Early Biomarker for Multiple Sclerosis Development Identified Years in Advance

News

Early Biomarker for Multiple Sclerosis Development Identified Years in Advance

Multiple sclerosis (MS) is a chronic inflammatory autoimmune disease primarily affecting the white matter of the central nervous system, with high disability rates. MS patients often exhibit acute demyelinating lesions and one or more chronic demyelinating lesions on MRI, indicating neuroinflammation precedes symptoms. These lesions comprise complex immune cell populations, including CD4 and CD8-positive T cells, activated macrophages, B cells, as well as immunoglobulins and complement deposition.

Several retrospective studies suggest that MS prodromal symptoms involve sustained neuroinflammation, with neuronal damage appearing several years before clinical symptoms, accompanied by elevated serum levels of neurofilament light chain (NfL), indicating axonal injury. While diagnostic autoantibodies have been found in other autoimmune diseases like systemic lupus erythematosus, type 1 diabetes, and rheumatoid arthritis years before symptoms, they have not been identified in MS.

Recently, in the journal Nature Medicine, a research team from the University of California, San Francisco, reported a set of autoantibody characteristics that appear years before clinical symptoms in approximately 10% of MS patients, providing diagnostic potential. The study also validated the diagnostic specificity in an independent cohort.

Researchers believe this discovery holds promise for early detection and intervention in MS, potentially transforming its management and treatment strategies by identifying high-risk individuals before symptoms appear.

The study utilized a large prospective MS cohort of over 10 million U.S. active-duty military personnel from the Gulf War era, obtaining the earliest serum samples (an average of 5 years before first MS onset) and samples from around 1 year after first MS onset from the Department of Defense Serum Repository (DoDSR). Ultimately, serum samples from 250 MS patients were retrieved and matched with 250 healthy controls based on age, gender, race, and serum collection date.

Early Biomarker for Multiple Sclerosis Development Identified Years in Advance

The researchers found elevated NfL levels in the pre-onset serum samples of these MS patients and conducted a serum proteomic analysis, identifying a unique immunogenic cluster present in both pre- and post-onset serum samples. Enrichment of peptides within this cluster was found in the serum antibodies of 27 MS patients but not in the matched control group.

There were 54 enriched peptides, and researchers identified a protein motif, the regular expression P-(SA)-x-(SGA)-R-(SN)-(LRKH), with the initial proline being the most conserved structure. The characteristic arginine-serine repeat sequence was highly representative in the enriched peptides. MS patients selected based on this characteristic had significantly higher serum NfL levels compared to other MS patients and controls, with consistent differences across serum collection time points.

The researchers validated these findings in the ORIGINS cohort at the University of California, San Francisco, which included 126 participants with serum and cerebrospinal fluid samples, 104 of whom were diagnosed with MS and the rest serving as controls, diagnosed with various non-MS neurological diseases such as varicella-zoster virus meningitis, opticospinal spectrum disorders, and vitamin B12 deficiency.

Eight out of the 104 MS patients in the ORIGINS cohort exhibited the same immunogenic cluster motif, similar to the DoDSR cohort, indicating a high specificity for MS. Among the 22 control participants, only 1 with opticospinal spectrum disorder showed low-level enrichment of the motif in serum samples, which was not detected in cerebrospinal fluid samples.

In conclusion, this study provides a specific biomarker for the preclinical stage of MS and confirms that the pathophysiology of MS begins years before symptoms appear, aligning with previous clinical analyses.

Furthermore, the researchers noted that the immunogenic cluster motif identified is not unique to MS patients but also exists in several pathogens, including Epstein-Barr virus, hepatitis C virus, Pseudomonas aeruginosa, Escherichia coli, and Aspergillus flavus. This corresponds with previous studies on MS mechanisms, particularly regarding Epstein-Barr virus. Further research into this motif is crucial to elucidate its exact origins. Researchers suggest focusing on exposure history, genetic risk factors, and the temporal dynamics of disease presentation.