CHIT1: A Promising Biomarker for Predicting Rapid Progression in Multiple Sclerosis

The recent study titled "CHIT1 at diagnosis predicts faster disability progression and reflects early microglial activation in multiple sclerosis" published in Nature Communications offers promising insights into the potential use of chitinase 1 (CHIT1) as a biomarker for predicting the progression of Multiple Sclerosis (MS). Below is a detailed summary and analysis of the findings from the article.

Introduction: The Challenge of Predicting MS Progression
Multiple sclerosis (MS) is a complex immune-mediated neurodegenerative disease affecting the central nervous system (CNS), characterized by unpredictable progression. While many advances have been made in understanding its pathophysiology, accurately predicting long-term outcomes for patients remains difficult. Current diagnostic markers, including blood and cerebrospinal fluid (CSF) biomarkers, often fail to provide reliable indicators of disease progression. This study focuses on five markers related to myeloid cell activation, with a particular emphasis on CHIT1, to determine their potential as early predictors of disease severity.

Key Findings: CHIT1 as a Predictor of Faster Disability Progression
CHIT1 was identified as the most robust marker for predicting faster disability progression in MS patients. Using a cohort of 192 MS patients, the authors performed both mixed-effects models and machine learning analyses to evaluate CHIT1 and other myeloid markers, including CHI3L1, sTREM2, GPNMB, and CCL18. The data showed that higher CHIT1 levels at the time of diagnosis were significantly associated with more rapid progression of disability over time, as assessed by standard MS severity metrics such as the Expanded Disability Status Scale (EDSS).

CHIT1 was not only correlated with current disability but also with future disability. The study showed that CHIT1 levels at diagnosis could explain around 30% of the variability in disability progression across patients, outperforming other clinical and molecular markers. CHIT1’s predictive power was further enhanced when clinical covariates such as age, sex, and disease course were included in the models.

Microglial Activation and CHIT1 Expression in MS
A central element of the study was identifying the cellular source of CHIT1 in the CNS. Through single-cell RNA sequencing (scRNA-seq) of CSF from 11 MS patients and the integration of existing CNS transcriptome data, CHIT1 was found to be primarily expressed by a subset of microglia. These CHIT1+ microglia were enriched in active MS lesions and were shown to reflect an activated, MS-associated state. The study further confirmed the presence of these CHIT1+ cells in active demyelinating lesions in brain tissue from post-mortem MS patients.

This microglial subset was characterized by pathways involved in lipid metabolism, foam cell differentiation, and phagocytosis, suggesting a role in myelin clearance during demyelination. Notably, these cells exhibited traits associated with a transition from homeostatic microglia to a more activated state, indicating that CHIT1 expression is a marker of this functional shift.

Implications for MS Treatment and Biomarker Development
The identification of CHIT1 as an early biomarker of microglial activation and disability progression in MS could have significant implications for both patient care and the development of new therapeutic strategies. With increasing interest in therapies targeting microglial activation, such as Bruton’s tyrosine kinase (BTK) inhibitors, biomarkers like CHIT1 could help stratify patients for more personalized treatment approaches. For example, patients with elevated CHIT1 levels at diagnosis could be candidates for early intervention with therapies that modulate microglial activity, potentially slowing disease progression.

Moreover, CHIT1 measurement could be a valuable addition to the clinical toolkit for MS, providing clinicians with a relatively simple and inexpensive method for identifying patients at higher risk for rapid disease progression. However, further validation of CHIT1 as a biomarker in larger, independent cohorts is necessary before its routine use in clinical practice.

Limitations and Future Directions
While the findings presented in this study are promising, the authors acknowledge several limitations. The primary limitation is the need for prospective validation in larger cohorts. Additionally, while CHIT1 showed significant promise as a biomarker for predicting disability progression, it was not associated with relapse rates, and further research is needed to determine its role in different aspects of MS pathogenesis.

Another challenge for implementing CHIT1 as a clinical biomarker is the presence of a common genetic variant (a 24-bp duplication in the CHIT1 gene) that affects CHIT1 expression and activity in approximately 35% of the European population. However, the study showed that this genetic variant did not substantially affect the correlation between CHIT1 levels and disability in their cohort, suggesting that CHIT1 remains a robust biomarker despite genetic variability.

Conclusion
This study highlights the potential of CHIT1 as a valuable biomarker for predicting faster disability progression in MS. By identifying a specific microglial subset that expresses CHIT1 and demonstrating its association with disease severity, the authors provide a strong rationale for further investigation into CHIT1’s role in MS. With further validation, CHIT1 could become an important tool in the clinical management of MS, aiding in early identification of high-risk patients and informing treatment strategies aimed at slowing disease progression.

References:
Beliën, J., Swinnen, S., D’hondt, R. et al. CHIT1 at diagnosis predicts faster disability progression and reflects early microglial activation in multiple sclerosis. Nat Commun 15, 5013 (2024).