Jing He

Low-density granulocytes (LDGs) have been implicated in the pathogenesis of several autoimmune diseases, yet their role in Sjögren’s disease (SjD) remains poorly understood. We enrolled 90 SjD patients and 30 healthy controls (HCs) and identified LDGs as CD14^−/lowCD15⁺ cells by flow cytometry, with intracellular interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α) staining, and further analyzed CD16 as a maturation marker in LDGs and T helper 17 (Th17) cell frequency. LDG percentages were significantly elevated in active SjD compared with inactive patients (p < 0.001) and HCs (p < 0.0001), and correlated positively with EULAR Sjögren’s Syndrome Disease Activity Index (ESSDAI) (r = 0.355, p = 0.0006), erythrocyte sedimentation rate (ESR) (r = 0.325, p = 0.0061), γ-globulin (r = 0.334, p = 0.0177), and Th17 frequency (r = 0.537, p = 0.0068). LDG expansion was accompanied by enrichment of immature CD16^−/low cells (r = −0.798, p = 0.0100). Patients with renal or pulmonary involvement showed higher LDG levels (p = 0.0004), and in SjD -associated interstitial lung disease (SjD-ILD) patients, LDG percentage showed a positive but non-significant trend with serum Krebs von den Lungen-6 (KL-6) levels (r = 0.497, p = 0.102). LDG levels decreased following treatment in longitudinally followed patients, and LDGs from active patients exhibited higher IL-6 and TNF-α production ratios relative to monocytes than those from inactive patients. Stratification by LDG levels revealed significant associations with disease activity, laboratory parameters, and organ involvement. These findings suggest that LDGs are associated with disease activity and organ involvement, may serve as potential biomarkers, and may contribute to the pathogenesis of SjD.

Cerebral malaria (CM) is a severe complication of Plasmodium infection, classically attributed to parasite sequestration and neuroinflammation. Here, we uncover a spleen-centered humoral autoimmune circuit that drives CM pathology. Proteomic analyses identify CD36 as a dominant host-derived antigen enriched in infected red blood cells (iRBCs), triggering anti-CD36 autoantibody production in patients with falciparum malaria. Although contributing to iRBCs clearance, these autoantibodies also target other CD36-expressing cells, thereby driving thrombocytopenia, endothelial injury, and macrophage activation, ultimately amplifying systemic inflammation. Mechanistically, Plasmodium infection recruits Ly6c⁺Glut1^hi macrophages to the spleen through the CCL2-CCR2 axis. These macrophages exhibit elevated proteasome activity and drive B cell activation and anti-CD36 antibody production. Targeting Ly6c⁺Glut1^hi macrophages, we develop Glutoborin, a GLUT1-directed proteasome inhibitor that preferentially suppresses their function, reduces autoantibody production, and alleviates CM-associated pathology in vivo. Together, these findings establish a spleen-centered anti-CD36 autoimmune circuit as a key driver of CM and nominate Ly6c⁺Glut1^hi macrophages as therapeutic targets.

To evaluate the clinical characteristics of leukopenia in hospitalized patients with Sjögren's disease (SjD), particularly its association with systemic organ involvement, immunological activity, and disease duration. This retrospective exploratory study of 200 hospitalized patients with SjD admitted to a tertiary medical center between 2017 and 2023. Patients were divided into leukopenia and normal white blood cell (WBC) groups according to WBC count. Demographic characteristics, hematologic parameters, inflammatory and immunological markers, and systemic organ involvement were compared between groups. Among patients with leukopenia, disease duration was further stratified into tertiles to explore duration-related patterns. Where data are available, multivariable logistic regression should be performed to explore whether leukopenia is associated with selected systemic manifestations after adjustment for disease duration and treatment exposure. Leukopenia occurred in 67 of 200 patients (33.5%). Compared with patients with normal WBC counts, patients with leukopenia had lower hemoglobin and platelet counts. The proportions of interstitial lung disease (ILD), pulmonary hypertension/suspected pulmonary arterial hypertension, peripheral nervous system involvement, and skin, joint, and muscle involvement were not significantly different between the leukopenia and normal WBC groups. In the leukopenia group, however, the prevalence of ILD increased across disease-duration quartiles, from 14.8% in Q1 (≤ 3 years) to 40.7% in Q4 (> 11 years). IgG and erythrocyte sedimentation rate were higher in early-duration leukopenic patients and lower in later-duration strata, suggesting a possible change in inflammatory activity rather than proven immune exhaustion. In this hospitalized SjD cohort, leukopenia was a common hematologic abnormality but was not significantly associated with most systemic manifestations in direct between-group comparisons. Within the leukopenic subgroup, a higher prevalence of ILD was observed across longer disease-duration strata, a hypothesis-generating finding rather than evidence of progression. These observations warrant validation in prospective longitudinal studies with standardized disease activity assessments, detailed treatment exposure records, and leukocyte subset analyses. Key Points • Leukopenia is common in Sjögren's disease, affecting approximately one-third of patients in this hospitalized cohort. • In leukopenic patients, longer disease duration is associated with a higher prevalence of ILD, an exploratory finding that warrants prospective validation rather than evidence of progression. • IgG and ESR levels decline across disease-duration strata in leukopenic patients, which may reflect duration- or treatment-related immune remodeling and not proven immune exhaustion.

Immune-related adverse events (irAEs) are associated with anti-PD-1/PD-L1 therapy in gastrointestinal cancers. Altered phenotypes and frequencies of T cell subsets play a critical role in irAEs. This study characterized the Tfh/Treg balance in irAEs patients and assessed the efficacy of LDIL-2 therapy in mouse models. A prospective study evaluating the immunological characteristics of 26 gastrointestinal cancer patients through both cellular and transcriptomic analyses before and after anti-PD-1/PD-L1 therapy was performed. Patients were categorized into two groups: the AE group (patients who developed irAEs during the follow-up period) and the NAE group (patients who did not). Meanwhile, MRL/MpJ-Fas^lpr mice, a lupus mouse model, and tumor-bearing C57BL/6 J mice were used to evaluate the efficacy of LDIL-2 in treating anti-PD-L1 induced irAEs and its impact on antitumor effectiveness. Our study discovered that in AE patients, Tfh-related genes were significantly upregulated during the early stages of anti-PD-1/PD-L1 therapy (IL-21: p < 0.01; PDCD1: p < 0.05), whereas the upregulation of Treg-related genes was less pronounced compared to Tfh-related genes. This distinction was not observed in NAE patients. Flow cytometry results further confirmed a substantial increase in the Tfh/Treg ratio in AE patients during the early stages of therapy (p < 0.001), a phenomenon absent in NAE patients. In MRL/MpJ-Fas^lpr mice, anti-PD-L1 therapy induced a shift in the Tfh/Treg ratio, along with severe organ inflammatory lesions and elevated anti-dsDNA antibody levels. In contrast, LDIL-2 treated mice maintained a balanced Tfh/Treg ratio, exhibiting significantly fewer organ inflammatory lesions and reduced anti-dsDNA production. Furthermore, in tumor-bearing mice, LDIL-2 did not impair the antitumor efficacy of anti-PD-L1 therapy. Our study underscores the importance of Tfh/Treg balance in the development of irAEs and demonstrates the potential of LDIL-2 as a therapeutic option for irAEs, providing a promising alternative to traditional immunosuppressive therapies for managing irAEs.

Objective: Idiopathic retroperitoneal fibrosis (RPF) is considered a ‘silent disease’ due to the lack of distinct disease biomarker. Our purpose was to study characteristic changes in circulating lymphocytes in RPF patients and explore their roles in etiopathogenesis. Methods: Twenty-three RPF patients were enrolled and followed up for 48 weeks of treatment. Changes of T and B lymphocyte subsets in their peripheral blood were measured, and their associations with disease activity and severity were evaluated. The proliferation, secretion and chemotactic functions of circulating follicular helper T (cTFH) cells were assessed by flow cytometry and RNA sequencing following CD4+ T cell sorting. Results: Among the changed lymphocytes, cTFH cells present a distinct pattern compared with other autoimmune conditions. They were significantly reduced in RPF patients but positively correlated with disease severity and TFH expansion in fibrotic tissues. Remarkably, they were further declined upon disease amelioration, indicating their potential as a disease marker. Further investigation revealed unchanged proliferation and low cytokine secretion in these cTFH cells. Instead, chemokine CXCL13 expression was markedly elevated in CD4+ T cells isolated from both fibrotic tissues and peripheral blood of RPF patients, whereas key cytokines IL-21, IL-6 and Bcl were elevated only in the fibrotic tissues. Conclusion: Our findings suggest that cTFH cells in the circulating blood of RPF do not expand but may undergo chemotactic migration to fibrotic tissues, marking a distinct feature of RPF and may serve as a potential biomarker.

Objective: Arthralgia, an early manifestation preceding definite rheumatoid arthritis (RA), represents a critical window to identify high‐risk individuals and implement timely interventions. However, the immunopathologic mechanisms underlying the transition from arthralgia to established RA remain incompletely defined. Methods: We employed a multiomics strategy integrating peripheral immune cell phenotyping, serum proteomics, and autoantibody profiling to investigate the immunopathologic continuum from preclinical to established RA. A prospective cohort of 346 patients with recent‐onset arthralgia was enrolled. Participants included healthy controls, self‐limiting arthralgia (SLA), arthralgia at risk of RA (at‐risk individuals, ARI), early RA, and established RA. RA development in ARI was ascertained through 24‐month follow‐up. Results: Compared with SLA, ARI showed immune dysregulation, including reduced Treg cells and a lower Treg/Th17 cell ratio, with related changes persisting into early RA. Serum proteomics revealed upregulation of C5, α‐1‐B glycoprotein, RPUSD4, WDR87, and FUBP2, which showed inverse associations with Treg cells. Autoantibody profiling identified stage‐specific reactivity, with ARI showing elevated antibodies against stress‐related proteins. Within 24 months, 18.4% of ARI progressed to RA (converters). Baseline immunophenotypic differences between converters and nonconverters were comparable, whereas longitudinal paired analyses revealed a reduction in Treg cells and Treg/Th17 cell ratio. Treg/Th17 cell ratio (area under the curve [AUC] 0.734) outperformed anti–cyclic citrullinated peptide (CCP; AUC 0.611) in discriminating ARI from SLA, particularly in patients who are anticitrullinated peptide antibodies negative (AUC 0.729). Combining Treg cells, anti‐CCP and Treg/Th17 cell ratio improved classification performance (AUC 0.783). Conclusion: These findings delineate a critical transition from reversible immune dysregulation to established autoimmunity along the arthralgia–RA continuum, suggesting that Treg cell–related dysregulation may be associated with progression toward persistent inflammatory arthritis.

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.

Low-dose interleukin 2 (Ld-IL2) has shown therapeutic effects in autoimmune diseases, particularly systemic lupus erythematosus (SLE), yet optimal dosage has not been established in clinical trials. In this multicentre, double-blind, phase IIb trial, 152 patients with active SLE were randomised (1:1:1:1) to receive subcutaneous IL2 (0.2, 0.5, or 1.0 million IU) or placebo every other day for 12 weeks, then weekly for another 12 weeks. At week 12, SRI-4 response rates were higher in the IL2 1 M IU (69.7%), 0.5 M IU (64.7%), and 0.2 M IU (42.9%) groups than the placebo control group (23.5%). Notably, these differences persisted until week 24 (P < 0.001). Moreover, achievement of LLDAS increased in a dose-dependent manner. Patients who received 1 M IU also showed significant reductions in PGA scores, anti-dsDNA antibody titres and prednisone dosages. Infection rates were lower in the IL2 groups compared with placebo. Ld-IL2 drove the expansion of regulatory T cells (Tregs) and altered Treg/effector T cell ratios. These findings highlight the dose-dependent efficacy of IL2 with a favourable safety profile. (Clinicaltrials.gov registration number: NCT04077684).

Dry eye disease (DED) is one of the most common features of Sjögren’s Disease (SjD) and lacks effective disease-modifying topical treatment. Pre

Objectives: The current diagnosis of rheumatoid arthritis (RA) remain challenging, with more than one-third of patients facing diagnostic ambiguity due to a paucity of reliable biomarkers. Our previous studies have unveiled the autoantigen, scavenger receptor A (SR-A) and the corresponding autoantibody, anti-citrullinated SR-A peptide antibody (anti-CSP) with promising diagnostic value for seronegative RA. This study aimed to further evaluate the diagnostic efficacy and clinical significance of SR-A and anti-CSP combination for RA. Methods: A large-scale multicenter study was performed, including RA patients, healthy controls and patients with other common rheumatic diseases, i.e. osteoarthritis, Sjögren's syndrome, and systemic lupus erythematosus. Diagnostic properties of SR-A and anti-CSP combination together with the classical biomarkers, including anti-cyclic citrullinated peptide antibody (anti-CCP) and rheumatoid factor (RF) were assessed by the receiver operating characteristic curve, sensitivity, specificity, positive and negative predictive values. Diagnosis of RA was based on the 2010 ACR/EULAR classification criteria. Results: Large-scale multicenter analysis encompassing one discovery cohort and one training cohort from Beijing as well as two validation cohorts from Inner Mongolia and Henan (n = 1672) revealed that SR-A, anti-CSP and anti-CCP combination demonstrated the optimal potential to improve the diagnosis of RA. SR-A and anti-CSP combination achieved the sensitivity of 84% and the specificity of 90%, improving the sensitivity of SR-A by 23% (84% vs 61%) and anti-CSP by 24% (84% vs 60%). The incorporation of anti-CCP further increased the sensitivity to 90%, with the specificity remaining at 88%. Conclusion: Combination of SR-A, anti-CSP and anti-CCP significantly enhanced the diagnostic accuracy of RA.