Session Information
Date: Saturday, November 16, 2024
Title: Vasculitis – Non-ANCA-Associated & Related Disorders Poster I
Session Type: Poster Session A
Session Time: 10:30AM-12:30PM
Background/Purpose: Giant cell arteritis (GCA) is a large vessel vasculitis characterized by inflammatory cell infiltration and destruction of the tunica media. In this study, we aim to analyze infiltrating macrophages and multinucleated giant cells (MNGCs) at the molecular level using immunohistochemistry.
Methods: Patients suspected of GCA and underwent temporal artery biopsy (TAB) as the diagnostic procedure before the treatment were recruited. RNA was extracted from the TAB blocks, and genome-wide gene expression profiling was performed. The data were analyzed for gene expression quantification, leading to the identification of differentially expressed genes. The resulting data were examined to reveal specific pathways and genes, and some of the molecules were followed up by immunohistochemistry. Enrichment of biological pathways and cell-type composition was also assessed. Histological and immunohistochemistry methods were employed to analyze tissue samples.
Results: We enrolled 16 untreated patients suspected of GCA who underwent TAB. Ten were diagnosed with GCA, while six were non-GCA. Two of the GCAs revealed atypical histopathology and clinical manifestation. Hematoxylin and eosin staining showed typical GCA cases exhibiting significant macrophage and MNGC infiltration.
Gene expression profiling revealed a clear separation between typical GCA (n=8) and others (n=8) in principal component analysis, with atypical GCA cases being clustered with non-GCA patients. We identified 2,002 upregulated and 1,681 downregulated genes in typical GCA (log2FC > 1, FDR < 0.05). Upregulated genes included those involved in adaptive immune responses (IGLL5, MZB1, JCHAIN, CTLA4) and macrophage-associated genes (CHI3L1, MARCO, FBP1). Cell-type enrichment analysis indicated significant contributions from CD4+ T cells, CD8+ T cells, macrophages, and multipotent progenitors. Pathway analysis highlighted enrichment in immune pathways, particularly those related to microglia and osteoclast differentiation, including markers like ACP5, MMP9, and DCSTAMP (Fig.1).
Immunohistochemistry confirmed that the MNGCs and surrounding macrophages in the tunica media strongly expressed MRC1 (CD206), a marker for tissue-remodeling macrophages. LRRC15, a marker of myofibroblasts suppressing cytotoxic CD8+ T cell, expressed in the myofibroblasts. Osteoclast markers ACP5 and ATP6V0D2 were explicitly expressed in MNGCs, not macrophages. VDR and TREM2 were detected in MNGCs and macrophages of GCA samples, indicating osteoclast-like properties in these cells. MMP12, a macrophage elastase involved in extracellular matrix degradation, was highly upregulated in MNGCs. HLA-DRA was present in MNGCs and macrophages, underlining their role in immune-stimulatory functions (Fig.2).
Conclusion: Infiltrating macrophages and MNGCs expressed MMP12, phagocytic or osteoclast-associated molecules that contribute to the pathogenetic features of GCA, including degradation of the tunica medium, induction of immune responses, and accumulation of myofibroblasts. The extended list of key molecules provides a solid baseline for elucidating the pathogenesis of GCA and developing therapeutic strategies.
To cite this abstract in AMA style:
Sugihara M, Watanabe N, Hara Y, Nishito Y, Kounoe M, Sekiyama K, Takamasu E, Chinen N, Shimada K, Kawaji H. Macrophage-Lineage Cells in Giant Cell Arteritis Express MMP12, Phagocytosis and Osteoclast-associated Molecules That May Contribute to Destruction of the Tunica Media [abstract]. Arthritis Rheumatol. 2024; 76 (suppl 9). https://acrabstracts.org/abstract/macrophage-lineage-cells-in-giant-cell-arteritis-express-mmp12-phagocytosis-and-osteoclast-associated-molecules-that-may-contribute-to-destruction-of-the-tunica-media/. Accessed .« Back to ACR Convergence 2024
ACR Meeting Abstracts - https://acrabstracts.org/abstract/macrophage-lineage-cells-in-giant-cell-arteritis-express-mmp12-phagocytosis-and-osteoclast-associated-molecules-that-may-contribute-to-destruction-of-the-tunica-media/