Pediatric cerebrospinal fluid immune profiling distinguishes pediatric-onset multiple sclerosis from other pediatric-onset acute neurological disorders

Background 

Multiple sclerosis (MS) is a disease that typically presents in adult age, often with optic neuritis, motor and/or sensory symptoms. It is an exclusion clinical diagnosis which relies on the McDonald criteria. Those criteria include dissemination of lesions in space, dissemination of lesions in time and clinical attacks or relapses. Other clues can point to this diagnosis, such as oligoclonal bands in the CSF. Patients with MS don’t typically undergo lumbar puncture, but this can be necessary to distinguish it from other autoimmune diseases. Specificity of oligoclonal bands in CSF of MS patients is debated, hence the need for clear biomarkers to distinguish MS from other demyelinating disorders.

Pediatric MS is much less common. In children, demyelinating disorders are often of genetic origin and are part of the differential diagnosis for MS, such as 4H leukoencephalopathy, vanishing white matter disease, etc.

Investigations looking into pediatric onset neuroinflammatory disease can be lengthy. Radiological findings can help distinguish between different diseases, but a. definitive diagnosis can only be found by CSF analysis.

The study highlighted here aimed to establish a complete CSF immune profile of pediatric-onset MS patients, other acute demyelinating syndromes (ADS) patients and healthy individuals. The preprint authors hypothesized that the CSF contains specific signatures for each disease/syndrome making the diagnostic more accurate which allows patients to be given the right treatment earlier in disease progression.

A short overview of immune cells and how they operate:

Immune Cell Type	Functional Role in CSF Immunity
T cells	Involved in immune surveillance, antigen recognition and immune coordination – They can recognize problems and help other cells do their jobs, like police patrols!
B cells	Responsible for antigen presentation and cytokine secretion, which can help sustain inflammation. They can also differentiate into ASCs.
Antibody Secreting Cells (ASCs)	Fully differentiated B cells that produce high levels of antibodies, recognizing pathogens like bacteria and viruses and neutralizing them. In autoimmune diseases like MS, these antibodies will recognize and destroy our own myelin sheath.
CD14+ Myeloid cells	Myeloid cells include monocytes and macrophages. They are involved in phagocytosis, cytokine production and antigen presentation. You can compare them to first responders; they clean up the mess in the inflamed area and alert other cells to come to the inflamed site.
Polymorphonuclear Neutrophils (PMNs)	Involved in the acute inflammatory response. They are most often recruited in response to infection or tissue damage. You rarely see them in a healthy CSF. They are like the SWAT team of our immune system, they show up quickly in case of a significant attack, such as infections!

 

Key Findings

B Cells are elevated in pediatric acquired demyelinating syndromes (ADS)

This study found that B cells are significantly elevated in the cerebrospinal fluid of children with acquired demyelinating syndromes, including MS and MOGAD, compared to other conditions.  . In fact, B-cell depleting therapies are highly effective in MS, while in MOGAD, their benefit is inconsistent, suggesting  B cells may play a different role in both diseases. This emphasizes the need to functionally characterize B cells in each disorder, which would guide more precise, disease-specific treatments in pediatric neuroinflammation.

Antibody-Secreting Cells (ASCs) and myeloid cell ratios distinguish MS from MOGAD

The authors found that ASCs were more common in the cerebrospinal fluid of MS patients, while CD14+ myeloid cells were found less often. The antibody-secreting cells (ASCs) to CD14+ myeloid cells ratio  effectively differentiated MS patients from MOGAD or acute demyelinating syndromes, serving as a potential biomarker for MS diagnosis.

In MS, there is an increased frequency of antibody-secreting cells and a decreased frequency of CD14+ myeloid cells (our first responders!). This led to the creation of the ASCs to CD14+ myeloid cells ratio, which helps distinguish MS from other ADS with high accuracy. Since MS is already hard to diagnose in kids and is often misdiagnosed, this new biomarker may help start the proper treatment faster.

Why we highlight this preprint

We think that this study is a great addition to the field of MS research, as it has the potential to become relevant in the clinic, and investigates a population for which we do not hold much data.

This study is fascinating because it is the first to characterize the CSF profile in both inflammatory disorders and non-inflammatory conditions in a pediatric population. The preprint authors also introduce a tangible and quantifiable clinical tool to analyze CSF immune profiles. This AMR ratio could help reduce reliance on diagnostic tests for CSF antibody testing.

Also, we were particularly interested in what this study means for the field of neuroimmunology in the future; will CSF immune profiles become standard practice when there is suspicion of dealing with neuroinflammatory diseases? Will these findings be included in the future McDonald criteria?

Questions for the authors

• Is the characteristic CSF immune signature in MS detectable before the development of radiological or pathological lesions?
• The age of the pediatric patients included in this study ranges from infancy to early adulthood. We wondered how puberty might affect the immune profile (ASCs, Myeloid T+ Cells, etc.) across these different syndromes, and how that influences the interpretation of your data. You highlighted how age might affect T cells phenotype from naive to memory in a non-inflammatory context, but how would that apply to disease?
• Would it be possible to predict the relapse tendency of the patients based on any specific signatures in the CSF immune profiling?

Tags: autoimmunity, immune cells, multiple sclerosis

doi: https://doi.org/10.1242/prelights.40954

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