Spatial transcriptomic analysis identifies a necroptosis-prone thyroid follicular cell state in Hashimoto’s thyroiditis

Endoplasmic reticulum stress in Hashimoto’s thyroiditis: a candidate amplification node linking thyroid-specific vulnerability and immune dysregulation

A testable positive-feedback perspective in which thyrocyte ERS injury and immune effector amplification may mutually reinforce one another is proposed, in which thyrocyte ERS injury and immune effector amplification may mutually reinforce one another.

Thyroid follicular cell-derived GDF15 attenuates inflammation and lipid dysregulation in Hashimoto's thyroiditis

Findings suggest a significant association between GDF15 and HT, though further research is required to establish definitive causality and reflect the limitations of the NaI-induced model.

Single-cell and spatial transcriptome profiling reveals innate-adaptive crosstalk in alopecia areata 2251484

Alopecia areata (AA) is an autoimmune disorder characterized by immune-mediated attack on hair follicles, resulting in non-scarring hair loss. The collapse of hair follicle (HF) immune privilege (IP) is widely regarded as a central pathogenic mechanism in AA. While CD8+ T cells have been extensively studied in this context, the contribution of macrophages to disease initiation and progression remains less defined. In this study, we investigated the roles of macrophages and CD8+ T cells in shaping immune cell recruitment and local immune dysregulation in AA lesions. Using single-cell transcriptomics, flow cytometry, and immunofluorescence during the development of an AA mouse model, we observed robust expansion and transcriptional reprogramming of CD8+ T cells, accompanied by prominent macrophage infiltration surrounding affected HFs. Interrogation of macrophage populations identified two transcriptionally distinct subpopulations: Folr2+ tissue-resident macrophages (TRMacs) and Folr2⁻ monocyte-derived macrophages (MoMacs). Each subset displayed unique gene-expression profiles enriched for pathways involved in T cell activation, leukocyte trafficking, and myeloid differentiation. Integration of spatial transcriptomic and flow cytometry imaging analyses revealed close spatial interactions between macrophage subsets and CD8+ T cells, with macrophage abundance positively correlating with CD8+ T cell infiltration. To assess functional relevance, we depleted macrophages with an antibody directed against colony-stimulating factor 1 receptor (CSF1R) in AA-grafted mice. Macrophage ablation markedly reduced both hair loss severity and the accumulation of cytotoxic NKG2D+ CD8+ T cells in lesional skin. Together, these findings support that macrophages play a pivotal role in driving local immune dysregulation in AA. Targeting macrophage subsets may represent a promising therapeutic approach for restoring HF immune privilege and ameliorating disease progression. n/a Basic Autoimmunity (BA)

MICA gene modulates immune microenvironment and comorbid mechanisms in diffuse large B-cell lymphoma and primary Sjögren’s syndrome

Integrated histopathology and single-cell transcriptomics reveal distinct pathological features and foamy macrophage characteristics in spinal tuberculosis and brucellar spondylitis

Background Spinal tuberculosis (STB) and brucellar spondylitis (BS) show substantial overlap in clinical and imaging manifestations, but their local immunopathological programs and corresponding cellular states have not been systematically compared. This study integrated histopathology and single-cell transcriptomics to compare lesion-level differences between STB and BS and to characterize macrophage states associated with the foamy cell reaction. Methods This retrospective case-control study included 80 STB cases and 80 BS cases treated between January 2020 and December 2024. H&E-stained lesion tissues from the full surgical cohort were reviewed for comparative histopathology. Fresh lesion nucleus pulposus tissue from six representative cases (STB = 3, BS = 3) underwent scRNA-seq re-analysis with cell-type annotation, myeloid subclustering, functional module scoring, GSVA, and CellChat analysis. Dual immunofluorescence for CD68 paired with CYP27A1, PLIN2, or PPARγ was used as tissue-level validation. The scRNA-seq workflow focused on the monocyte-macrophage lineage to evaluate lipid-remodelled states associated with the foamy cell reaction. Tissue-level immunofluorescence and supplementary statistical summaries were interpreted as orthogonal support for the transcriptomic findings rather than as stand-alone diagnostic criteria. Results Histopathological comparison showed that STB and BS were both dominated by chronic inflammation but exhibited distinct lesion patterns. STB was characterized mainly by tuberculous nodules, caseous necrosis, Langhans giant cells, and granulomatous inflammation, whereas BS more often showed plasma cell infiltration, foamy cell reaction, eosinophil infiltration, and fibrotic repair. These between-group differences were statistically significant (P < 0.05 or P < 0.01, as appropriate). scRNA-seq yielded 67,274 high-quality cells and identified nine major cell types. Re-clustering of the Mono_Macrophage_DC lineage identified 15 subclusters, among which Macro4 was relatively enriched in BS. Rather than showing the highest value for every broad foam-cell-related metric, Macro4 was supported by convergent evidence including relative enrichment in BS, coordinated expression of PPARG, APOE, APOC1, PLIN2, and CYP27A1, and higher lipid-droplet-formation and cholesterol-efflux-related programs in BS_Macro4. Dual immunofluorescence showed higher CD68-normalized overlap fractions for CYP27A1, PLIN2, and PPARγ in BS lesion tissues than in STB lesion tissues (P < 0.05). CellChat analysis further suggested that Macro4 contributed relatively more to the HGF-MET signalling context in BS, although these ligand-receptor relationships should be interpreted as transcriptome-inferred candidate interactions. Conclusions STB and BS exhibit distinct local immunopathological programs. STB is characterized by a granulomatous-necrotizing inflammatory pattern, whereas BS more often shows a chronic inflammatory and tissue-repair-associated lesion background with a more prominent foamy cell reaction. Macro4 is best interpreted as a BS-associated lipid-remodelled macrophage state supported by convergent histological and transcriptomic evidence. These findings provide a lesion-level cellular framework for further pathological and mechanistic study rather than a validated stand-alone diagnostic cutoff.

Spatial transcriptomic analysis of kidney biopsies identifies activation of complement and SPP1 networks in Staphylococcus infection-associated glomerulonephritis

Background Staphylococcus infection-associated glomerulonephritis (SAGN) has emerged as the leading cause of infection-related glomerulonephritis (IRGN) in the Western subcontinents, but pathogenesis remains poorly understood in the absence of animal models and detailed molecular mechanisms. Methods To dissect the complex underlying immunopathology, we analyzed formalin-fixed paraffin-embedded kidney biopsy tissues from three patients with SAGN and one normal control kidney (NCK) using single-cell spatial transcriptomics (analyzing a total of 3,993 cell-specific transcriptomes). The SAGN biopsies showed diffuse endocapillary hypercellularity with focal crescents. Following annotation of various cell types, we constructed cell communication networks using CellChat to identify ligand–receptor interactions in normal and SAGN kidneys. Results Secreted phosphoprotein 1 (SPP1/osteopontin) emerged as the most enriched signaling network in SAGN with markedly increased autocrine and paracrine SPP1–CD44 activity among tubular segments and parietal epithelial cells (PECs). In contrast, SPP1-integrin signaling was mainly observed in healthy control kidneys. Consistent with previous reports, complement pathway activation was detected exclusively in diseased kidneys, with PECs as principal signal receivers, suggesting the potential role in crescent formation. Transcripts for C2, C3, CD55, Factor B, and Factor D showed significant upregulation in SAGN. In contrast, vascular endothelial growth factor (VEGF), angiopoietin-like proteins (ANG PTL), and progranulin/granulin networks exhibited decreased communication probabilities in SAGN versus NCK, suggesting the suppression of protective angiogenic and anti-inflammatory signaling. Immunofluorescence staining for SPP1 showed increased staining in renal tubular segments in SAGN biopsies, supporting our transcriptomic data. Conclusion SPP1 and complement pathways appear to drive pro-inflammatory responses, while protective VEGF signaling is compromised, providing potential therapeutic targets for this disease.