Neutralizing anti–IL-1 receptor antagonist autoantibodies induce inflammatory and fibrotic mediators in IgG4-related disease

Justin A. Jarrell; Matthew C. Baker; Cory A. Perugino; Hang Liu; Michelle S. Bloom; Takashi Maehara; Heidi H. Wong; Tobias V. Lanz; Julia Z. Adamska; Sarah Kongpachith; Jeremy Sokolove; John H. Stone; Shiv S. Pillai; William H. Robinson

doi:10.1016/j.jaci.2021.05.002

Neutralizing anti–IL-1 receptor antagonist autoantibodies induce inflammatory and fibrotic mediators in IgG4-related disease

Justin A. Jarrell, Matthew C. Baker, Cory A. Perugino, Hang Liu, Michelle S. Bloom, Takashi Maehara, Heidi H. Wong, Tobias V. Lanz, Julia Z. Adamska, Sarah Kongpachith, Jeremy Sokolove, John H. Stone, Shiv S. Pillai, William H. Robinson

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Abstract

Background: IgG4-related disease (IgG4-RD) is a fibroinflammatory condition involving loss of B-cell tolerance and production of autoantibodies. However, the relevant targets and role of these aberrant humoral immune responses are not defined. Objective: Our aim was to identify novel autoantibodies and autoantigen targets that promote pathogenic responses in IgG4-RD. Methods: We sequenced plasmablast antibody repertoires in patients with IgG4-RD. Representative mAbs were expressed and their specificities characterized by using cytokine microarrays. The role of anti–IL-1 receptor antagonist (IL-1RA) autoantibodies was investigated by using in vitro assays. Results: We identified strong reactivity against human IL-1RA by using a clonally expanded plasmablast-derived mAb from a patient with IgG4-RD. Plasma from patients with IgG4-RD exhibited elevated levels of reactivity against IL-1RA compared with plasma from the controls and neutralized IL-1RA activity, resulting in inflammatory and fibrotic mediator production in vitro. IL-1RA was detected in lesional tissues from patients with IgG4-RD. Patients with anti–IL-1RA autoantibodies of the IgG4 subclass had greater numbers of organs affected than did those without anti–IL-1RA autoantibodies. Peptide analyses identified IL-1RA epitopes targeted by anti–IL-1RA antibodies at sites near the IL-1RA/IL-1R interface. Serum from patients with systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) also had elevated levels of anti–IL-1RA autoantibodies compared with those of the controls. Conclusion: A subset of patients with IgG4-RD have anti–IL-1RA autoantibodies, which promote proinflammatory and profibrotic meditator production via IL-1RA neutralization. These findings support a novel immunologic mechanism underlying the pathogenesis of IgG4-RD. Anti–IL-1RA autoantibodies are also present in a subset of patients with SLE and RA, suggesting a potential common pathway in multiple autoimmune diseases.

Original language	English
Pages (from-to)	358-368
Number of pages	11
Journal	Journal of Allergy and Clinical Immunology
Volume	149
Issue number	1
DOIs	https://doi.org/10.1016/j.jaci.2021.05.002
Publication status	Published - Jan 2022
Externally published	Yes

All Science Journal Classification (ASJC) codes

Immunology and Allergy
Immunology

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.jaci.2021.05.002

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Jarrell, J. A., Baker, M. C., Perugino, C. A., Liu, H., Bloom, M. S., Maehara, T., Wong, H. H., Lanz, T. V., Adamska, J. Z., Kongpachith, S., Sokolove, J., Stone, J. H., Pillai, S. S., & Robinson, W. H. (2022). Neutralizing anti–IL-1 receptor antagonist autoantibodies induce inflammatory and fibrotic mediators in IgG4-related disease. Journal of Allergy and Clinical Immunology, 149(1), 358-368. https://doi.org/10.1016/j.jaci.2021.05.002

Jarrell, JA, Baker, MC, Perugino, CA, Liu, H, Bloom, MS, Maehara, T, Wong, HH, Lanz, TV, Adamska, JZ, Kongpachith, S, Sokolove, J, Stone, JH, Pillai, SS & Robinson, WH 2022, 'Neutralizing anti–IL-1 receptor antagonist autoantibodies induce inflammatory and fibrotic mediators in IgG4-related disease', Journal of Allergy and Clinical Immunology, vol. 149, no. 1, pp. 358-368. https://doi.org/10.1016/j.jaci.2021.05.002

@article{9a939ca235c246529485e419d4d9c7a6,

title = "Neutralizing anti–IL-1 receptor antagonist autoantibodies induce inflammatory and fibrotic mediators in IgG4-related disease",

abstract = "Background: IgG4-related disease (IgG4-RD) is a fibroinflammatory condition involving loss of B-cell tolerance and production of autoantibodies. However, the relevant targets and role of these aberrant humoral immune responses are not defined. Objective: Our aim was to identify novel autoantibodies and autoantigen targets that promote pathogenic responses in IgG4-RD. Methods: We sequenced plasmablast antibody repertoires in patients with IgG4-RD. Representative mAbs were expressed and their specificities characterized by using cytokine microarrays. The role of anti–IL-1 receptor antagonist (IL-1RA) autoantibodies was investigated by using in vitro assays. Results: We identified strong reactivity against human IL-1RA by using a clonally expanded plasmablast-derived mAb from a patient with IgG4-RD. Plasma from patients with IgG4-RD exhibited elevated levels of reactivity against IL-1RA compared with plasma from the controls and neutralized IL-1RA activity, resulting in inflammatory and fibrotic mediator production in vitro. IL-1RA was detected in lesional tissues from patients with IgG4-RD. Patients with anti–IL-1RA autoantibodies of the IgG4 subclass had greater numbers of organs affected than did those without anti–IL-1RA autoantibodies. Peptide analyses identified IL-1RA epitopes targeted by anti–IL-1RA antibodies at sites near the IL-1RA/IL-1R interface. Serum from patients with systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) also had elevated levels of anti–IL-1RA autoantibodies compared with those of the controls. Conclusion: A subset of patients with IgG4-RD have anti–IL-1RA autoantibodies, which promote proinflammatory and profibrotic meditator production via IL-1RA neutralization. These findings support a novel immunologic mechanism underlying the pathogenesis of IgG4-RD. Anti–IL-1RA autoantibodies are also present in a subset of patients with SLE and RA, suggesting a potential common pathway in multiple autoimmune diseases.",

author = "Jarrell, {Justin A.} and Baker, {Matthew C.} and Perugino, {Cory A.} and Hang Liu and Bloom, {Michelle S.} and Takashi Maehara and Wong, {Heidi H.} and Lanz, {Tobias V.} and Adamska, {Julia Z.} and Sarah Kongpachith and Jeremy Sokolove and Stone, {John H.} and Pillai, {Shiv S.} and Robinson, {William H.}",

note = "Funding Information: Supported by grants from the Stanford Graduate Fellowship (to J.A.J.), the Rheumatology Research Foundation (to M.C.B. and C.A.P.), and the National Institutes of Health (grants T32AI07290 [to J.A.J.], 2T32AR050942-11 [to M.C.B.], T32AR007258 [to C.A.P.], UM1 AI1144295 [to J.H.S.], U19 AI110495 [to S.S.P.], and R01AR06367604 and U19AI11049103 [to W.H.R.]). Publisher Copyright: {\textcopyright} 2021 American Academy of Allergy, Asthma & Immunology",

year = "2022",

month = jan,

doi = "10.1016/j.jaci.2021.05.002",

language = "English",

volume = "149",

pages = "358--368",

journal = "Journal of Allergy and Clinical Immunology",

issn = "0091-6749",

publisher = "Mosby Inc.",

number = "1",

}

TY - JOUR

T1 - Neutralizing anti–IL-1 receptor antagonist autoantibodies induce inflammatory and fibrotic mediators in IgG4-related disease

AU - Jarrell, Justin A.

AU - Baker, Matthew C.

AU - Perugino, Cory A.

AU - Liu, Hang

AU - Bloom, Michelle S.

AU - Maehara, Takashi

AU - Wong, Heidi H.

AU - Lanz, Tobias V.

AU - Adamska, Julia Z.

AU - Kongpachith, Sarah

AU - Sokolove, Jeremy

AU - Stone, John H.

AU - Pillai, Shiv S.

AU - Robinson, William H.

N1 - Funding Information: Supported by grants from the Stanford Graduate Fellowship (to J.A.J.), the Rheumatology Research Foundation (to M.C.B. and C.A.P.), and the National Institutes of Health (grants T32AI07290 [to J.A.J.], 2T32AR050942-11 [to M.C.B.], T32AR007258 [to C.A.P.], UM1 AI1144295 [to J.H.S.], U19 AI110495 [to S.S.P.], and R01AR06367604 and U19AI11049103 [to W.H.R.]). Publisher Copyright: © 2021 American Academy of Allergy, Asthma & Immunology

PY - 2022/1

Y1 - 2022/1

N2 - Background: IgG4-related disease (IgG4-RD) is a fibroinflammatory condition involving loss of B-cell tolerance and production of autoantibodies. However, the relevant targets and role of these aberrant humoral immune responses are not defined. Objective: Our aim was to identify novel autoantibodies and autoantigen targets that promote pathogenic responses in IgG4-RD. Methods: We sequenced plasmablast antibody repertoires in patients with IgG4-RD. Representative mAbs were expressed and their specificities characterized by using cytokine microarrays. The role of anti–IL-1 receptor antagonist (IL-1RA) autoantibodies was investigated by using in vitro assays. Results: We identified strong reactivity against human IL-1RA by using a clonally expanded plasmablast-derived mAb from a patient with IgG4-RD. Plasma from patients with IgG4-RD exhibited elevated levels of reactivity against IL-1RA compared with plasma from the controls and neutralized IL-1RA activity, resulting in inflammatory and fibrotic mediator production in vitro. IL-1RA was detected in lesional tissues from patients with IgG4-RD. Patients with anti–IL-1RA autoantibodies of the IgG4 subclass had greater numbers of organs affected than did those without anti–IL-1RA autoantibodies. Peptide analyses identified IL-1RA epitopes targeted by anti–IL-1RA antibodies at sites near the IL-1RA/IL-1R interface. Serum from patients with systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) also had elevated levels of anti–IL-1RA autoantibodies compared with those of the controls. Conclusion: A subset of patients with IgG4-RD have anti–IL-1RA autoantibodies, which promote proinflammatory and profibrotic meditator production via IL-1RA neutralization. These findings support a novel immunologic mechanism underlying the pathogenesis of IgG4-RD. Anti–IL-1RA autoantibodies are also present in a subset of patients with SLE and RA, suggesting a potential common pathway in multiple autoimmune diseases.

AB - Background: IgG4-related disease (IgG4-RD) is a fibroinflammatory condition involving loss of B-cell tolerance and production of autoantibodies. However, the relevant targets and role of these aberrant humoral immune responses are not defined. Objective: Our aim was to identify novel autoantibodies and autoantigen targets that promote pathogenic responses in IgG4-RD. Methods: We sequenced plasmablast antibody repertoires in patients with IgG4-RD. Representative mAbs were expressed and their specificities characterized by using cytokine microarrays. The role of anti–IL-1 receptor antagonist (IL-1RA) autoantibodies was investigated by using in vitro assays. Results: We identified strong reactivity against human IL-1RA by using a clonally expanded plasmablast-derived mAb from a patient with IgG4-RD. Plasma from patients with IgG4-RD exhibited elevated levels of reactivity against IL-1RA compared with plasma from the controls and neutralized IL-1RA activity, resulting in inflammatory and fibrotic mediator production in vitro. IL-1RA was detected in lesional tissues from patients with IgG4-RD. Patients with anti–IL-1RA autoantibodies of the IgG4 subclass had greater numbers of organs affected than did those without anti–IL-1RA autoantibodies. Peptide analyses identified IL-1RA epitopes targeted by anti–IL-1RA antibodies at sites near the IL-1RA/IL-1R interface. Serum from patients with systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) also had elevated levels of anti–IL-1RA autoantibodies compared with those of the controls. Conclusion: A subset of patients with IgG4-RD have anti–IL-1RA autoantibodies, which promote proinflammatory and profibrotic meditator production via IL-1RA neutralization. These findings support a novel immunologic mechanism underlying the pathogenesis of IgG4-RD. Anti–IL-1RA autoantibodies are also present in a subset of patients with SLE and RA, suggesting a potential common pathway in multiple autoimmune diseases.

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U2 - 10.1016/j.jaci.2021.05.002

DO - 10.1016/j.jaci.2021.05.002

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SN - 0091-6749

VL - 149

SP - 358

EP - 368

JO - Journal of Allergy and Clinical Immunology

JF - Journal of Allergy and Clinical Immunology

IS - 1

ER -

Neutralizing anti–IL-1 receptor antagonist autoantibodies induce inflammatory and fibrotic mediators in IgG4-related disease

Abstract

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