IgG4-related disease and B-cell malignancy due to an IKZF1 gain-of-function variant - 26/04/24

Doi : 10.1016/j.jaci.2024.03.018

Blanca García-Solís, PhD ^a,^b,^c,^{^{∗
These authors contributed equally to this work.}}, María Tapia-Torres, MD ^d,^{^{∗
These authors contributed equally to this work.}}, Ana García-Soidán, MD ^e, Elisa Hernández-Brito, PhD ^e, María Teresa Martínez-Saavedra, MSc ^e, José M. Lorenzo-Salazar, MSc ^f, Sonia García-Hernández, MD ^g, Ana Van Den Rym, PhD ^a,^b,^c, Karan Mayani, MD ^d, José Vicente Govantes-Rodríguez, MD ^d, Adrian Gervais, MSc ^h,ⁱ, Paul Bastard, MD, PhD ^h,^i,^j,^k, Anne Puel, PhD ^h,^i,^j, Jean-Laurent Casanova, MD, PhD ^h,^i,^j,^l,^m, Carlos Flores, PhD ^f,^n,^o,^p, Rebeca Pérez de Diego, PhD ^a,^b,^c,^⁎ , Carlos Rodríguez-Gallego, PhD ^e,^p,^q,^⁎
^a Laboratory of Immunogenetics of Human Diseases, IdiPAZ Institute for Health Research, La Paz University Hospital, Madrid, Spain
^b Innate Immunity Group, IdiPAZ Institute for Health Research, La Paz University Hospital, Madrid, Spain
^c Interdepartmental Group of Immunodeficiencies, Madrid, Spain
^d Department of Hematology, La Palma University Hospital, Breña Alta, Spain
^e Department of Immunology, University Hospital of Gran Canaria Dr Negrin, Las Palmas de Gran Canaria, Spain
^f Genomics Division, Instituto Tecnológico y de Energías Renovables (ITER), Santa Cruz de Tenerife, Spain
^g Department of Pathological Anatomy, University Hospital of Canarias, La Laguna, Spain
^h Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Necker Hospital for Sick Children, Paris, France
ⁱ Paris Cité University, Imagine Institute, Paris, France
^j St Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY
^k Hematology-Immunology and Rheumatology Unit, Necker Hospital for Sick Children, Assistance Publique-Hôpitaux de Paris (AP-HP), Paris, France
^l Howard Hughes Medical Institute, New York, NY
^m Department of Pediatrics, Necker Hospital for Sick Children, Assistance Publique-Hôpitaux de Paris (AP-HP), Paris, France
ⁿ Research Unit, Hospital Universitario Ntra. Sra. de Candelaria, Santa Cruz de Tenerife, Spain
^o CIBER de Enfermedades Respiratorias (CIBERES), Instituto de Salud Carlos III, Madrid, Spain
^p Department of Clinical Sciences, University Fernando Pessoa Canarias, Las Palmas de Gran Canaria, Spain
^q Department of Medical and Surgical Sciences, School of Medicine, University of Las Palmas de Gran Canaria, Las Palmas de Gran Canaria, Spain

^∗Corresponding author: Carlos Rodríguez-Gallego, PhD, Department of Immunology, University Hospital of Gran Canaria Dr Negrin, C/Barranco de la ballena s/n, Las Palmas de Gran Canaria 35010, Spain.Department of ImmunologyUniversity Hospital of Gran Canaria Dr NegrinC/Barranco de la ballena s/nLas Palmas de Gran Canaria35010Spain^∗Rebeca Pérez de Diego, PhD, Laboratory of Immunogenetics of Human Diseases, IdiPAZ Institute for Health Research, La Paz University Hospital, Paseo de la Castellana 261, Madrid 28046, Spain.Laboratory of Immunogenetics of Human DiseasesIdiPAZ Institute for Health ResearchLa Paz University HospitalPaseo de la Castellana 261Madrid28046Spain

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Graphical abstract

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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, T_H2, 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.

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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, T_EM, T_EMRA, Tfh