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Intrathecally synthesized signaling axis IgG1-CXCL10 is a potential predictor of multiple sclerosis activity

Feb 20, 2024 | Neuroscience (Featured)

Multiple sclerosis (MS) is one of the most important neurological diseases, characterized by multiple areas of inflammation and demyelination in the white matter of the brain and spinal cord. Neuroinflammation and CNS tissue damage in MS result in the release of various secretory products, cytokines, immunoglobulins, and damage-associated molecules in the cerebrospinal fluid (CSF). In this study, the authors from the United States investigated the intrathecal synthesis of 46 inflammatory mediators and 14 markers of glial activation or central nervous system (CNS) injury in MS spectrum patients. These levels were compared to those in patients with non-inflammatory neurological diseases. Significant proteins were subjected to a series of techniques to characterize the correlation between intrathecal inflammation, CNS injury, glial activation, and disease activity. 

There are currently four recognized MS courses: clinically isolated syndrome (CIS), relapsing-remitting MS (RRMS), primary progressive MS (PPMS), and secondary progressive MS (SPMS). The most common MS phenotype is RRMS, which affects around 85% of patients. 

Chemokines are small proteins that attract different cytokines, cells, and substances to specific sites. They regulate cell positioning and are involved in a wide range of biological processes, including homeostasis, angiogenesis, immune response, inflammation, chemotaxis, and metastases. Depending on the number of amino acids between the first two cysteine residues, the chemokines are classified into four subfamilies, CXC, CC, CX3C, and XC. A recent study has shown that chemokine fractalkine (CX3CL1) plays a pro-regenerative role in a demyelinating mouse model, increasing the production of oligodendrocytes and in vivo remyelination from activated parenchymal oligodendrocyte precursor cells.





About the study

The authors evaluated the intrathecal synthesis of 46 inflammatory mediators and 14 markers of CNS injury or glial activation in CSF samples obtained from MS spectrum patients. They investigated how these intrathecal proteins relate to short-term disease activity (less than 12 months) in a relapsing-remitting form of MS.

After lumbar puncture (LP), patients with MS underwent clinical assessment at regular intervals, including brain and spine magnetic resonance imaging (MRI). They were followed for at least 12 months. Patients who developed clinical and/or radiologic disease activity were classified as “active” (n = 18), whereas patients without disease activity were classified as “nonactive” (n = 29.) Disease activity in patients with CIS corresponded to conversion to RRMS, so, they were subclassified as “converters” or “non-converters” based on their conversion status at the end of a 12-month follow-up.

Neuroinflammatory mediators and biomarkers were categorized into three categories: intrathecally synthesized inflammatory mediators, CNS injury biomarkers, and glial activation biomarkers.

The category of intrathecally synthesized inflammatory mediators included interferon-gamma (IFNγ), interleukin 1 beta (IL-1β), IL-2, IL-4, IL-6, IL-10, IL-16, tumor necrosis factor alpha (TNFα), CXC motif chemokine ligand 1 (CXCL)1, CXCL2, CXCL5, CXCL6, CXCL9, CXCL10, CXCL11, CXCL12, CXCL13, CXCL16, CX3CL1 (fractalkine), CC motif chemokine ligand 1 (CCL)1, CCL2, CCL3, CCL7, CCL8, CCL11, CCL13, CCL15, CCL17, CCL19, CCL20, CCL21, CCL22, CCL23, CCL24, CCL25, CCL26, CCL27, MIF, granulocyte macrophage colony-stimulating factor (GM-CSF), and immunoglobulins (Ig)A, IgM, IgG1, IgG2, IgG3, and IgG4.

The category of CNS injury biomarkers included fibroblast growth factor 21 (FGF.21), myelin basic protein (MBP), neurofilament light chain (NfL), Tau[pT231], Tau(total), amyloid-beta peptide 1-40 (Aβ1-40), amyloid-beta peptide 1–42 (Aβ1-42), and neurogranin (NRGN).

The category of glial (astrocytes and microglia) activation biomarkers included glial fibrillary acidic protein (GFAP), soluble receptor for advanced glycation end products (sRAGE), S100 calcium-binding protein B (S100B), soluble triggering receptor expressed on myeloid cells 2 (sTREM2), chitinase 3 like 1 (Chi3L1), kallikrein-related peptidase 6 (KLK6), and neural cell adhesion molecule 1 (NCAM1).




The study included 47 patients with MS and 27 controls with noninflammatory neurologic diseases (25 patients with headache syndromes, one with cognitive dysfunction, and one with noninflammatory epilepsy). Patients diagnosed within the MS spectrum met the criteria and underwent LP during their first acute demyelinating event.

23 patients had RRMS and 24 had CIS. Over the following 12 months, 18 patients (38%) had signs of disease activity. Based on the 2017 McDonald criteria, disease activity in patients with CIS corresponded to conversion to RRMS. The remaining 29 patients (62%), including 13 patients with RRMS and 16 with CIS had no disease activity in the first year after LP.

The age was significantly lower among patients with active MS, effectively distinguishing those with active disease from those with non-active disease. Other parameters, including gender, immunoglobulin index, lesions present at diagnosis, and time from activity to LP could not predict disease activity.

16 proteins were differentially expressed in MS patients compared to controls, including CXCL9, CXCL10, CXCL13, CCL11, CCL13, CCL22, CCL26, IL-1β, IL-4, IL-10, IgG1, IgM, IFNγ, TNFα, and NfL. Except for NfL, all were classified as “inflammatory”. No single or combined intrathecally synthesized protein had a significant predictive value for short-term (less than 12 months) disease activity.

Patients with active MS shared several connections with non-active MS, including CCL26-IL-10, CCL11-IL-1β, CXCL13-CCL22, and IFNγ-CXCL9, showing MS-specific inflammatory phenotypes. Patients with active MS shared two connections with controls, CCL26-IL6 and IL6-CCL22, whereas patients with non-active MS shared only one connection, IL-6-TNFα, with controls. 

There was a positive correlation between the expression of IgG1 and CXCL10 in patients with active MS, and in CIS converters, but not CIS non-converters. The authors emphasized that previous studies have shown a positive correlation between increased intrathecal synthesis of IgG and CSF level of CXCL10 in patients with relapsing-remitting or primary progressive MS. The predictive power of this connection was much stronger in patients with CIS than in patients with active MS, and it was independent of age.

 CXCL10, also known as IFNγ-induced protein 10 (IP-10), has a role in chemotaxis, apoptosis, cell growth, and angiogenesis. However, its primary function is immune cell trafficking to inflamed sites, especially antibody-secreting cells and T cells.  Proinflammatory conditions lead to the secretion of CXCL10 in various cells, such as monocytes, neutrophils, dendritic cells, microglia, and astrocytes. The authors stated that a positive correlation between IgG1 and CXCL10 has been previously reported as a potential predictor of CIS conversion. This suggests that the interaction between IgG1 and CXCL10 may play a crucial role in disease activity, particularly in the initial stages of the disease.



This study has shown that a specific intrathecally synthesized signaling axis IgG1 and CXCL10, is a potential predictor of MS activity and/or conversion from clinically isolated syndrome to relapsing-remitting MS. The authors proposed that elevated basal levels of CSF CXCL10 secreted by glial cells in patients with active MS, including CIS converters, may increase the recruitment and differentiation of antibody-producing plasma cells in the CNS, and contribute to increased intrathecal production of IgG.

This article was published in the Neurology: Neuroimmunology & Neuroinflammation.



Journal Reference

Welsh N, Disano K, Linzey M, et al. CXCL10/IgG1 Axis in Multiple Sclerosis as a Potential Predictive Biomarker of Disease Activity. Neurol Neuroimmunol Neuroinflamm 2024;11:e200200. (Open Access).


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