Tissue degrading and remodelling molecules in giant cell arteritis.

Objectives: GCA is a granulomatous vasculitis affecting large vessels, leading to intimal occlusion accompanied by the accumulation of myofibroblasts. Histopathologically, GCA is characterized by destruction of the tunica media and hypertrophy of the intima with invasion of activated CD4+ T cells, macrophages and multinucleated giant cells (MNGCs). Despite these well-defined histopathological features, the molecular pathology of GCA has largely remained elusive. We aimed to characterize the pathologic features of GCA at the molecular level.

Methods: To identify key molecules involved in GCA pathogenesis, we conducted genome-wide gene expression profiling on arterial lesions obtained through temporal artery biopsy of 16 patients who had not received any prior treatment. The resulting data were examined to reveal specific pathways and genes, and some of the molecules were followed up by immunohistochemistry.

Results: Our analysis revealed a unique gene expression pattern in GCA lesions, including enrichment of immune cells and phagocytic pathways related to microglia and osteoclasts. Subsequent immunohistochemistry analysis identified the presence of MMP12 (macrophage elastase), HLA-DRA, and phagocytosis- and osteoclast-associated molecules in infiltrating macrophages and MNGCs. Additionally, we discovered LRRC15-expressing cells in the tunica intima, suggesting a myofibroblast subpopulation that suppresses cytotoxic CD8+ T cells. These molecules were upregulated in other granulomatous diseases affecting not only arteries but also lymph nodes.

Conclusion: Our study revealed novel molecules associated with the pathological features of GCA, providing a foundation for better understanding of GCA pathogenesis and development of targeted therapeutic strategies.