Microvascular and Structural Remodeling of the Extracellular Matrix in Autoimmune Organ Damage: A Histopathological and Biomarker Perspective; Article Review

Abstract

Autoimmune diseases induce injury to the organs via interactions between immune dysregulation, microvascular dysfunction and extracellular matrix (ECM) remodeling. Injury of the endothelial cells, alterations in capillary flow, recruitment of inflammatory cells, and chronic stimulation of the stromal cells can alter the production, organization, crosslinking and degradation of matrix proteins. These alterations are responsible for the tissue stiffness, basement-membrane alterations, capillary rarefaction, and subsequent fibrosis. This narrative review brings together evidence on these mechanisms in systemic sclerosis, systemic lupus erythematosus (with particular focus on lupus nephritis) and rheumatoid arthritis (RA) and investigates the connection between histopathological findings and candidate biomarkers. Markers such as collagen turnover fragments, matrix metalloproteinases and tissue inhibitors of metalloproteinases (TIMPs), transforming growth factor (TGF)–β-related markers, endothelial activation markers, angiogenic factors and urinary inflammatory or renal injury proteins have been examined in the reviewed biomarker classes. The evidence suggests that the use of ECM-related biomarkers could support the clinical and histological evaluation, although most are still under investigation or are context specific. Disease heterogeneity, assay differences and the presence of systemic sources of analytes and the inability to differentiate active inflammation from the underlying structural damage make their interpretation difficult. Histopathology has a key role in the case where there is a requirement for tissue level classification, and additional information on biological activity and change over time may come from the vascular assessment and/or biomarker panels. To move towards clinical translation, there is a need for standardized assays, longitudinal cohorts, prespecified histological endpoints, external validation and proof of the value of biomarkers over conventional clinical parameters.