Multiple Sclerosis: CHIT1 and SERPINA3 as Candidate CSF Biomarkers of Progressive Biology

Multiple sclerosis (MS) is an extraordinarily complex disease. It’s not just about relapses and remissions—the immune system’s attacks on myelin—but also about the slow, often hidden, progressive processes in the brain and spinal cord that can quietly erode neurological function over years.

While imaging and clinical assessments help capture aspects of disease activity, researchers and clinicians have long searched for biomarkers in cerebrospinal fluid (CSF) that could distinguish between relapsing and progressive biology in MS. Such biomarkers could:

Clarify disease mechanisms (e.g., which cell types are driving damage).

Serve as prognostic tools, helping identify who is at risk for progression.

Track treatment effects, offering a faster readout than waiting years for disability changes.

This is where CHIT1 (chitotriosidase-1) and SERPINA3 (serpin family A member 3) enter the story.

Two Biomarkers, Two Different Cell Types
Previous CSF proteomic work pointed to these molecules as potential windows into progressive MS biology:

CHIT1: An enzyme produced by activated myeloid cells, including microglia—the brain’s resident immune cells. Microglia have been implicated in the slow expansion of chronic lesions (so-called slowly expanding lesions, or SELs).

SERPINA3: A protein secreted by reactive astrocytes, the star-shaped support cells in the brain that become activated in neuroinflammatory conditions.

Both proteins could serve as molecular “fingerprints” of the non-relapsing, smoldering pathology that characterizes progressive MS.

The OBOE Study: Putting CHIT1 and SERPINA3 to the Test
The Ocrelizumab Biomarker Outcome Evaluation (OBOE) study provided a unique opportunity to test these biomarkers in a well-characterized MS population. Researchers measured CHIT1 and SERPINA3 in CSF samples from:

Healthy controls (n=30)

People with relapsing MS (pwRMS) (n=79)

People with primary progressive MS (pwPPMS) (n=22)

Using enzyme-linked immunosorbent assays (ELISA), they compared baseline levels, correlated them with MRI and other fluid biomarkers, and then tracked changes after one year of ocrelizumab treatment—a B-cell depleting therapy that is effective in both relapsing and progressive MS.

What They Found
1. CHIT1 is elevated in both relapsing and progressive MS
Compared to healthy individuals, CHIT1 levels were higher in both pwRMS and pwPPMS.

CHIT1 correlated not only with progressive biology (SEL volume, R=0.38) but also with acute activity (T1 gadolinium-enhancing lesions, R=0.33; CSF neurofilament light chain, R=0.58).

Interpretation: CHIT1 may reflect microglial activation relevant to both relapse-related damage and slow, progressive lesion expansion.

2. SERPINA3 is more specific to progressive disease
Elevated only in pwPPMS, not in pwRMS. Strong correlations with progressive pathology markers: SEL volume (R=0.39) and CSF GFAP (R=0.44), a marker of astrocytic injury.

Interpretation: SERPINA3 may serve as a signature of astrocyte-driven pathology unique to progressive MS biology.

3. Ocrelizumab selectively reduces CHIT1, not SERPINA3
After 52 weeks, CHIT1 levels fell significantly:

pwRMS: median −41%

pwPPMS: median −27%

SERPINA3 levels remained unchanged following ocrelizumab.

Interpretation: B-cell depletion dampens microglial activity (reflected in CHIT1), but may not directly affect astrocytic responses (SERPINA3).

Why This Matters
This study adds quantitative confirmation to the idea that CHIT1 and SERPINA3 are candidate biomarkers of progressive MS biology. Importantly:

CHIT1 appears to be a dynamic marker, responsive to therapy, and could help track microglial activity in both relapsing and progressive disease.

SERPINA3 may serve as a more stable marker of astrocytic involvement in progression, less sensitive to B-cell targeting therapies but potentially valuable for monitoring smoldering disease.

Together, they reflect different aspects of the MS pathology landscape.

Looking Ahead
These findings raise exciting possibilities: Could CHIT1 serve as a treatment response biomarker, helping clinicians monitor therapeutic effects more directly than MRI or clinical scales?

Might SERPINA3 help identify patients with astrocyte-driven progression, potentially guiding stratification in clinical trials targeting non-B-cell pathways?

Could a multi-marker panel (CHIT1, SERPINA3, NfL, GFAP) provide a comprehensive picture of acute and progressive disease processes?

Of course, validation in larger and longitudinal cohorts will be essential, as will testing how these biomarkers behave under other therapies.

Final Thoughts
MS is not a single disease process but a tapestry of immune, glial, and neurodegenerative mechanisms unfolding over time. Studies like this one remind us that progress comes not only from new drugs but also from better tools to measure the biology we want to change.

With CHIT1 and SERPINA3, we may be one step closer to decoding the hidden language of progression in MS.

Disclaimer: This blog post is based on the provided research article and is intended for informational purposes only. It is not intended to provide medical advice. Please consult with a healthcare professional for any health concerns.

References:
Bar-Or, A., Gelfand, J., Agbim, C., von Büdingen, H. C., Cameron, B., Herman, A., ... & Cross, A. (2025, April). Evaluation of CHIT1 and SERPINA3 as Candidate Cerebrospinal Fluid Biomarkers of Progressive Biology in Multiple Sclerosis (S33. 003). In Neurology (Vol. 104, No. 7_Supplement_1, p. 2542). Hagerstown, MD: Lippincott Williams & Wilkins.