Complement proteins show promise as neurosarcoidosis markers
Small U.K. study points to possible blood and CSF biomarker panels
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Levels of specific immune complement proteins in blood and cerebrospinal fluid, including C3, factor B, and C5, showed strong potential for distinguishing people with neurosarcoidosis from those without the disease, according to a small study in the U.K.
Combinations of several complement proteins yielded more discriminative potential, while combining complement proteins with neurofilament light chain (NfL), a marker of nerve damage, helped distinguish people with relapsing neurosarcoidosis from those with stable disease.
These “findings underscore the central role of the complement system, neuroinflammation and neuronal injury in the [disease mechanisms] of NS [neurosarcoidosis],” and highlight “the potential value of a multi-biomarker approach for diagnosing and monitoring NS,” the researchers wrote.
Study explores immune system markers
Sarcoidosis is caused by an overactive immune system that leads to the formation of small clumps of inflammatory cells, called granulomas, in several tissues and organs. When granulomas develop in and around the nervous system, the disease is called neurosarcoidosis.
Neurosarcoidosis may be difficult to diagnose due to the variability of its development (acute or chronic), non-specific symptoms, and lack of sensitive and specific biomarkers. Monitoring treatment response can also be challenging because reliable biomarkers of disease activity are lacking.
Problems with the complement system, which is part of the immune response, have been implicated in sarcoidosis and neurodegenerative diseases marked by inflammation. However, “the role of complement in NS remains poorly understood,” the researchers wrote.
The complement system consists of three pathways — classical, alternative, and lectin — that all converge on activation of the complement protein C3 and then the terminal pathway.
Now, a team of researchers in the U.K. explored the diagnostic and prognostic value of complement proteins and of NfL, a marker of nerve damage, in people with neurosarcoidosis.
For that, they analyzed blood and cerebrospinal fluid — CSF, the fluid that surrounds the brain and spinal cord — samples from 28 adults with highly probable neurosarcoidosis who were followed at a specialized U.K. center. Samples from 30 individuals without sarcoidosis were used as study controls.
Researchers analyzed blood and CSF samples
Patients had a mean age of 41.9 years and were mainly men (64.2%). The most common disease phenotypes included involvement of the brain tissue, or parenchyma, in 39.3% of patients, the spinal cord in 28.6%, peripheral nerves — those outside the brain and spinal cord — in 10.7%, and optic nerves — the nerves that carry information between the eyes and the brain — in 10.7%. Most patients (60.7%) had not received previous treatment and were considered treatment-naïve.
In blood samples, levels of complement factor B (FB) and NfL were significantly higher in neurosarcoidosis patients relative to controls, while levels of the complement C3 protein were significantly lower.
In the CSF, the neurosarcoidosis group had significantly elevated levels of complement components, with C3, FB, and C5 “showing the most significant differences,” the team wrote.
“These findings suggest dysregulation of complement alternative pathway with increased activation (reflected in elevated FB levels) and consumption (reflected by reduced C3),” the researchers wrote. “The increase in NfL levels suggests ongoing neuronal injury.”
When assessing the ability of blood levels of complement proteins to distinguish neurosarcoidosis, C3 showed the strongest individual blood biomarker discriminative performance, with a mean test area under the curve (AUC) value of 0.923 in cross-validation. AUC ranges from zero to one, and the higher the value, the better the biomarker is at distinguishing people with the disease from those without it.
Combining levels of several complement proteins improved the discriminative performance, with FB plus C3 achieving an AUC of 0.996, and factor H plus C3 an AUC of 0.991. In this dataset, three biomarker combinations, such as FB/C9/C3 or C3/C5/factor I, achieved perfect discrimination, with an AUC of one.
This suggests that, in this dataset, “integrating multiple complement markers, particularly FB, C9, or C5, dramatically enhances diagnostic accuracy,” the researchers wrote.
Marker combinations improved performance
Similar results were seen in the CSF, with FB alone achieving a mean test AUC of 0.95, and the triple combination FB/C9/factor H reaching a mean test AUC of 0.993, for discriminating people with neurosarcoidosis from those without.
For differentiating the 18 people with relapsing neurosarcoidosis from the eight people with stable disease, individual blood biomarkers showed modest discriminative potential, with AUC values ranging from 0.646 to 0.667. Combinations of several biomarkers improved discriminative potential, with AUC values up to 0.944. Among participants with available CSF data, multi-biomarker panels such as the terminal complement complex/factor H/C5 allowed perfect discrimination.
The overall patterns remained largely unchanged after adjusting biomarker models for age and sex.
An exploratory analysis comparing biomarker levels between treatment-naïve and corticosteroid-treated patients found no significant differences between groups.
Overall, these “findings support the potential of [blood] biomarkers for non-invasive diagnostic strategies but suggest that CSF panels may be particularly useful for monitoring disease progression,” the researchers wrote. They also show “that complement dysregulation could serve as a biomarker of the disease activity but also as a therapeutic target in NS, warranting further investigation.” The researchers noted that larger studies are needed to validate the findings, including against other conditions that can mimic neurosarcoidosis.
