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ResearchIn-Press PreviewAutoimmunityImmunology Open Access | 10.1172/JCI204095

Migration-dependent extrafollicular programming of pre-plasmablast age-associated B cells drives lupus pathogenesis

Taiichiro Shirai,1 Kentaro Kuzuya,1 Mizuki Kishi,1 Shinya Ichikawa,2 Shuhei Sakakibara,3 Akiko Nakai,1 Sarah Leach,1 Yu-Chen Liu,4 Daisuke Motooka,4 Daisuke Okuzaki,4 Masashi Narazaki,5 Atsushi Kumanogoh,5 Tomohiro Kurosaki,6 Jun Saegusa,2 and Kazuhiro Suzuki1

1Laboratory of Immune Response Dynamics, WPI Immunology Frontier Research Ce, The University of Osaka, Osaka, Japan

2Department of Rheumatology and Clinical Immunology, Graduate School of Medicine, Kobe University, Hyogo, Japan

3Laboratory of Systems Immunology, WPI Immunology Frontier Research Center, The University of Osaka, Osaka, Japan

4Laboratory of Human Immunology (Single Cell Genomics), WPI Immunology Front, The University of Osaka, Osaka, Japan

5Department of Respiratory Medicine and Clinical Immunology, Graduate School of Medicine, The University of Osaka, Osaka, Japan

6Laboratory of Lymphocyte Differentiation, WPI Immunology Frontier Research , The University of Osaka, Osaka, Japan

Find articles by Shirai, T. in: PubMed | Google Scholar

1Laboratory of Immune Response Dynamics, WPI Immunology Frontier Research Ce, The University of Osaka, Osaka, Japan

2Department of Rheumatology and Clinical Immunology, Graduate School of Medicine, Kobe University, Hyogo, Japan

3Laboratory of Systems Immunology, WPI Immunology Frontier Research Center, The University of Osaka, Osaka, Japan

4Laboratory of Human Immunology (Single Cell Genomics), WPI Immunology Front, The University of Osaka, Osaka, Japan

5Department of Respiratory Medicine and Clinical Immunology, Graduate School of Medicine, The University of Osaka, Osaka, Japan

6Laboratory of Lymphocyte Differentiation, WPI Immunology Frontier Research , The University of Osaka, Osaka, Japan

Find articles by Kuzuya, K. in: PubMed | Google Scholar

1Laboratory of Immune Response Dynamics, WPI Immunology Frontier Research Ce, The University of Osaka, Osaka, Japan

2Department of Rheumatology and Clinical Immunology, Graduate School of Medicine, Kobe University, Hyogo, Japan

3Laboratory of Systems Immunology, WPI Immunology Frontier Research Center, The University of Osaka, Osaka, Japan

4Laboratory of Human Immunology (Single Cell Genomics), WPI Immunology Front, The University of Osaka, Osaka, Japan

5Department of Respiratory Medicine and Clinical Immunology, Graduate School of Medicine, The University of Osaka, Osaka, Japan

6Laboratory of Lymphocyte Differentiation, WPI Immunology Frontier Research , The University of Osaka, Osaka, Japan

Find articles by Kishi, M. in: PubMed | Google Scholar

1Laboratory of Immune Response Dynamics, WPI Immunology Frontier Research Ce, The University of Osaka, Osaka, Japan

2Department of Rheumatology and Clinical Immunology, Graduate School of Medicine, Kobe University, Hyogo, Japan

3Laboratory of Systems Immunology, WPI Immunology Frontier Research Center, The University of Osaka, Osaka, Japan

4Laboratory of Human Immunology (Single Cell Genomics), WPI Immunology Front, The University of Osaka, Osaka, Japan

5Department of Respiratory Medicine and Clinical Immunology, Graduate School of Medicine, The University of Osaka, Osaka, Japan

6Laboratory of Lymphocyte Differentiation, WPI Immunology Frontier Research , The University of Osaka, Osaka, Japan

Find articles by Ichikawa, S. in: PubMed | Google Scholar

1Laboratory of Immune Response Dynamics, WPI Immunology Frontier Research Ce, The University of Osaka, Osaka, Japan

2Department of Rheumatology and Clinical Immunology, Graduate School of Medicine, Kobe University, Hyogo, Japan

3Laboratory of Systems Immunology, WPI Immunology Frontier Research Center, The University of Osaka, Osaka, Japan

4Laboratory of Human Immunology (Single Cell Genomics), WPI Immunology Front, The University of Osaka, Osaka, Japan

5Department of Respiratory Medicine and Clinical Immunology, Graduate School of Medicine, The University of Osaka, Osaka, Japan

6Laboratory of Lymphocyte Differentiation, WPI Immunology Frontier Research , The University of Osaka, Osaka, Japan

Find articles by Sakakibara, S. in: PubMed | Google Scholar |

1Laboratory of Immune Response Dynamics, WPI Immunology Frontier Research Ce, The University of Osaka, Osaka, Japan

2Department of Rheumatology and Clinical Immunology, Graduate School of Medicine, Kobe University, Hyogo, Japan

3Laboratory of Systems Immunology, WPI Immunology Frontier Research Center, The University of Osaka, Osaka, Japan

4Laboratory of Human Immunology (Single Cell Genomics), WPI Immunology Front, The University of Osaka, Osaka, Japan

5Department of Respiratory Medicine and Clinical Immunology, Graduate School of Medicine, The University of Osaka, Osaka, Japan

6Laboratory of Lymphocyte Differentiation, WPI Immunology Frontier Research , The University of Osaka, Osaka, Japan

Find articles by Nakai, A. in: PubMed | Google Scholar

1Laboratory of Immune Response Dynamics, WPI Immunology Frontier Research Ce, The University of Osaka, Osaka, Japan

2Department of Rheumatology and Clinical Immunology, Graduate School of Medicine, Kobe University, Hyogo, Japan

3Laboratory of Systems Immunology, WPI Immunology Frontier Research Center, The University of Osaka, Osaka, Japan

4Laboratory of Human Immunology (Single Cell Genomics), WPI Immunology Front, The University of Osaka, Osaka, Japan

5Department of Respiratory Medicine and Clinical Immunology, Graduate School of Medicine, The University of Osaka, Osaka, Japan

6Laboratory of Lymphocyte Differentiation, WPI Immunology Frontier Research , The University of Osaka, Osaka, Japan

Find articles by Leach, S. in: PubMed | Google Scholar

1Laboratory of Immune Response Dynamics, WPI Immunology Frontier Research Ce, The University of Osaka, Osaka, Japan

2Department of Rheumatology and Clinical Immunology, Graduate School of Medicine, Kobe University, Hyogo, Japan

3Laboratory of Systems Immunology, WPI Immunology Frontier Research Center, The University of Osaka, Osaka, Japan

4Laboratory of Human Immunology (Single Cell Genomics), WPI Immunology Front, The University of Osaka, Osaka, Japan

5Department of Respiratory Medicine and Clinical Immunology, Graduate School of Medicine, The University of Osaka, Osaka, Japan

6Laboratory of Lymphocyte Differentiation, WPI Immunology Frontier Research , The University of Osaka, Osaka, Japan

Find articles by Liu, Y. in: PubMed | Google Scholar |

1Laboratory of Immune Response Dynamics, WPI Immunology Frontier Research Ce, The University of Osaka, Osaka, Japan

2Department of Rheumatology and Clinical Immunology, Graduate School of Medicine, Kobe University, Hyogo, Japan

3Laboratory of Systems Immunology, WPI Immunology Frontier Research Center, The University of Osaka, Osaka, Japan

4Laboratory of Human Immunology (Single Cell Genomics), WPI Immunology Front, The University of Osaka, Osaka, Japan

5Department of Respiratory Medicine and Clinical Immunology, Graduate School of Medicine, The University of Osaka, Osaka, Japan

6Laboratory of Lymphocyte Differentiation, WPI Immunology Frontier Research , The University of Osaka, Osaka, Japan

Find articles by Motooka, D. in: PubMed | Google Scholar

1Laboratory of Immune Response Dynamics, WPI Immunology Frontier Research Ce, The University of Osaka, Osaka, Japan

2Department of Rheumatology and Clinical Immunology, Graduate School of Medicine, Kobe University, Hyogo, Japan

3Laboratory of Systems Immunology, WPI Immunology Frontier Research Center, The University of Osaka, Osaka, Japan

4Laboratory of Human Immunology (Single Cell Genomics), WPI Immunology Front, The University of Osaka, Osaka, Japan

5Department of Respiratory Medicine and Clinical Immunology, Graduate School of Medicine, The University of Osaka, Osaka, Japan

6Laboratory of Lymphocyte Differentiation, WPI Immunology Frontier Research , The University of Osaka, Osaka, Japan

Find articles by Okuzaki, D. in: PubMed | Google Scholar |

1Laboratory of Immune Response Dynamics, WPI Immunology Frontier Research Ce, The University of Osaka, Osaka, Japan

2Department of Rheumatology and Clinical Immunology, Graduate School of Medicine, Kobe University, Hyogo, Japan

3Laboratory of Systems Immunology, WPI Immunology Frontier Research Center, The University of Osaka, Osaka, Japan

4Laboratory of Human Immunology (Single Cell Genomics), WPI Immunology Front, The University of Osaka, Osaka, Japan

5Department of Respiratory Medicine and Clinical Immunology, Graduate School of Medicine, The University of Osaka, Osaka, Japan

6Laboratory of Lymphocyte Differentiation, WPI Immunology Frontier Research , The University of Osaka, Osaka, Japan

Find articles by Narazaki, M. in: PubMed | Google Scholar |

1Laboratory of Immune Response Dynamics, WPI Immunology Frontier Research Ce, The University of Osaka, Osaka, Japan

2Department of Rheumatology and Clinical Immunology, Graduate School of Medicine, Kobe University, Hyogo, Japan

3Laboratory of Systems Immunology, WPI Immunology Frontier Research Center, The University of Osaka, Osaka, Japan

4Laboratory of Human Immunology (Single Cell Genomics), WPI Immunology Front, The University of Osaka, Osaka, Japan

5Department of Respiratory Medicine and Clinical Immunology, Graduate School of Medicine, The University of Osaka, Osaka, Japan

6Laboratory of Lymphocyte Differentiation, WPI Immunology Frontier Research , The University of Osaka, Osaka, Japan

Find articles by Kumanogoh, A. in: PubMed | Google Scholar |

1Laboratory of Immune Response Dynamics, WPI Immunology Frontier Research Ce, The University of Osaka, Osaka, Japan

2Department of Rheumatology and Clinical Immunology, Graduate School of Medicine, Kobe University, Hyogo, Japan

3Laboratory of Systems Immunology, WPI Immunology Frontier Research Center, The University of Osaka, Osaka, Japan

4Laboratory of Human Immunology (Single Cell Genomics), WPI Immunology Front, The University of Osaka, Osaka, Japan

5Department of Respiratory Medicine and Clinical Immunology, Graduate School of Medicine, The University of Osaka, Osaka, Japan

6Laboratory of Lymphocyte Differentiation, WPI Immunology Frontier Research , The University of Osaka, Osaka, Japan

Find articles by Kurosaki, T. in: PubMed | Google Scholar

1Laboratory of Immune Response Dynamics, WPI Immunology Frontier Research Ce, The University of Osaka, Osaka, Japan

2Department of Rheumatology and Clinical Immunology, Graduate School of Medicine, Kobe University, Hyogo, Japan

3Laboratory of Systems Immunology, WPI Immunology Frontier Research Center, The University of Osaka, Osaka, Japan

4Laboratory of Human Immunology (Single Cell Genomics), WPI Immunology Front, The University of Osaka, Osaka, Japan

5Department of Respiratory Medicine and Clinical Immunology, Graduate School of Medicine, The University of Osaka, Osaka, Japan

6Laboratory of Lymphocyte Differentiation, WPI Immunology Frontier Research , The University of Osaka, Osaka, Japan

Find articles by Saegusa, J. in: PubMed | Google Scholar

1Laboratory of Immune Response Dynamics, WPI Immunology Frontier Research Ce, The University of Osaka, Osaka, Japan

2Department of Rheumatology and Clinical Immunology, Graduate School of Medicine, Kobe University, Hyogo, Japan

3Laboratory of Systems Immunology, WPI Immunology Frontier Research Center, The University of Osaka, Osaka, Japan

4Laboratory of Human Immunology (Single Cell Genomics), WPI Immunology Front, The University of Osaka, Osaka, Japan

5Department of Respiratory Medicine and Clinical Immunology, Graduate School of Medicine, The University of Osaka, Osaka, Japan

6Laboratory of Lymphocyte Differentiation, WPI Immunology Frontier Research , The University of Osaka, Osaka, Japan

Find articles by Suzuki, K. in: PubMed | Google Scholar

Published July 14, 2026 - More info

J Clin Invest. https://doi.org/10.1172/JCI204095.
Copyright © 2026, Shirai et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Published July 14, 2026 - Version history
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Abstract

Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by autoantibody production. Extrafollicular (EF) B cell responses contribute to SLE pathogenesis, with age-associated B cells (ABCs) giving rise to autoantibody-secreting plasmablasts (PBs). However, the migratory cues governing this EF trajectory remain unclear. Here, we identify a distinct ABC state with PB precursor characteristics (pre-PB ABCs) and reveal a migration-dependent program underlying their generation. Single-cell analysis of SLE patients and model mice showed that pre-PB ABCs were enriched in autoreactive clones and poised for PB differentiation. Their frequency correlated with autoantibody titers and disease activity, underscoring their pathogenic relevance. We further demonstrated that the oxysterol receptor EBI2 directed ABCs to EF niches within splenic bridging channels, promoting pre-PB ABC formation and autoreactive PB output. This process depended on the COMMD3/8 complex, a positive regulator of chemoattractant receptor signaling. Beyond EBI2-mediated ABC migration to EF niches, the COMMD3/8 complex was also required for trafficking of autoantibody-secreting cells to the bone marrow and infiltration of ABCs into the kidney. Accordingly, COMMD3/8 complex inhibition ameliorated disease in murine SLE models. These findings define a migration-dependent mechanism driving the EF differentiation of ABCs into autoreactive PBs and shaping the tissue distribution of pathogenic B cells, highlighting this program as a potential therapeutic target in SLE.

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  • Version 1 (July 14, 2026): In-Press Preview
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