Xiang Lin

Sjögren’s disease (SjD) is a chronic autoimmune disorder characterized by progressive dysfunction of the exocrine glands, driven primarily by aberrant T- and B-cell activation. Current therapeutic strategies remain largely symptomatic and are frequently limited by off-target effects and long-term toxicity, underscoring an urgent need for safer, mechanism-based adjunctive approaches. In recent years, nutritional interventions and medicinal herbs have emerged as promising complementary strategies, owing to their capacity to modulate immune–metabolic pathways and restore immune homeostasis. Nutrients such as n-3 polyunsaturated fatty acids (PUFAs) and short-chain fatty acids (SCFAs) exert well-documented anti-inflammatory effects and influence immune cell differentiation via immunometabolic reprogramming. Concurrently, bioactive constituents derived from medicinal herbs offer multi-target regulation of inflammatory signaling and lymphocyte function. This review synthesizes current advances in the immunomodulatory roles of dietary components and edible herbs in the context of SjD, focusing on their mechanistic convergence on T-cell subsets, B-cell responses, and the gut–immune axis. By integrating traditional knowledge with contemporary immunological insights, this article aims to provide a conceptual framework for the rational integration of nutritional and herbal strategies into the clinical management of SjD.

Type I interferon (IFN-I) is highly prevalent in autoimmune disorders and is intricately involved in disease pathogenesis, including Sjögren’s disease (SjD), also known as Sjögren’s syndrome. Although the T follicular helper (Tfh) cell response has been shown to drive SjD development in a mouse model of experimental Sjögren’s syndrome (ESS), the connection between IFN-I and the Tfh cell response remains unclear. As the activation of stimulator of interferon genes (STING) induces IFN-I production, we first demonstrated that mice deficient in STING or IFN-I signaling presented diminished Tfh cells and were completely resistant to ESS development. However, the STING–IFN-I axis does not directly influence Tfh cell differentiation. Instead, IFN-I signaling in B cells was essential for mounting Tfh cell responses, as evidenced in Cd19CreIfnar1flox mice, which also showed resistance to ESS development. Mechanistic analyses revealed that IFN-I drove CXCR5 expression in innate-like marginal zone B cells via the MEKK3–OCT2 axis, facilitating their migration into the follicular area. Additionally, IFN-I promoted interleukin-6 production in B cells via the MEKK3–ERK5 axis, resulting in hyperactive Tfh cell responses. In SjD patients, STING activation was predominantly observed in circulating CD14+ monocytes and was positively correlated with disease activity and effector T-cell responses. Pharmaceutical inhibition of either STING or IFNAR1 yielded moderate improvements in ESS mice with chronic inflammation, but combination therapy markedly improved outcomes and led to signs of disease remission. Our findings elucidate a novel mechanism by which IFN-I bridges innate and Tfh cell responses, suggesting new therapeutic avenues for SjD and related autoimmune disorders.

Sjögren's disease (SjD), or Sjögren's syndrome, is a chronic autoimmune condition that targets exocrine glands, leading to dryness symptoms. With the treatment plan for SjD having remained unchanged for the past decade, there is a critical need for innovative therapeutic strategies. To bridge the gap between mouse models and human patients, we have established a mouse model of experimental Sjögren's syndrome with a human immune system (HIS‐ESS). Immunizing mice with antigens derived from human salivary epithelial cells results in HIS‐ESS mice that display clinical features of SjD that include salivary dysfunction, increased serum autoantibodies, and dysregulated immune responses. Effector T cell subsets such as Th1, Th17, and T follicular helper (Tfh) cells are also elevated in HIS‐ESS mice. Thus, this humanized model can effectively recapitulate SjD outcomes and immunopathogenesis, offering a promising platform for drug screening and preclinical research. © 2025 Wiley Periodicals LLC.Basic Protocol: Establishment of humanized mouse models of primary Sjögren's syndromeSupport Protocol 1: Irradiation of neonatal miceSupport Protocol 2: Preparation of proteins from A‐253 human salivary epithelial cellsSupport Protocol 3: Determination of mouse saliva flow rate

T follicular helper (Tfh) cells are crucially involved in the pathogenesis of autoimmune disorders, including Sjögren’s disease (SjD, also known as Sjögren’s syndrome), by promoting effector B cell responses and autoantibodies production. However, targeting Tfh cells remains challenging. In this study, we identified that calycosin (Caly), a natural flavonoid, effectively suppressed pathogenic Tfh cell responses, although it did not affect the plasmacytic differentiation of B cells. Under Tfh polarization conditions, Caly rapidly bound to the master transcription factor, BATF, in both human and murine CD4⁺ T cells and thus potently disrupted BATF-mediated Maf gene transcription. Methotrexate (MTX), a first-line medication in the treatment of autoimmune disorders, mainly suppresses B cell responses but fails to target Tfh cells. In a mouse model of experimental Sjögren’s syndrome (ESS) that we previously established, MTX synergized with Caly in attenuating the disease pathology and autoantibodies in ESS mice with chronic inflammation, with signs of disease remission. This immunomodulatory function was also validated in peripheral blood mononuclear cells from patients with SjD. Thus, Caly may serve as a novel inhibitor of BATF in suppressing Tfh-cell-mediated humoral autoimmunity and elicit a synergistic effect in combination with B-cell-targeting strategies.

Recreational use of nitrous oxide (N₂O) has risen dramatically over the past decades. This study aimed to examine its rewarding effect and the underlying mechanisms. The exposure of mice to a subanesthetic concentration (20%) of N₂O for 30 min for 4 consecutive days paired with N₂O in the morning and paired with the air in the afternoon produced apparent rewarding behavior in the conditioned place preference (CPP) paradigm. This was abrogated by microinjection into the nucleus accumbens (NAc) of the dopamine (DA) D1 receptor antagonist SCH23390, but not the D2 antagonist haloperidol. N₂O robustly enhanced DAergic neuronal activity of the ventral tegmental area (VTA) and the concentration of DA in the NAc. The repeated N₂O exposure also upregulated the expression of brain-derived neurotrophic factor (BDNF) in the VTA and its multiple downstream mediators in the NAc. Conversely, VTA focal knockdown of BDNF and the inhibition of the downstream mediators suppressed the N₂O-induced rewarding effect and the DAergic neuronal activity of the VTA. Further, the combined intervention of BDNF knockdown and D1 antagonist significantly inhibited the N₂O-induced rewarding effect in mice, which was greater than that of BDNF knockdown alone, but was not significantly different from that of D1 antagonist alone. These results indicate that the rewarding properties of N₂O at subanesthetic concentration are associated with its upregulation of the VTA-NAc DA reward pathway probably via mediation of D1 receptor and BDNF/TrkB signaling. Among them, the modulation of BDNF may be the upstream of D1 receptor involved in N₂O rewarding effect.

Regulatory B cells (Bregs) play a crucial role in maintaining immune tolerance and preventing autoimmune diseases. However, in autoimmune conditions, the quantity and function of Bregs are often impaired, leading to pro-inflammatory microenvironment and immune dysregulation. This review provides an in-depth examination of how Bregs are affected in various autoimmune diseases, including multiple sclerosis, rheumatoid arthritis, systemic lupus erythematosus, Sjögren’s disease, autoimmune diabetes, and other autoimmune conditions. By summarizing the alterations in Bregs phenotype and function in these specific diseases, we conclude that the Bregs response is complex and variable, showing inconsistent trend across different diseases or even within the same disease. Thus, understanding the heterogeneous nature of Bregs in the autoimmune pathogenesis facilitates novel therapeutic strategies to re-establish immune equilibrium.

Sjögren’s syndrome (SS) or Sjögren’s disease (SjD) is a systemic autoimmune disease clinically manifested as sicca symptoms. This disease primarily impacts the functionality of exocrine glands, specifically the lacrimal and salivary glands (SG). SG fibrosis, an irreversible morphological change, is a severe consequence that occurs in the later stages of the disease due to sustained inflammation. However, the mechanism underlying SG fibrosis in SS remains under-investigated. Glandular fibrosis may arise from chronic sialadenitis, in which the interactions between infiltrating lymphocytes and epithelial cells potentially contributes to fibrotic pathogenesis. Thus, both immune and non-immune cells are closely involved in this process, while their interplays are not fully understood. The molecular mechanism of tissue fibrosis is partly associated with an imbalance of immune responses, in which the transforming growth factor-beta (TGF-β)-dependent epithelial-mesenchymal transition (EMT) and extracellular matrix remodeling are recently investigated. In addition, viral infection has been implicated in the pathogenesis of SS. Viral-specific innate immune response could exacerbate the autoimmune progression, resulting in overt inflammation in SG. Notably, post-COVID patients exhibit typical SS symptoms and severe inflammatory sialadenitis, which are positively correlated with SG damage. In this review, we discuss the immune and non-immune risk factors in SG fibrosis and summarize the evidence to understand the mechanisms upon autoimmune progression in SS.

Ethnopharmacological treatments have shown beneficial effects in the clinical practice of autoimmune disorders. However, the underlying mechanism of immunomodulatory effects remains challenging, given the complicate composition of herbal medicines. Here, we developed an immunological approach to interrogate the T helper cell response. Through data mining, we hypothesized that Chinese medicine formula Yu-Ping-Feng might be a promising candidate for treating primary Sjögren syndrome, a common autoimmune disease manifested by exocrine gland dysfunction. We took advantage of a mouse model of experimental Sjögren syndrome that we previously established for Yu-Ping-Feng formula treatment. Yu-Ping-Feng therapy ameliorated the experimental Sjögren syndrome pathology in mice with active disease, showing improved salivary function and decreased serum levels of autoantibodies. Phenotypic analysis suggested that both effector T and B cells were significantly suppressed. Using coculture assay and adoptive transfer models, we demonstrated that Yu-Ping-Feng formula directly restrained effector/memory T-cell expansion and differentiation into Th17 and T follicular helper cells, the key subsets in experimental Sjögren syndrome pathogenesis. Importantly, we recruited 20 patients with primary Sjögren syndrome and conducted a pilot study of 8-wk therapy of Yu-Ping-Feng formula. Yu-Ping-Feng treatment effectively improved fatigue symptoms and exocrine gland functions, as well as reduced serum IgG/IgA levels, while effector T- and B-cell subsets were significantly decreased. There was a trend of reduction on disease activity, but not statistically significant. Together, our findings suggest a novel approach to assess the immunomodulatory effects of Yu-Ping-Feng formula, which may be favorable for patients with autoimmune disorders.