IgG4-related disease and B-cell malignancy due to an IKZF1 gain-of-function variant
Copyright © 2024. Published by Elsevier Inc..
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.
| Medienart: |
E-Artikel |
|---|
| Erscheinungsjahr: |
2024 |
|---|---|
| Erschienen: |
2024 |
| Enthalten in: |
Zur Gesamtaufnahme - year:2024 |
|---|---|
| Enthalten in: |
The Journal of allergy and clinical immunology - (2024) vom: 04. Apr. |
| Sprache: |
Englisch |
|---|
| Beteiligte Personen: |
García-Solís, Blanca [VerfasserIn] |
|---|
| Links: |
|---|
| Themen: |
Allergy |
|---|
| Anmerkungen: |
Date Revised 28.04.2024 published: Print-Electronic Citation Status Publisher |
|---|
| doi: |
10.1016/j.jaci.2024.03.018 |
|---|
| funding: |
|
|---|---|
| Förderinstitution / Projekttitel: |
|
| PPN (Katalog-ID): |
NLM370693515 |
|---|
| LEADER | 01000caa a22002652 4500 | ||
|---|---|---|---|
| 001 | NLM370693515 | ||
| 003 | DE-627 | ||
| 005 | 20240428232014.0 | ||
| 007 | cr uuu---uuuuu | ||
| 008 | 240406s2024 xx |||||o 00| ||eng c | ||
| 024 | 7 | |a 10.1016/j.jaci.2024.03.018 |2 doi | |
| 028 | 5 | 2 | |a pubmed24n1391.xml |
| 035 | |a (DE-627)NLM370693515 | ||
| 035 | |a (NLM)38579942 | ||
| 035 | |a (PII)S0091-6749(24)00330-0 | ||
| 040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
| 041 | |a eng | ||
| 100 | 1 | |a García-Solís, Blanca |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a IgG4-related disease and B-cell malignancy due to an IKZF1 gain-of-function variant |
| 264 | 1 | |c 2024 | |
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a ƒaComputermedien |b c |2 rdamedia | ||
| 338 | |a ƒa Online-Ressource |b cr |2 rdacarrier | ||
| 500 | |a Date Revised 28.04.2024 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status Publisher | ||
| 520 | |a Copyright © 2024. Published by Elsevier Inc. | ||
| 520 | |a 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 | ||
| 520 | |a OBJECTIVE: We studied 7 relatives with autoimmune/inflammatory and lymphoproliferative manifestations to identify the immunologic disturbances and the genetic cause of their disease | ||
| 520 | |a METHODS: We analyzed biopsy results and performed whole-exome sequencing and immunologic studies | ||
| 520 | |a 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 | ||
| 520 | |a 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 | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a IKAROS | |
| 650 | 4 | |a IKZF1 | |
| 650 | 4 | |a IgG4-related disease | |
| 650 | 4 | |a Primary immunodeficiency | |
| 650 | 4 | |a allergy | |
| 650 | 4 | |a gain-of-function | |
| 650 | 4 | |a inborn errors of immunity | |
| 650 | 4 | |a lymphoma | |
| 650 | 4 | |a multiple myeloma | |
| 700 | 1 | |a Tapia-Torres, María |e verfasserin |4 aut | |
| 700 | 1 | |a García-Soidán, Ana |e verfasserin |4 aut | |
| 700 | 1 | |a Hernández-Brito, Elisa |e verfasserin |4 aut | |
| 700 | 1 | |a Martínez-Saavedra, María Teresa |e verfasserin |4 aut | |
| 700 | 1 | |a Lorenzo-Salazar, José M |e verfasserin |4 aut | |
| 700 | 1 | |a García-Hernández, Sonia |e verfasserin |4 aut | |
| 700 | 1 | |a Van Den Rym, Ana |e verfasserin |4 aut | |
| 700 | 1 | |a Mayani, Karan |e verfasserin |4 aut | |
| 700 | 1 | |a Govantes-Rodríguez, José Vicente |e verfasserin |4 aut | |
| 700 | 1 | |a Gervais, Adrian |e verfasserin |4 aut | |
| 700 | 1 | |a Bastard, Paul |e verfasserin |4 aut | |
| 700 | 1 | |a Puel, Anne |e verfasserin |4 aut | |
| 700 | 1 | |a Casanova, Jean-Laurent |e verfasserin |4 aut | |
| 700 | 1 | |a Flores, Carlos |e verfasserin |4 aut | |
| 700 | 1 | |a Pérez de Diego, Rebeca |e verfasserin |4 aut | |
| 700 | 1 | |a Rodríguez-Gallego, Carlos |e verfasserin |4 aut | |
| 773 | 0 | 8 | |i Enthalten in |t The Journal of allergy and clinical immunology |d 1971 |g (2024) vom: 04. Apr. |w (DE-627)NLM000018449 |x 1097-6825 |7 nnns |
| 773 | 1 | 8 | |g year:2024 |g day:04 |g month:04 |
| 856 | 4 | 0 | |u http://dx.doi.org/10.1016/j.jaci.2024.03.018 |3 Volltext |
| 912 | |a GBV_USEFLAG_A | ||
| 912 | |a GBV_NLM | ||
| 951 | |a AR | ||
| 952 | |j 2024 |b 04 |c 04 | ||