The extrafollicular response is sufficient to drive initiation of autoimmunity and early disease hallmarks of lupus

Lasse F. Voss; Amanda J. Howarth; Thomas R. Wittenborn; Sandra Hummelgaard; Kristian Juul-Madsen; Kristian S. Kastberg; Mathias K. Pedersen; Lisbeth Jensen; Anastasios D. Papanastasiou; Thomas Vorup-Jensen; Kathrin Weyer; Søren E. Degn

doi:10.3389/fimmu.2022.1021370

The extrafollicular response is sufficient to drive initiation of autoimmunity and early disease hallmarks of lupus

Lasse F. Voss, Amanda J. Howarth, Thomas R. Wittenborn, Sandra Hummelgaard, Kristian Juul-Madsen, Kristian S. Kastberg, Mathias K. Pedersen, Lisbeth Jensen, Anastasios D. Papanastasiou, Thomas Vorup-Jensen, Kathrin Weyer, Søren E. Degn^*

^*Corresponding author for this work

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaper › Journal article › Research › peer-review

Abstract

Introduction: Many autoimmune diseases are characterized by germinal center (GC)-derived, affinity-matured, class-switched autoantibodies, and strategies to block GC formation and progression are currently being explored clinically. However, extrafollicular responses can also play a role. The aim of this study was to investigate the contribution of the extrafollicular pathway to autoimmune disease development. Methods: We blocked the GC pathway by knocking out the transcription factor Bcl-6 in GC B cells, leaving the extrafollicular pathway intact. We tested the impact of this intervention in two murine models of systemic lupus erythematosus (SLE): a pharmacological model based on chronic epicutaneous application of the Toll-like receptor (TLR)-7 agonist Resiquimod (R848), and 564Igi autoreactive B cell receptor knock-in mice. The B cell intrinsic effects were further investigated in vitro and in autoreactive mixed bone marrow chimeras. Results: GC block failed to curb autoimmune progression in the R848 model based on anti-dsDNA and plasma cell output, superoligomeric DNA complexes, and immune complex deposition in glomeruli. The 564Igi model confirmed this based on anti-dsDNA and plasma cell output. In vitro, loss of Bcl-6 prevented GC B cell expansion and accelerated plasma cell differentiation. In a competitive scenario in vivo, B cells harboring the genetic GC block contributed disproportionately to the plasma cell output. Discussion: We identified the extrafollicular pathway as a key contributor to autoimmune progression. We propose that therapeutic targeting of low quality and poorly controlled extrafollicular responses could be a desirable strategy to curb autoreactivity, as it would leave intact the more stringently controlled and high-quality GC responses providing durable protection against infection.

Original language	English
Article number	1021370
Journal	Frontiers in Immunology
Volume	13
ISSN	1664-3224
DOIs	https://doi.org/10.3389/fimmu.2022.1021370
Publication status	Published - Dec 2022

Keywords

autoantibodies
autoimmunity
B cells
extrafollicular responses
germinal centers
systemic lupus erythematosus
TLR7

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Voss, L. F., Howarth, A. J., Wittenborn, T. R., Hummelgaard, S., Juul-Madsen, K., Kastberg, K. S., Pedersen, M. K., Jensen, L., Papanastasiou, A. D., Vorup-Jensen, T., Weyer, K., & Degn, S. E. (2022). The extrafollicular response is sufficient to drive initiation of autoimmunity and early disease hallmarks of lupus. Frontiers in Immunology, 13, Article 1021370. https://doi.org/10.3389/fimmu.2022.1021370

@article{6e5d2edbbc1a463d9d9841f0940e820d,

title = "The extrafollicular response is sufficient to drive initiation of autoimmunity and early disease hallmarks of lupus",

abstract = "Introduction: Many autoimmune diseases are characterized by germinal center (GC)-derived, affinity-matured, class-switched autoantibodies, and strategies to block GC formation and progression are currently being explored clinically. However, extrafollicular responses can also play a role. The aim of this study was to investigate the contribution of the extrafollicular pathway to autoimmune disease development. Methods: We blocked the GC pathway by knocking out the transcription factor Bcl-6 in GC B cells, leaving the extrafollicular pathway intact. We tested the impact of this intervention in two murine models of systemic lupus erythematosus (SLE): a pharmacological model based on chronic epicutaneous application of the Toll-like receptor (TLR)-7 agonist Resiquimod (R848), and 564Igi autoreactive B cell receptor knock-in mice. The B cell intrinsic effects were further investigated in vitro and in autoreactive mixed bone marrow chimeras. Results: GC block failed to curb autoimmune progression in the R848 model based on anti-dsDNA and plasma cell output, superoligomeric DNA complexes, and immune complex deposition in glomeruli. The 564Igi model confirmed this based on anti-dsDNA and plasma cell output. In vitro, loss of Bcl-6 prevented GC B cell expansion and accelerated plasma cell differentiation. In a competitive scenario in vivo, B cells harboring the genetic GC block contributed disproportionately to the plasma cell output. Discussion: We identified the extrafollicular pathway as a key contributor to autoimmune progression. We propose that therapeutic targeting of low quality and poorly controlled extrafollicular responses could be a desirable strategy to curb autoreactivity, as it would leave intact the more stringently controlled and high-quality GC responses providing durable protection against infection.",

keywords = "autoantibodies, autoimmunity, B cells, extrafollicular responses, germinal centers, systemic lupus erythematosus, TLR7",

author = "Voss, {Lasse F.} and Howarth, {Amanda J.} and Wittenborn, {Thomas R.} and Sandra Hummelgaard and Kristian Juul-Madsen and Kastberg, {Kristian S.} and Pedersen, {Mathias K.} and Lisbeth Jensen and Papanastasiou, {Anastasios D.} and Thomas Vorup-Jensen and Kathrin Weyer and Degn, {S{\o}ren E.}",

year = "2022",

month = dec,

doi = "10.3389/fimmu.2022.1021370",

language = "English",

volume = "13",

journal = "Frontiers in Immunology",

issn = "1664-3224",

publisher = "Frontiers Research Foundation",

}

Voss, LF, Howarth, AJ, Wittenborn, TR , Hummelgaard, S , Juul-Madsen, K , Kastberg, KS, Pedersen, MK, Jensen, L, Papanastasiou, AD, Vorup-Jensen, T , Weyer, K & Degn, SE 2022, 'The extrafollicular response is sufficient to drive initiation of autoimmunity and early disease hallmarks of lupus', Frontiers in Immunology, vol. 13, 1021370. https://doi.org/10.3389/fimmu.2022.1021370

The extrafollicular response is sufficient to drive initiation of autoimmunity and early disease hallmarks of lupus. / Voss, Lasse F.; Howarth, Amanda J.; Wittenborn, Thomas R. et al.
In: Frontiers in Immunology, Vol. 13, 1021370, 12.2022.

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaper › Journal article › Research › peer-review

TY - JOUR

T1 - The extrafollicular response is sufficient to drive initiation of autoimmunity and early disease hallmarks of lupus

AU - Voss, Lasse F.

AU - Howarth, Amanda J.

AU - Wittenborn, Thomas R.

AU - Hummelgaard, Sandra

AU - Juul-Madsen, Kristian

AU - Kastberg, Kristian S.

AU - Pedersen, Mathias K.

AU - Jensen, Lisbeth

AU - Papanastasiou, Anastasios D.

AU - Vorup-Jensen, Thomas

AU - Weyer, Kathrin

AU - Degn, Søren E.

PY - 2022/12

Y1 - 2022/12

N2 - Introduction: Many autoimmune diseases are characterized by germinal center (GC)-derived, affinity-matured, class-switched autoantibodies, and strategies to block GC formation and progression are currently being explored clinically. However, extrafollicular responses can also play a role. The aim of this study was to investigate the contribution of the extrafollicular pathway to autoimmune disease development. Methods: We blocked the GC pathway by knocking out the transcription factor Bcl-6 in GC B cells, leaving the extrafollicular pathway intact. We tested the impact of this intervention in two murine models of systemic lupus erythematosus (SLE): a pharmacological model based on chronic epicutaneous application of the Toll-like receptor (TLR)-7 agonist Resiquimod (R848), and 564Igi autoreactive B cell receptor knock-in mice. The B cell intrinsic effects were further investigated in vitro and in autoreactive mixed bone marrow chimeras. Results: GC block failed to curb autoimmune progression in the R848 model based on anti-dsDNA and plasma cell output, superoligomeric DNA complexes, and immune complex deposition in glomeruli. The 564Igi model confirmed this based on anti-dsDNA and plasma cell output. In vitro, loss of Bcl-6 prevented GC B cell expansion and accelerated plasma cell differentiation. In a competitive scenario in vivo, B cells harboring the genetic GC block contributed disproportionately to the plasma cell output. Discussion: We identified the extrafollicular pathway as a key contributor to autoimmune progression. We propose that therapeutic targeting of low quality and poorly controlled extrafollicular responses could be a desirable strategy to curb autoreactivity, as it would leave intact the more stringently controlled and high-quality GC responses providing durable protection against infection.

AB - Introduction: Many autoimmune diseases are characterized by germinal center (GC)-derived, affinity-matured, class-switched autoantibodies, and strategies to block GC formation and progression are currently being explored clinically. However, extrafollicular responses can also play a role. The aim of this study was to investigate the contribution of the extrafollicular pathway to autoimmune disease development. Methods: We blocked the GC pathway by knocking out the transcription factor Bcl-6 in GC B cells, leaving the extrafollicular pathway intact. We tested the impact of this intervention in two murine models of systemic lupus erythematosus (SLE): a pharmacological model based on chronic epicutaneous application of the Toll-like receptor (TLR)-7 agonist Resiquimod (R848), and 564Igi autoreactive B cell receptor knock-in mice. The B cell intrinsic effects were further investigated in vitro and in autoreactive mixed bone marrow chimeras. Results: GC block failed to curb autoimmune progression in the R848 model based on anti-dsDNA and plasma cell output, superoligomeric DNA complexes, and immune complex deposition in glomeruli. The 564Igi model confirmed this based on anti-dsDNA and plasma cell output. In vitro, loss of Bcl-6 prevented GC B cell expansion and accelerated plasma cell differentiation. In a competitive scenario in vivo, B cells harboring the genetic GC block contributed disproportionately to the plasma cell output. Discussion: We identified the extrafollicular pathway as a key contributor to autoimmune progression. We propose that therapeutic targeting of low quality and poorly controlled extrafollicular responses could be a desirable strategy to curb autoreactivity, as it would leave intact the more stringently controlled and high-quality GC responses providing durable protection against infection.

KW - autoantibodies

KW - autoimmunity

KW - B cells

KW - extrafollicular responses

KW - germinal centers

KW - systemic lupus erythematosus

KW - TLR7

UR - http://www.scopus.com/inward/record.url?scp=85145075196&partnerID=8YFLogxK

U2 - 10.3389/fimmu.2022.1021370

DO - 10.3389/fimmu.2022.1021370

M3 - Journal article

C2 - 36591222

SN - 1664-3224

VL - 13

JO - Frontiers in Immunology

JF - Frontiers in Immunology

M1 - 1021370

ER -

The extrafollicular response is sufficient to drive initiation of autoimmunity and early disease hallmarks of lupus

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