. Three patients suffered from life-threatening COVID-19 pneumonia, one of whom had autoantibodies neutralizing interferon (IFN)-α. The recently described IKZF1 gain-of-function p.R183H variant was found in the five affected relatives tested and in a six-year-old asymptomatic girl. Immunological analysis revealed hypergammaglobulinemia and high frequencies of certain lymphocyte subsets (exhausted B cells, effector memory CD4 T cells, Tand CD28CD57CD4+ 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 three patients. Heterozygosity for gain-of-function IKZF1 variants underlies autoimmunity/inflammatory diseases, IgG4-RD and B-cell malignancies, the onset of which may occur in adulthood. Clinical and immunological data are similar to those for patients with unexplained IgG4-RD. Patients may therefore benefit from treatments inhibiting pathways displaying IKAROS-mediated overactivity.

Overview

  • The study investigates the relationship between monoallelic loss-of-function and gain-of-function IKZF1 variants and their impact on autoimmune/inflammatory diseases, IgG4-related disease (IgG4-RD), and B-cell malignancies. The study analyzed biopsy results and performed whole-exome sequencing and immunological studies on seven relatives with these conditions. The mean age of disease onset was 25.2 years, and six patients suffered from autoimmune/inflammatory diseases, four had confirmed IgG4-RD, and five developed B-cell malignancies. The study found that heterozygosity for gain-of-function IKZF1 variants underlies autoimmunity/inflammatory diseases, IgG4-RD, and B-cell malignancies, and that clinical and immunological data are similar to those for patients with unexplained IgG4-RD. The study suggests that treatments inhibiting pathways displaying IKAROS-mediated overactivity may be beneficial for patients with these conditions.

Comparative Analysis & Findings

  • The study compared the outcomes observed under different experimental conditions or interventions, specifically the relationship between monoallelic loss-of-function and gain-of-function IKZF1 variants and their impact on autoimmune/inflammatory diseases, IgG4-RD, and B-cell malignancies. The study found that heterozygosity for gain-of-function IKZF1 variants underlies these conditions and that clinical and immunological data are similar to those for patients with unexplained IgG4-RD. The study also found that treatments inhibiting pathways displaying IKAROS-mediated overactivity may be beneficial for patients with these conditions.

Implications and Future Directions

  • The study's findings have significant implications for the field of research and clinical practice, as they suggest that treatments inhibiting pathways displaying IKAROS-mediated overactivity may be beneficial for patients with autoimmune/inflammatory diseases, IgG4-RD, and B-cell malignancies. The study also identifies limitations, such as the small sample size, and suggests future research directions, such as larger studies to validate the findings and investigate the underlying mechanisms of IKZF1-mediated overactivity.
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