Work

Spatial transcriptomics reveals distinct phenotype of proliferating and interferon-activated T lymphocytes in macrophage activation syndrome driven liver inflammation in systemic juvenile idiopathic arthritis

Year: 2026

Type: article

Abstract: Identify pathways and candidate biomarkers that distinguish various liver pathologies in systemic juvenile idiopathic arthritis (SJIA) with the focus on liver-predominant macrophage activation syndrome (SJIA-MAS). Formalin-fixed, paraffin-embedded liver tissues from SJIA-MAS ( n = 6), SJIA without MAS ( n = 1), autoimmune hepatitis (AIH, n = 7), familial HLH (FHLH, n = 6), steatohepatitis (SH, n = 3), and controls (Ctrl, n = 3) were analyzed by histology and using the NanoString GeoMx Digital Spatial Profiler (DSP). CD3E, CD68 and cytokeratin 8/18 antibodies were used to select regions enriched for T lymphocytes, macrophages, or hepatocytes, respectively. Spatially resolved gene expression data was Q3-normalized and subjected to principal component and clustering analysis. Differentially expressed genes were identified using Mann-Whitney U-test. Histologically, SJIA-MAS liver biopsies were distinguished by extensive portal and intra-sinusoidal expansion of activated CD163 + histiocytes and T lymphocytes (predominantly CD8+). Spatial transcriptomics revealed a markedly distinct phenotype in T lymphocyte enriched regions in SJIA-MAS liver tissue. In addition to pathways driving activation and survival, T lymphocyte regions in SJIA-MAS were distinguished by activation of IFNƔ-induced signaling including CXCL9 overexpression. Strong IFN-induced signatures were also observed in hepatocyte-enriched areas in SJIA-MAS and FHLH. T cell regions in SJIA-MAS could be distinguished by upregulated IFN-induced signaling. Considering that T cells have emerged as the main source of IFN-Ɣ in MAS, this may reflect an amplification loop contributing to uncontrolled activation and expansion of these cells. Our data also suggest that in SJIA-MAS, IFN-Ɣ may be a direct driver of liver injury and, therefore, serve as a therapeutic target.

Source: Arthritis Research & Therapy

DOI: 10.1186/s13075-026-03894-8