Investigation of type IV collagen biomarkers in multiple sclerosis

Multiple sclerosis (MS) is characterized as an inflammatory neurodegenerative disease in the central nervous system (CNS), presenting with significant inter- and intra individual heterogeneity. The pathological hallmarks of active MS lesions are blood brain barrier (BBB) disruption, inflammation, and demyelination with axonal damage. Blood-based biomarkers reflecting tissue changes in immunology and/or neurobiology may reflect MS pathology and be easily accessible. The basement membrane (BM) is a specialized form of extracellular matrix (ECM), which is primarily composed of type IV collagen and modulated in inflammatory conditions.

We hypothesized that BM biomarkers, quantifying type IV collagen fragments, could be diagnostic blood-based biomarkers in patients with MS.

A monoclonal antibody was raised against the cleavage site of canstatin, the C-terminal of type IV collagen-alpha-2 chain, and employed in an ELISA assay. The assay was developed, technically evaluated, and evaluated in serum from patients diagnosed with MS and compared to healthy donors. The assay was named CAN. To test the role of different blood-based biomarkers of type IV collagen in MS, we evaluated the CAN biomarker together with biomarkers of type IV collagen alpha-1 (C4M), type IV collagen alpha-3 (TUM), and type IV collagen 7S domain (PROC4) in serum from patients with MS and healthy donors.

The type IV collagen biomarkers CAN, TUM, and PROC4 had significantly higher levels in MS patients compared to healthy donors (CAN: 7.4 ng/mL vs. 4.9 ng/mL, p = 0.0046; TUM: 2.0 ng/mL vs. 0.7 ng/mL, p < 0.0001; and PROC4: 248.4 ng/mL vs. 160.2 ng/mL, p = 0.0067). No difference were found for C4M. TUM presented the best diagnostic power with an AUC of 0.996.

These findings are exploratory and hypothesis generating, indicating type IV collagen plays a role in the basement membrane turnover found in MS lesions, and the different collagen chains have different expression levels. These findings need to be validated in larger cohorts and longitudinal studies.