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Page 24 Toscano et al. Neuroimmunol Neuroinflammation 2021;8:14-41 I http://dx.doi.org/10.20517/2347-8659.2020.12

Together with other lymphoid chemokines, it favors the organization of germinal centers in lymphoid
follicles, including meningeal tertiary lymphoid organs in the CNS [122] . Indeed, CXCL13 has been found to
be overexpressed in active MS lesions and in intrameningeal B-cell follicles of chronic white matter lesions,
sustaining humoral autoimmunity and disease activity [122,123] . Not coincidentally, mice lacking CXCL13
develop milder forms of disease [124] , and its expression correlates with intrathecal Ig syntesis [125] .

In a recent meta-analysis conducted on 226 studies about the role of several cytokines in patients with MS,
CSF CXCL13 levels proved to differentiate well between patients with MS and controls and to decrease
after DMDs [126,127] . Accordingly, in a study by Khademi and coworkers, CSF CXCL13 was found to be
significantly higher in infectious neurological diseases and MS. The latter group showed significantly higher
values than CIS and other controls [128] . However, its lack of high specificity was confirmed by overexpression
of CXCL13 in the CNS in other diseases, such as neuroborreliosis and primary CNS lymphoma [129] . Next to
its diagnostic role, it also proved to be higher in CIS converting to clinically definite MS [130] and to correlate
with both clinical and radiological disease activity [127,128] . Currently, its role as predictive for CIS conversion
[3]
has an intermediate level of evidence, needing replication in additional cohorts .

Elevated levels of CSF CXCL13 also seem to decrease after B-cell depleting treatment such as
rituximab [129,131] , after methylprednisolone [127] and NTZ [127,132] . High CSF CXCL13 levels also correlated with
low expression of immunoregulatory IL-10 and TGF-β1 [127] . On the basis of this evidence, CSF CXCL13 has
been mainly suggested as a disease activity and treatment response biomarker.

MMP-9
MMPs are zinc-endopeptidases, able to catalyze the cleavage of many substrates in several physiological and
physiopathological processes. Indeed, MMPs play a role in tissue remodeling, angiogenesis and cell migration,
but also in inflammation, wound healing and malignancies [133] . During inflammation, many molecules
are able to activate MMPs, including reactive oxygen species and both TNF-α and IL-17 via NF-kB [134,135] .
MMPs, in turn, are able to activate cytokines, adhesion molecules, receptors and microglia [136,137] . Moreover,
MMPs may determine BBB dysfunction by proteolyzing capillary basement membrane and tight junction
proteins between endothelial cells [133,138] .

MMPs seem to be involved in several neurological diseases, such as MS, Alzheimer’s disease, Parkinson’s
disease, cancer and cerebrovascular diseases [133] . In EAE, elevated levels of several MMPs have been found,
considered responsible for major severity of the disease [133,139,140] . It has been supposed that MMPs may act
in MS through the digestion of myelin basic protein (MBP) as well, besides favoring leukocyte leakage
at post-capillary venules [138] . Among six subfamilies, gelatinases (MMP-2 and MMP-9) are constitutively
expressed in brain and best explored in MS pathogenesis [133] . Particularly, there is slightly more evidence
about MMP-9 as a disease activity biomarker in MS, while results on MMP-2 are more controversial [141,142] .

Elevated levels of MMP-9 have been detected in serum and CSF of patients affected by MS and other
neurological diseases compared with controls, showing an association with disease activity [143-149] . In a
study by Lee and coworkers, higher values of MMP-9 were found during clinical relapses, also related to a
greater number of MRI gadolinium-enhancing (Gd+) lesions [144] . Similarly, another study confirmed higher
concentrations of CSF MMP-9 in MS patients compared with controls, more in RRMS compared with
PPMS ones, but there was no unequivocal association with clinical disease activity [148] .

Considering the role in MMP inhibition played by tissue inhibitors of MMPs (TIMPs), the ratio MMP-9/
TIMPs has also been considered as an equally valid biomarker and has been found to be increased in the
serum of MS patients compared with controls, accordingly to elevated MMP-9 levels [149] .