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Toscano et al. Neuroimmunol Neuroinflammation 2021;8:14-41 I http://dx.doi.org/10.20517/2347-8659.2020.12 Page 23
[94]
form, it is expressed by dendritic cells and promotes Th17 and Treg differentiation . Moreover, it is
[95]
thought to mediate the upregulation of Th1 and Th17 cytokines, mainly IFN-γ and IL-17 , and the
[96]
inhibition of pro-apoptotic proteins, favoring T cell survival . It has been suggested that a specific subset
of Th1 cells, particularly arising in CSF during relapses, produces OPN, high levels of IFN-γ and matrix
[97]
metalloproteinase-9 (MMP-9) after polyclonal stimulation, playing a pathogenetic role .

In experimental models of relapsing-remitting experimental autoimmune encephalomyelitis (EAE), OPN
expression was constantly evidenced in microglia next to periventricular lesions and in neurons limited to
[98]
the relapse phase, which increased in mice with greater disease severity . Moreover, when recombinant
OPN was given to mice, severe relapses occurred after 1-3 days. Conversely, knockout mice for OPN
[96]
seemed to be protected from the development of severe EAE .

Accordingly, immunohistochemistry analysis of MS brain lesions in humans identified marked OPN
expression immediately near the lesions, in vascular endothelial cells, microglia and astrocytes, which was
greater in more active lesions [98,99] .

High levels of OPN have been found in plasma of RRMS patients, with greater concentrations in patients
with active disease compared with those without exacerbations [100-103] and during relapses compared with
remissions [102,104,105] . Similar results were found in other studies [96,101,106] , with significantly higher CSF and
serum OPN levels in MS patients compared with controls [102,107-110] . A positive correlation between IL-17
and both OPN and IL-23 concentrations has also been found [106] . Moreover, CSF concentrations of OPN
in MS patients, re-evaluated 5 years after sampling, proved to be not only elevated but also related to the
occurence of relapses and to clinical severity [111] . It has been supposed that the increase in OPN during
relapses has an inverse correlation with the concentration of serum extracellular proteasome, with marked
effects on chemotaxis [112] . However, other studies did not find a clear association between OPN levels and
disease activity [107,113] .

According to some studies, SPMS patients exhibited elevated OPN values as well compared with
controls [102,107] , while a significant difference was not reported by other studies [104] . In a recent meta-analysis
by Agah and coworkers, all MS patient subtypes showed higher OPN levels compared with controls, except
for CIS [101] . However, greater concentrations were found in RRMS patients compared with all other groups
and in those with exacerbations compared with patients with stable disease.

IFN-β proved to downregulate OPN and IL-17 in MS patients and to decrease the incidence of EAE and
the amount of Th1 and Th17 cells in mice [114,115] . Indeed, RRMS patients treated with IFN-β showed OPN
at similar levels compared to untreated patients in remission phase . Glatiramer acetate and NTZ lead
[96]
to the decrease of plasma OPN levels as well [107,116] . Several polymorphisms of the OPN gene have been
investigated to find an association with disease course or activity [117-120] . A few have been correlated with the
level of disability [118] , with disease course and risk for conversion to SPMS [119,120] , and with susceptibility to
MS development and relapse rate [121] .

Additional studies are needed to confirm the role of OPN as a useful disease activity biomarker.

C-X-C motif ligand 13
C-X-C motif ligand 13 (CXCL13), also known as B cell attracting chemokine (BCA-1), is a protein favoring
the chemotaxis of mature B lymphocytes by interaction with its receptor CXCR5. This receptor is also
expressed by CD4+ T follicular helper cells, CD4+ Th17 cells, activated Treg cells and a subgroup of CD8+
T cells [122] .