Long-lived IgE plasma cells persist in secondary lymphoid tissues using a navitoclax-sensitive survival program

Zhoujie Ding; Wade-Vallance Adam; Mark R Downling; Alexandra R Dvorscek; Catherine Pitt; Jesse Mulder; Kristy  O'Donnell; Craig McKenzie; Alexandra Bosak  Karaviotis; Julia Scrofani; Olaf Perdijk; Danika L Hill; Isaak Quast; David M Tarlinton; Christopher D C  Allen; Marcus J Robinson

doi:10.1016/j.immuni.2025.10.006

Long-lived IgE plasma cells persist in secondary lymphoid tissues using a navitoclax-sensitive survival program

Zhoujie Ding
, Wade-Vallance Adam
, Mark R Downling
, Alexandra R Dvorscek
, Catherine Pitt
, Jesse Mulder
, Kristy O'Donnell
, Craig McKenzie
, Alexandra Bosak Karaviotis
, Julia Scrofani
, Olaf Perdijk
, Danika L Hill
, Isaak Quast
, David M Tarlinton
, Christopher D C Allen
, Marcus J Robinson^*

^*Corresponding author for this work

Pharmacology

Department of Immunology, Monash University, Melbourne, VIC, Australia.
Cardiovascular Research Institute, University of California, San Francisco, San Francisco, CA, USA; Sandler Asthma Basic Research Center, University of California, San Francisco, San Francisco, CA, USA.
Department of Clinical Haematology, Royal Melbourne Hospital and Peter MacCallum Cancer Centre, Parkville, VIC, Australia; Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, VIC, Australia
Department of Immunology, Monash University, Melbourne, VIC, Australia
Monash University
Cardiovascular Research Institute, University of California, San Francisco, San Francisco, CA, USA; Sandler Asthma Basic Research Center, University of California, San Francisco, San Francisco, CA, USA; Department of Anatomy, University of California, San Francisco, San Francisco, CA, USA

Research output: Contribution to journal › Article › Academic › peer-review

Abstract

Long-term allergies can exhibit persistent concentrations of circulating immunoglobulin E (IgE). Here, we examined the lifespan of IgE antibody-secreting cells (ASCs) to determine whether the IgE that sustains allergies receives contributions from long-lived cells or relies more heavily on constant ASC production. In mouse aeroallergy, IgE ASCs localized to the lungs, mediastinal lymph nodes, spleen, and bone marrow (BM). IgE ASC production continued for months after allergen exposure ceased. We identified long-lived IgE ASCs residing predominantly outside the BM, with a half-life exceeding 49 days; in contrast, most IgE ASCs had a 3-day half-life. Long-lived IgE ASCs matured phenotypically, became quiescent, retained their surface B cell receptors, but showed low expression of the BM homing receptor CXCR4. They were hierarchically more reliant on the navitoclax-sensitive anti-apoptotic molecules BCL2, BCLXL, and BCLW than MCL1. Thus, continual production of short-lived IgE ASCs and retention of long-lived IgE ASCs outside the BM together drive IgE persistence, perpetuating allergic disease.

Original language	English
Pages (from-to)	2704-2716.e4
Journal	Immunity
Volume	58
Issue number	11
DOIs	https://doi.org/10.1016/j.immuni.2025.10.006
Publication status	Published - 11 Nov 2025

Bibliographical note

Publisher Copyright:
© 2025 The Authors

Funding

We thank Rory Markovic and the Monash Animal Research Platform for support with mouse welfare. We thank Melanie Le Page and the ARAFlowcore for flow cytometry support. We thank Philip D. Hodgkin for helpful discussions regarding the modeling. We thank Giovanna Pomilio and Andrew Wei for providing reagents for pilot studies on survival protein reliance. We thank members of the Tarlinton laboratory for input during project development. This work was supported by Australian National Health and Medical Research Council (NHMRC) grants to M.J.R. (APP1185294 and APP2028727) and D.M.T. (APP1175411) ; Monash University FLP fellowships to M.J.R. and Z.D.; a Doctoral Foreign Study Award from the Canadian Institute of Health Research (DFD-170769) to A.K.W.-V.; and the National Heart, Lung, and Blood Institute (DP2HL117752) and National Institute of Allergy and Infectious Diseases (R21AI178523, R21AI178524, and R01AI130470) of the National Institutes of Health grants to C.D.C.A. I.Q. was supported by an NHMRC Peter Doherty Fellowship (APP1145136) . C.D.C.A. also received funding from the Program for Breakthrough Biomedical Research, which is partially funded by the Sandler Foundation. The graphical abstract was created in Biorender (Ding Z., 2025; https://BioRender.com /iwznfod) .

Funders	Funder number
Australian National Health and Medical Research Council (NHMRC)	APP1185294, APP2028727, APP1175411
Monash University FLP fellowships
Canadian Institute of Health Research	DFD-170769
National Heart, Lung, and Blood Institute	DP2HL117752
National Institute of Allergy and Infectious Diseases	R21AI178523, R21AI178524, R01AI130470
National Institutes of Health
NHMRC Peter Doherty Fellowship	APP1145136
Program for Breakthrough Biomedical Research - Sandler Foundation

Keywords

ABT-263
BCL
BCL2
IgE
MCL1
allergy
antibody-secreting cell
apoptosis
plasma cell
plasmablast

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Cite this

Ding, Z., Adam, W.-V., Downling, M. R., Dvorscek, A. R., Pitt, C., Mulder, J., O'Donnell, K., McKenzie, C., Karaviotis, A. B., Scrofani, J., Perdijk, O., Hill, D. L., Quast , I., Tarlinton, D. M., Allen, C. D. C., & Robinson, M. J. (2025). Long-lived IgE plasma cells persist in secondary lymphoid tissues using a navitoclax-sensitive survival program. Immunity, 58(11), 2704-2716.e4. https://doi.org/10.1016/j.immuni.2025.10.006

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title = "Long-lived IgE plasma cells persist in secondary lymphoid tissues using a navitoclax-sensitive survival program",

abstract = "Long-term allergies can exhibit persistent concentrations of circulating immunoglobulin E (IgE). Here, we examined the lifespan of IgE antibody-secreting cells (ASCs) to determine whether the IgE that sustains allergies receives contributions from long-lived cells or relies more heavily on constant ASC production. In mouse aeroallergy, IgE ASCs localized to the lungs, mediastinal lymph nodes, spleen, and bone marrow (BM). IgE ASC production continued for months after allergen exposure ceased. We identified long-lived IgE ASCs residing predominantly outside the BM, with a half-life exceeding 49 days; in contrast, most IgE ASCs had a 3-day half-life. Long-lived IgE ASCs matured phenotypically, became quiescent, retained their surface B cell receptors, but showed low expression of the BM homing receptor CXCR4. They were hierarchically more reliant on the navitoclax-sensitive anti-apoptotic molecules BCL2, BCLXL, and BCLW than MCL1. Thus, continual production of short-lived IgE ASCs and retention of long-lived IgE ASCs outside the BM together drive IgE persistence, perpetuating allergic disease. ",

keywords = "ABT-263, BCL, BCL2, IgE, MCL1, allergy, antibody-secreting cell, apoptosis, plasma cell, plasmablast",

author = "Zhoujie Ding and Wade-Vallance Adam and Downling, \{Mark R\} and Dvorscek, \{Alexandra R\} and Catherine Pitt and Jesse Mulder and Kristy O'Donnell and Craig McKenzie and Karaviotis, \{Alexandra Bosak\} and Julia Scrofani and Olaf Perdijk and Hill, \{Danika L\} and Isaak Quast and Tarlinton, \{David M\} and Allen, \{Christopher D C\} and Robinson, \{Marcus J\}",

note = "Publisher Copyright: {\textcopyright} 2025 The Authors",

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day = "11",

doi = "10.1016/j.immuni.2025.10.006",

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Ding, Z, Adam, W-V, Downling, MR, Dvorscek, AR, Pitt, C, Mulder, J, O'Donnell, K, McKenzie, C, Karaviotis, AB, Scrofani, J, Perdijk, O, Hill, DL, Quast , I, Tarlinton, DM, Allen, CDC & Robinson, MJ 2025, 'Long-lived IgE plasma cells persist in secondary lymphoid tissues using a navitoclax-sensitive survival program', Immunity, vol. 58, no. 11, pp. 2704-2716.e4. https://doi.org/10.1016/j.immuni.2025.10.006

TY - JOUR

T1 - Long-lived IgE plasma cells persist in secondary lymphoid tissues using a navitoclax-sensitive survival program

AU - Ding, Zhoujie

AU - Adam, Wade-Vallance

AU - Downling, Mark R

AU - Dvorscek, Alexandra R

AU - Pitt, Catherine

AU - Mulder, Jesse

AU - O'Donnell, Kristy

AU - McKenzie, Craig

AU - Karaviotis, Alexandra Bosak

AU - Scrofani, Julia

AU - Perdijk, Olaf

AU - Hill, Danika L

AU - Quast , Isaak

AU - Tarlinton, David M

AU - Allen, Christopher D C

AU - Robinson, Marcus J

PY - 2025/11/11

Y1 - 2025/11/11

N2 - Long-term allergies can exhibit persistent concentrations of circulating immunoglobulin E (IgE). Here, we examined the lifespan of IgE antibody-secreting cells (ASCs) to determine whether the IgE that sustains allergies receives contributions from long-lived cells or relies more heavily on constant ASC production. In mouse aeroallergy, IgE ASCs localized to the lungs, mediastinal lymph nodes, spleen, and bone marrow (BM). IgE ASC production continued for months after allergen exposure ceased. We identified long-lived IgE ASCs residing predominantly outside the BM, with a half-life exceeding 49 days; in contrast, most IgE ASCs had a 3-day half-life. Long-lived IgE ASCs matured phenotypically, became quiescent, retained their surface B cell receptors, but showed low expression of the BM homing receptor CXCR4. They were hierarchically more reliant on the navitoclax-sensitive anti-apoptotic molecules BCL2, BCLXL, and BCLW than MCL1. Thus, continual production of short-lived IgE ASCs and retention of long-lived IgE ASCs outside the BM together drive IgE persistence, perpetuating allergic disease.

AB - Long-term allergies can exhibit persistent concentrations of circulating immunoglobulin E (IgE). Here, we examined the lifespan of IgE antibody-secreting cells (ASCs) to determine whether the IgE that sustains allergies receives contributions from long-lived cells or relies more heavily on constant ASC production. In mouse aeroallergy, IgE ASCs localized to the lungs, mediastinal lymph nodes, spleen, and bone marrow (BM). IgE ASC production continued for months after allergen exposure ceased. We identified long-lived IgE ASCs residing predominantly outside the BM, with a half-life exceeding 49 days; in contrast, most IgE ASCs had a 3-day half-life. Long-lived IgE ASCs matured phenotypically, became quiescent, retained their surface B cell receptors, but showed low expression of the BM homing receptor CXCR4. They were hierarchically more reliant on the navitoclax-sensitive anti-apoptotic molecules BCL2, BCLXL, and BCLW than MCL1. Thus, continual production of short-lived IgE ASCs and retention of long-lived IgE ASCs outside the BM together drive IgE persistence, perpetuating allergic disease.

KW - ABT-263

KW - BCL

KW - BCL2

KW - IgE

KW - MCL1

KW - allergy

KW - antibody-secreting cell

KW - apoptosis

KW - plasma cell

KW - plasmablast

UR - https://www.scopus.com/pages/publications/105020780950

U2 - 10.1016/j.immuni.2025.10.006

DO - 10.1016/j.immuni.2025.10.006

M3 - Article

SN - 1074-7613

VL - 58

SP - 2704-2716.e4

JO - Immunity

JF - Immunity

IS - 11

ER -

Long-lived IgE plasma cells persist in secondary lymphoid tissues using a navitoclax-sensitive survival program

Abstract

Bibliographical note

Funding

Keywords

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