Loss of an IgG plasma cell checkpoint in lupus

Jolien Suurmond, Yemil Atisha-Fregoso, Emiliano Marasco, Ashley N Barlev, Naveed Ahmed, Silvia A Calderon, Mei Yin Wong, Meggan C Mackay, Cynthia Aranow, Betty Diamond

Research output: Contribution to journalArticle

Abstract

BACKGROUND: IgG anti-nuclear antibodies (ANA) are a feature of several autoimmune diseases. These antibodies arise through defects in central or peripheral tolerance checkpoints. The specific checkpoints breached in autoimmune disease are not fully understood.

OBJECTIVES: To study whether autoreactive plasma cells in lupus models and SLE patients arise as a consequence of defective antigen-specific selection or a global enhancement of IgG PC differentiation.

METHODS AND RESULTS: We optimized and validated a novel technique to detect naturally occurring ANA+ B cells and PC. We observed a major checkpoint for generation of ANA+ IgG+ PC in both non-autoimmune mice and healthy human subjects. Interestingly, we observed increased numbers of ANA+ IgG+ PC despite normal tolerance checkpoints in immature and naïve B cells in lupus-prone MRL/lpr and NZB/W mice as well as patients with systemic lupus erythematosus (SLE). This increase was due to increased numbers of total IgG+ PC rather than lack of selection against ANA+ PC.

CONCLUSION: Using a method that permits quick and accurate quantification of autoreactive B cells and PC in vivo within a native B cell repertoire in mice and humans, we demonstrate the importance of a checkpoint that restricts the generation of IgG plasma cells and protects against IgG ANA. Our observations suggest a fundamentally revised understanding of SLE: that it is a disease of aberrant B cell differentiation rather than a defect in antigen-specific B cell tolerance.

CLINICAL IMPLICATION: Therapies for SLE might need to be targeted at IgG plasma cell differentiation rather than antigen-specific tolerance.

Original languageEnglish
JournalJournal of Allergy and Clinical Immunology
DOIs
Publication statusE-pub ahead of print - Nov 12 2018
Externally publishedYes

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Plasma Cells
Immunoglobulin G
Anti-Idiotypic Antibodies
B-Lymphocytes
Systemic Lupus Erythematosus
Autoimmune Diseases
Cell Differentiation
Central Tolerance
Inbred NZB Mouse
Peripheral Tolerance
Antigens
B-Lymphoid Precursor Cells
Differentiation Antigens
Healthy Volunteers
Antibodies

Cite this

Suurmond, J., Atisha-Fregoso, Y., Marasco, E., Barlev, A. N., Ahmed, N., Calderon, S. A., ... Diamond, B. (2018). Loss of an IgG plasma cell checkpoint in lupus. Journal of Allergy and Clinical Immunology. https://doi.org/10.1016/j.jaci.2018.10.041

Loss of an IgG plasma cell checkpoint in lupus. / Suurmond, Jolien; Atisha-Fregoso, Yemil; Marasco, Emiliano; Barlev, Ashley N; Ahmed, Naveed; Calderon, Silvia A; Wong, Mei Yin; Mackay, Meggan C; Aranow, Cynthia; Diamond, Betty.

In: Journal of Allergy and Clinical Immunology, 12.11.2018.

Research output: Contribution to journalArticle

Suurmond, J, Atisha-Fregoso, Y, Marasco, E, Barlev, AN, Ahmed, N, Calderon, SA, Wong, MY, Mackay, MC, Aranow, C & Diamond, B 2018, 'Loss of an IgG plasma cell checkpoint in lupus', Journal of Allergy and Clinical Immunology. https://doi.org/10.1016/j.jaci.2018.10.041
Suurmond J, Atisha-Fregoso Y, Marasco E, Barlev AN, Ahmed N, Calderon SA et al. Loss of an IgG plasma cell checkpoint in lupus. Journal of Allergy and Clinical Immunology. 2018 Nov 12. https://doi.org/10.1016/j.jaci.2018.10.041
Suurmond, Jolien ; Atisha-Fregoso, Yemil ; Marasco, Emiliano ; Barlev, Ashley N ; Ahmed, Naveed ; Calderon, Silvia A ; Wong, Mei Yin ; Mackay, Meggan C ; Aranow, Cynthia ; Diamond, Betty. / Loss of an IgG plasma cell checkpoint in lupus. In: Journal of Allergy and Clinical Immunology. 2018.
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AU - Atisha-Fregoso, Yemil

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AU - Barlev, Ashley N

AU - Ahmed, Naveed

AU - Calderon, Silvia A

AU - Wong, Mei Yin

AU - Mackay, Meggan C

AU - Aranow, Cynthia

AU - Diamond, Betty

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N2 - BACKGROUND: IgG anti-nuclear antibodies (ANA) are a feature of several autoimmune diseases. These antibodies arise through defects in central or peripheral tolerance checkpoints. The specific checkpoints breached in autoimmune disease are not fully understood.OBJECTIVES: To study whether autoreactive plasma cells in lupus models and SLE patients arise as a consequence of defective antigen-specific selection or a global enhancement of IgG PC differentiation.METHODS AND RESULTS: We optimized and validated a novel technique to detect naturally occurring ANA+ B cells and PC. We observed a major checkpoint for generation of ANA+ IgG+ PC in both non-autoimmune mice and healthy human subjects. Interestingly, we observed increased numbers of ANA+ IgG+ PC despite normal tolerance checkpoints in immature and naïve B cells in lupus-prone MRL/lpr and NZB/W mice as well as patients with systemic lupus erythematosus (SLE). This increase was due to increased numbers of total IgG+ PC rather than lack of selection against ANA+ PC.CONCLUSION: Using a method that permits quick and accurate quantification of autoreactive B cells and PC in vivo within a native B cell repertoire in mice and humans, we demonstrate the importance of a checkpoint that restricts the generation of IgG plasma cells and protects against IgG ANA. Our observations suggest a fundamentally revised understanding of SLE: that it is a disease of aberrant B cell differentiation rather than a defect in antigen-specific B cell tolerance.CLINICAL IMPLICATION: Therapies for SLE might need to be targeted at IgG plasma cell differentiation rather than antigen-specific tolerance.

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