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Not marginal but central: type I interferons unleash marginal zone B cells in Sjögren’s disease

Cellular & Molecular Immunology volume 22, pages 1642–1644 (2025)Cite this article

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A Correction to this article was published on 18 November 2025

The Original Article was published on 10 September 2025

This article has been updated

Sjögren’s disease (SjD) is an autoimmune and inflammatory disease characterized by immune-mediated impairment of salivary and lacrimal gland functions, causing dryness in the mouth and eyes. SjD also involves other exocrine glands in the respiratory and gastrointestinal tracts and the skin and has a wide and variable range of extraglandular and systemic manifestations [1]. Despite being a complex, heterogeneous and still incurable disease, several important immunological observations point to the key pathogenic mechanisms of SjD, which can guide treatment. First, B cells are recognized as drivers of SjD, with many patients having aberrant B cell accumulation and autoantibody deposition in target organs and an increased incidence of B cell lymphomas. Second, the strong genetic association with certain human leukocyte antigen class II (HLA-II) alleles and the increased number of follicular helper T (TFH) cells in the circulation and affected exocrine glands of SjD patients suggest a critical role of T‒B cell interactions in secondary and tertiary lymphoid tissues in activating and sustaining pathogenic B cells in SjD. Third, type I interferons (IFN-Is) are often elevated in the blood and the affected exocrine glands and are correlated with adverse prognoses. However, the intricate interactions among pathogenic B cells, TFH cells and IFN-Is in local and systemic inductive tissues and target tissues are not well understood. A study on this topic by Cellular and Molecular Immunology [2] revealed that marginal zone B cells as a link of IFN-Is and TFH responses critical to the development of experimental SjD in mice and likely SjD in humans.

Splenic MZ B cells are located at the interface of the arterial circulation and the immune cell-rich white pulp. They express B cell receptors (BCRs) enriched in polyreactivity to microbe-associated molecular patterns (MAMPs) and damage-associated molecular patterns (DAMPs) and can rapidly respond to antigens or an increase in immune-activating factors in the blood to mount extrafollicular responses, resulting in the production of low-affinity IgM and, to a lesser extent, IgG and IgA [4]. Suited to such innate immune functions, MZ B cells have higher levels of many pattern recognition receptors (PRRs) and IFNAR1 than do follicular (FO) B cells [2]. MZ B cells also have considerable autoreactivity, perhaps to perform housekeeping functions or as a nonanergic mechanism to counter the evolutionary mimicry of microbes to self-antigens [5]. Conceivably, the functions of MZ B cells need to be tightly regulated. As FO exclusion of self-reactive B cells is an important mechanism of peripheral tolerance, this study revealed that IFN-Is play an important role in helping FO-excluded B cells bypass this critical immune checkpoint in the pathogenesis of SjD and perhaps other B cell-driven autoimmune diseases, such as systemic lupus erythematosus (SLE), rheumatoid arthritis (RA) or scleroderma [1], which occur in approximately half of SjD patients. In fact, FO shuttling of MZ B cells has been observed in mouse models of systemic lupus erythematosus (SLE) and after immunization [6, 7]. The authors showed that FO shuttling of MZ B cells involves changes in the expression of chemotactic receptors and cell adhesion molecules, which dislodge MZ B cells, promote follicular entry, and are guided by single-cell RNA sequencing (scRNA-Seq) to identify key signaling mechanisms underlying some of these IFN-I-induced changes. There are likely many more changes in MZ B cells and their MZ niche, and the use of additional high-resolution approaches, such as spatial-ATAC-RNA-Seq, can yield more complete insights into the key signals and mechanisms that hold MZ B cells in check under a steady state and unleash them into poised behaviors such as FO entry, cytokine expression, TFH stimulation and antibody production under disease-precipitating conditions. Additionally, these effects of IFN-Is should be verified in human MZ B cells because major differences exist in the MZ niche composition, the MZ B cell repertoire and the role of IL-6 in TFH cell differentiation between humans and mice.

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Change history

  • 10 November 2025

    The original online version of this article was revised: the wrong article file was originally published, it has now been replaced with the correct file.

  • 18 November 2025

    A Correction to this paper has been published: https://doi.org/10.1038/s41423-025-01370-y

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Acknowledgements

This work is supported by grants from the U.S. National Institutes of Health (AI163045 to KC) and the Spanish Ministry of Science, Innovation and Universities (RTI2018-093894-B-I00 to AC).

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  1. These authors contributed equally: Alice Werynski, Chun-Xiao Li, Yujing Hao.

Authors and Affiliations

  1. Doctor of Medicine Program, Wayne State University, Detroit, MI, USA

    Alice Werynski

  2. Department of Obstetrics and Gynecology, Wayne State University, Detroit, MI, USA

    Chun-Xiao Li, Yujing Hao & Kang Chen

  3. Graduate Program of Immunology and Microbiology, Wayne State University, Detroit, MI, USA

    Yujing Hao & Kang Chen

  4. Hospital del Mar and Catalan Institute for Research and Advanced Studies, Barcelona, Spain

    Andrea Cerutti

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Correspondence to Kang Chen.

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The original online version of this article was revised: the wrong article file was originally published, it has now been replaced with the correct file.

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Werynski, A., Li, CX., Hao, Y. et al. Not marginal but central: type I interferons unleash marginal zone B cells in Sjögren’s disease. Cell Mol Immunol 22, 1642–1644 (2025). https://doi.org/10.1038/s41423-025-01353-z

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