Yuan Liu

Thymic negative selection is characterized by the apoptosis of autoreactive thymocytes and plays a critical role in maintaining self‐tolerance. Numerous apoptosis‐related genes influence cell fate during T‐cell development. The PERP protein functions in apoptosis induction and as a tumor suppressor; however, p53 targets the Perp promoter, leading to its downregulation in various cancers. We investigated the specific role of Perp by studying conditional knock‐out mice exhibiting partial thymic T‐cell development defects and a significant accumulation of thymic CD4SP T‐cells. Ex vivo and in vivo analyses revealed that Perp regulates the survival of thymic T‐cell subsets during clonal deletion, particularly CD4SP T‐cells following TCR stimulation. These floxed mice also exhibited an expansion of the Helios ⁺ CD4SP thymocyte population. Moreover, middle‐aged floxed mice exhibited excessive accumulation of activated CD4 ⁺ T‐cells in peripheral blood, alongside T cell‐mediated autoimmune arthritis. These findings indicate that conditional Perp knockout mice exhibit a deficiency in thymic negative selection and heightened susceptibility to autoimmunity with aging.

The management of rheumatoid arthritis (RA) has advanced into the realm of targeted therapies; however, these therapies often lack tissue specificity and cause systemic adverse effects. Fibroblast-activating protein α (FAPα⁺) expressing fibroblast-like synoviocytes (FLSs) are critical pathogenic cell components in RA and are particularly abundant in inflamed joints, whereas they are minimal in other tissues. Consequently, FAPα⁺ FLSs are emerging as promising therapeutic targets for treating RA. However, strategies to specifically target FAPα⁺ FLSs in RA remain underdeveloped. To bridge this gap, we developed a novel compound, FAPI-Gly-Pro-MTX (FM), which integrates a FAPα⁺ tracer, FAPα inhibitor (FAPI), with the traditional drug methotrexate (MTX) via a glycine-proline dipeptide that can be cleaved by the dipeptidyl peptidase activity of FAPα. In an arthritis mouse model, FM selectively targeted FAPα⁺ FLSs in inflamed joints, facilitating the localized release of MTX and resulting in the significant alleviation of arthritis symptoms while minimizing systemic toxicity. Importantly, the presence of FAPI ensured that FM induced cell death specifically when FAPα⁺ FLSs were presented, thereby enhancing safety. Consequently, FM demonstrated considerable clinical potential as a safe and effective off-the-shelf therapeutic option for targeting FAPα⁺ FLSs in patients with RA. a FAPα⁺ FLSs are induced by various inflammatory cytokines in inflamed joints and aggravate inflammation and bone destruction; b FM selectively delivers MTX to FAPα⁺ FLSs in RA-inflamed joints and minimizes off-target effects; c Conventional MTX administration lacks cell specificity, leading to systemic adverse effects.

The disease "Sjögren syndrome" has been widely known as a "syndrome" for a long time. However, this nomenclature and its classification as "primary" and "secondary" have raised debates in recent years. The word "syndrome" denotes an aggregate of symptoms and signs that are associated with a morbid process, independent of pathogenesis. It is now well recognized that "Sjögren syndrome" is an independent systemic autoimmune disease with specific clinical manifestations, serological markers and associated underlying pathogenesis mechanisms. Thus, the use of "syndrome" to designate this disease is not accurate. Furthermore, the traditional distinction between "primary" and "secondary" forms fails to account for the complex interplay between overlapping autoimmune diseases. Based on this background, the International Task Force on Nomenclature of Sjögren disease was established with the aim to develop a rational consensus on the nomenclature of Sjögren syndrome. Following the literature review and collecting experiences from both international professionals as well as patients, the International Task Force on Nomenclature of Sjögren disease published the "2023 International Rome Consensus for the Nomenclature of Sjögren disease" in 2025. The consensus issued five recommendations, officially recommended the use of "Sjögren disease" as nomenclature for this disease, and the acronym "SjD" be used for its abbreviation. It also recommended the descriptor "associated" should be used in lieu of "secondary" for Sjögren disease occurring in association with a second systemic autoimmune disease. The change from "Sjögren syndrome" to "Sjögren disease" improved clarity in both clinical practice and research, highlighted the distinct pathogenesis of this disorder.

Viral infections are implicated in the pathogenesis of autoimmune diseases, including Sjögren’s disease (SjD), but the mechanisms linking viral antigens to disease development remain poorly understood. To address this, we conducted shotgun metagenomic sequencing of saliva samples from 35 patients with SjD and 25 healthy controls. The salivary virome of the patients with SjD, particularly those with high disease activity, had an expansion of Siphoviridae bacteriophages and increased eukaryotic viral sequences, including Vientovirus. This virus was associated with lacrimal gland dysfunction and elevated anti-SSA/Ro52 autoantibody levels. Alignment analysis and cross-blocking assay identified molecular mimicry between the Vientovirus capsid protein and the autoantigen SSA/Ro52. Mice immunized with a Vientovirus capsid peptide developed anti-SSA/Ro52 antibodies and showed immunological features resembling those of patients with SjD. These findings highlight distinct virome profiles in SjD and provide mechanistic evidence supporting the role of Vientovirus in triggering autoimmunity through molecular mimicry.

Objective: Corticosteroid‐resistant secondary immune thrombocytopenia (ITP) is a challenging condition in clinical practice. This study aimed to explore the clinical and immunological characteristics of corticosteroid‐resistant secondary ITP associated with connective tissue diseases (CTD‐ITP).Methods: We conducted a retrospective analysis of 201 CTD‐ITP hospitalized patients between 2014 and 2022. Patients were categorized as corticosteroid‐resistant or corticosteroid‐sensitive, and their demographic, clinical, and immunological data were compared. Logistic regression analysis was employed to identify independent predictors of corticosteroid resistance.Results: Corticosteroid resistance was observed in 27.4% of patients. Compared with the corticosteroid‐sensitive group, the corticosteroid‐resistant group exhibited a higher percentage of CD3⁺ T cell (71.38% vs. 64.70%, p = 0.004) and CD3⁺CD8⁺ T cell (38.55% vs. 28.95%, p = 0.003), but a lower percentage of CD19⁺ B cell (13.70% vs. 22.45%, p = 0.001) in peripheral blood. No significant differences were found in other demographics, clinical features, or autoantibody profiles. The multivariable logistic regression analysis showed that higher percentage of CD3⁺CD8⁺ T cells (OR = 1.170, 95% CI: 1.014–1.350, p = 0.031) was an independent risk factor for corticosteroid resistance in CTD‐ITP patients.Conclusion: This study revealed the potential role of higher CD3⁺CD8⁺ T cells in corticosteroid resistance among CTD‐ITP patients, and provided the potential biomarker for predicting corticosteroid therapy response.

Objective To investigate the prevalence, clinical and immune characteristics of patients with primary Sjögren syndrome (pSjS) with positive thyroid autoantibodies (TABs) in Chinese population. Methods 391 cases of pSjS were retrospectively analyzed. Patients with positive thyroid autoantibodies (TABs), the presence of either thyroglobulin antibody (TG-Ab), thyroid peroxidase antibody (TPO-Ab), or thyrotropin receptor antibody (TR-Ab), or any combination of these were defined as positive TABs group, and patients without any TABs were defined as negative TABs group. The clinical manifestations and laboratory results were compared between the two groups. Results Among the 391 pSjS patients, the TABs were positive in 32.99% (129/391) patients. In the positive TABs group, the prevalence of Raynaud phenomenon was higher, the prevalence of interstitial lung disease (ILD) and low complement 4 (C4) level were significantly lower. Additionally, the levels of serum globulin, immunoglobulin (Ig) G and IgM were higher compared with patients with negative TABs. Age, ILD, RF and anti-SSA were negatively correlated with the coexistence of TABs, while C-reactive protein (CRP) was positively correlated. Conclusion PSjS was closely related to autoimmune thyroid abnormalities. The prevalence of autoimmune thyroid diseases (AITDs) and TABs in pSjS was high, pSjS patients with positive TABs might represent a milder subset of the disease with a better prognosis with low risk of ILD. Key Points • PSjS was closely related to autoimmune thyroid abnormalities, the prevalence of autoimmune thyroid diseases (AITDs) and TABs in pSjS were high. • The prevalence of interstitial lung disease (ILD) and low complement 4 (C4) level were significantly lower in the positive TABs group. PSjS patients with positive TABs may represent a milder subset of the disease with a better prognosis.

Objective Axial spondyloarthritis (axSpA) is characterized by active inflammation and structural damage. To date, there is no imaging tool can alone visualize all those changes well. PET/CT imaging with gallium-68-labeled fibroblast activation protein inhibitor (⁶⁸Ga-FAPI) provide extra ability for CT in detecting active inflammation in addition to its advantage in assessing structural damage. This study aims to explore the utility of ⁶⁸Ga-FAPI-46 PET/CT for assessing active inflammation in axSpA. Methods Between July 2023 to July 2024, 22 patients with axSpA and 12 healthy volunteers were prospectively enrolled. Disease activity and parameters associated with inflammation were evaluated at enrollment. Participants then underwent ⁶⁸Ga-FAPI-46 PET/CT for assessment of FAPI uptake across joints. ⁶⁸Ga-FAPI-46 uptake was semi-quantitatively evaluated by using a three-point scale. The sum of points was calculated to generate ⁶⁸Ga-FAPI-46 PET/CT-derived FAPI uptake scores. Patients receiving biologics therapy were grouped as responders or non-responders according to clinical follow-up. Results Compared to healthy volunteers, patients with axSpA exhibited significantly higher ⁶⁸Ga-FAPI-46 uptake in several joints, especially in spine (p < 0.001). ⁶⁸Ga-FAPI-46 PET/CT scores in spine showed strong correlation with the Ankylosing Spondylitis Disease Activity Score (ASDAS), inflammatory indicators such as c-reactive protein (CRP), and inflammation visualized by magnetic resonance imaging (MRI). Biologic responders displayed markedly higher baseline ⁶⁸Ga-FAPI-46 PET/CT scores in the spine (median: 36.5 vs. 4.0, p = 0.017) and total joints (median: 53.5 vs. 11.0, p = 0.015) compared to non-responders. Conclusion ⁶⁸Ga-FAPI-46 PET/CT has the potential to serve as a dual-function imaging tool, integrating the structural imaging capabilities of CT with the ability to detect inflammation. Clinical trial registration NCT05999643.

Background: Dyslipidemia presents in various autoimmune diseases, and the serum lipid profile in systemic lupus erythematosus (SLE) has not yet been clearly defined. This study aims to evaluate the level of serum lipids in patients with SLE.Methods: A case–control study evaluated four conventional sera lipids—total cholesterol (TC), triglyceride (TG), high-density lipoprotein (HDL), and low-density lipoprotein (LDL)—in patients with SLE compared to healthy controls (HCs). Correlations between serum lipids and clinical characteristics were analyzed in patients with SLE. A systematic review and meta-analysis were conducted to assess the epidemiology of lipid profiles in patients with SLE, and a random-effects meta-analysis was performed for data synthesis.Results: TC and TG were elevated significantly, and HDL decreased in patients with SLE compared to HCs. Elevated lipids were associated with progressive disease activity. TC, TG, and HDL were elevated in patients with SLE and were associated with decreased IgG, increased 24-h proteinuria, white blood cells (WBCs), and neutrophils. Decreased HDL and increased TG were associated with an increase in the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI). Patients with SLE who took glucocorticoids (GCs) may have experienced increases in TC and TG, while those who took hydroxychloroquine (HCQ) may have experienced increases in TC and HDL. Eleven eligible studies including the present study on associations between serum lipids and SLE were reviewed by the meta-analysis. The results demonstrated elevated TC (MD = 0.85, 95% CI 0.82 to 0.89, p < 0.00001) and TG (MD = 0.96, 95% CI 0.94 to 0.99, p < 0.00001) levels in SLE, while HDL decreased (MD = −0.19, 95% CI −0.20 to −0.17, p < 0.00001).Conclusions: Dyslipidemia is present in SLE. There was a significant association between SLE disease activity and TC, TG, and HDL. The exact pathogenesis of metabolic disorders in SLE needs to be further addressed.

Minor salivary gland (MSG) biopsy is a critical but invasive method for the classification of primary Sjögren’s disease (pSjD). Here we aimed to identify salivary proteins as potential biomarkers and to establish a non-invasive prediction model for pSjD. Liquid chromatography-tandem mass spectrometry was conducted on whole saliva samples from patients with pSjD and non-Sjögren control subjects (non-pSjD). Proteins involved in immune processes were upregulated in the pSjD group, such as complement C3 (C3), complement factor B (CFB), clusterin (CLU), calreticulin (CALR), and neutrophil elastase (NE), which were further confirmed by ELISA. Multivariate logistic regression analyses were performed to identify markers that differentiated pSjD from non-pSjD; receiver operating characteristic (ROC) curves were constructed. A diagnostic model based on the combination of salivary biomarkers (CFB, CLU, and NE), serum autoantibodies (anti-SSA /Ro60 and anti-SSA/Ro52), and Schirmer’s test was evaluated in 186 patients (derivation cohort) with replication in 72 patients (validation cohort). In multivariate analyses, CFB, CLU, and NE were independent predictors of pSS. A model based on the combination of salivary biomarkers (CFB, CLU, and NE), serum autoantibodies (anti-SSA and anti-Ro52), and Schirmer’s test achieved significant discrimination of pSS. In the derivation cohort, the area under curve (AUC) of the ROC was 0.930 (95% CI 0.877–0.965, P < 0.001), with a sensitivity and specificity of 84.85% and 92.45%, respectively. Notably, similar results were obtained in a validation cohort. The 6-biomarker panel could provide a novel non-invasive tool for the classification of pSjD.