C-Reactive Protein and Neurological Autoimmune Diseases: Bridging the Diagnostic and Pathogenic Gap

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

According to the actual interest for neuroinflammation, the topic of C-Reactive Protein is an interesting one, because the link between systemic and neuronal inflammation is not yet fully understood.

The topic is relevant to the field, as several autoimmune processes are discovered but yet not all of them and the need for biomarkers in the diagnostic process is an important one, and CRP is an easy-to-use biomarker on a global scale, whose validity has been demonstrated.

Reading this article is a way of understanding what CRP is, which are the influences and interferences in the immune system and the manners it can interfere with systemic inflammation but also with neuroinflammation, so I think it is a comprehensive material to study
I think the way the article is structured is very well organised.I really appreciated the figures, which are very instructive and easy to understand.

Author Response

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Author Response File: Author Response.pdf

Reviewer 2 Report

Comments and Suggestions for Authors

This manuscript presents an extensive narrative review addressing the role of C-reactive protein (CRP) in neurological autoimmune diseases, including multiple sclerosis (MS), neuromyelitis optica spectrum disorder (NMOSD), Guillain-Barre syndrome (GBS), and myasthenia gravis (MG). The topic is clinically relevant and timely, and the manuscript assembles a large body of literature spanning molecular mechanisms, systemic inflammation, and clinical correlations. However, while the review is comprehensive in scope, several conceptual, structural, and methodological issues limit its clarity and translational impact in its current form.

• In several sections, particularly those discussing pain perception, depression, and neurodegeneration, CRP appears to be positioned as a direct mechanistic driver rather than a downstream or associative marker of inflammation. In many cited studies, CRP functions primarily as a surrogate of systemic inflammatory burden rather than as a causative agent.
• Although MS, NMOSD, GBS, and MG are all discussed, the manuscript does not consistently compare how CRP behaves differently across these disorders. At times, conclusions appear generalized despite substantial differences in immunopathology (e.g., astrocytopathy in NMOSD vs. antibody-mediated synaptopathy in MG).
• CRP is highly sensitive but poorly specific. Important confounding variables, such as obesity, infection, metabolic syndrome, corticosteroid use, and disease-modifying therapies are acknowledged only briefly and not systematically integrated into the interpretation of clinical findings.
• The distinction between pentameric CRP and monomeric CRP is mechanistically important and well described. However, the clinical feasibility of measuring mCRP, particularly in serum or CSF, is not sufficiently addressed.
• Several sections, particularly within MS and pain-related pathways, are overly detailed and partially repetitive. Moderate condensation would improve readability without sacrificing content.
• Minor inconsistencies in abbreviations (e.g., hs-CRP vs. high-sensitivity CRP) and disease nomenclature should be corrected for uniformity.
• While informative, some figures include dense mechanistic pathways that may overinterpret causality. Figure legends could more clearly distinguish hypothetical models from evidence-based pathways.
• The Conclusions section largely reiterates prior sections and could be strengthened by more explicitly stating unresolved questions, negative findings, and areas where CRP has failed to demonstrate clinical utility.

Author Response

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Author Response File: Author Response.pdf

Reviewer 3 Report

Comments and Suggestions for Authors

Major Comments:

1. The title promises to bridge a "Diagnostic Gap," but CRP is notoriously non-specific. The review must critically evaluate studies that define specific CRP cut-off points or kinetic profiles that distinguish, for example, an MS relapse from a urinary tract infection. Without this, the "diagnostic" claim is overstated.
2. A fundamental challenge in neuroimmunology is the Blood-Brain Barrier (BBB). Does systemic CRP correlate with intrathecal inflammation in the diseases discussed? The authors need to dedicate a specific section to the transport of CRP across the BBB or its local production by glia/neurons. Does a normal serum CRP rule out active CNS neuroinflammation? This discussion is crucial for the "Pathogenic Gap" aspect of the title.
3. In chronic inflammatory conditions like MS, standard CRP is often normal. The manuscript mentions hs-CRP in the references (Ref 90, 91), but the main text needs to clearly distinguish between standard clinical CRP and hs-CRP. Reviewing the utility of hs-CRP in "silent" progression or subclinical inflammation is essential for a "state-of-the-art" review.
4. Does CRP actively contribute to myelin damage (e.g., via complement activation), or is it merely a bystander? The Introduction mentions CRP’s "mechanistic roles," but the text provided focuses largely on associations. The authors should include a dedicated section on the molecular mechanism: specifically, CRP's interaction with C1q in the CNS context and its role in phagocytosis of myelin debris.
5. How do modern therapies affect CRP? For example, anti-CD20 therapies (Ocrelizumab, Rituximab) or anti-IL-6 receptor drugs (Satralizumab for NMOSD) profoundly alter inflammatory profiles. The review must address how these drugs confound the interpretation of CRP levels. Can CRP still be used as a marker for relapse in a patient on immunosuppressants?

6. This review claims CRP has prognostic relevance. The authors need to summarize longitudinal data. Does early high CRP predict long-term disability accumulation (EDSS in MS)? The review should separate "biomarker of activity" (relapse) from "biomarker of prognosis" (long-term outcome).

Minor Comments:

1. Some references are foundational but very old. Ensure that claims about "current evidence" are supported by citations from the last 5–7 years, especially regarding molecular mechanisms.
2. Ensure consistent terminology regarding "relapse," "flare," and "exacerbation" across the different disease sections.
3. Define all abbreviations (e.g., NMOSD, GBS) explicitly upon first use in the main text, even if defined in the abstract.

Author Response

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Author Response File: Author Response.pdf

Round 2

Reviewer 3 Report

Comments and Suggestions for Authors

The author has made revisions to all the issues raised. There are no further comments.