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Nociti. Neuroimmunol Neuroinflammation 2020;7:291-9 I http://dx.doi.org/10.20517/2347-8659.2020.25 Page 293

In the advanced stages of the disease, the infiltration of immune cells into the CNS is reduced, whereas
ongoing CNS-compartmentalized inflammation seems to dominate progressive phases of MS. During this
progressive phase, the role of B cells in driving inflammation seems to be prominent, particularly within
[23]
meningeal inflammation . In this phase, the B cell functions are antibody production, cytokine secretion,
antigen presentation and ectopic formation of follicle-like structures [23-25] . The latter seem to maintain a high
level of humoral response and other autoimmune mechanisms, in the CNS, independently from peripheral
inflammation. This is very relevant during progressive MS phase, with the BBB being relatively intact and
[26]
the contribution to disease from entry of peripheral immune cells into the brain fairly exiguous .

Activated microglia also plays a central role in neuroinflammation because it can sustain ongoing
[27]
inflammation . Microglia activation, in MS, is diffusely present in the lesions, in normal-appearing
white and in grey matter . Activated microglia, secreting pro-inflammatory cytokines, such as IL-1, IL-6,
[28]
TNF-alfa, and IFN, promoting phagocytic activity, and presenting antigens via MHC Class II to CD4+
T cells , causes damage to oligodendrocytes; moreover, microglia inducing mitochondrial dysfunction,
[27]
[29]
through reactive oxygen and nitrogen species, contributes to neuronal damage .

In addition, activation of astrocytes into demyelinating lesions contribute to oligodendrocyte injury and
axonal degeneration . So far, theories of either innate immune cells in the CNS are dysregulated and
[30]
drive primary degeneration, or react against an unidentified primary injury causing tissue damage remain
unknown.

NEUROINFLAMMATION IN MS: THE NEUROPROTECTIVE EFFECT
Evidence for neuroprotective functions of immune cells
Some evidences have unexpectedly shown that some cells of the immune system might have a protective
function during inflammation. This neuroprotective effect may be partially mediated with the production
of anti-inflammatory cytokines (TGF-beta, IL-10 etc.) and secretion of pro-inflammatory cytokines (such
as IL-6, IFN-gamma, TNF-alfa) in a dose- and time-dependent manner [31-33] . Immune cells also induce
neuroprotection by production and local secretion of neurotrophic factors [11,12,34] . neural growth factor
(NGF) was the first neurotrophin shown to be produced by T and B lymphocytes, macrophages, and
[35]
[12]
mastcells . The expression of BDNF by immune cells was also subsequently described . In particular,

CD4+ and CD8+T lymphocytes, B lymphocytes, and monocytes in the human peripheral immune system
[12]
can produce BDNF . Moreover, neurotrophin receptors expressed by immune cells can also be targeted by
autocrine or paracrine neurotrophin actions. Therefore, neurotrophins seem to mediate bidirectional cross-
[11]
talk between the immune and nervous systems .
Evidence for neuroprotective function of microglia and astrocytes
Resident CNS cells also exercise a defensive action against immune-mediated attacks, aside from being
involved in neuroinflammation. Microglia has an important role in neuroprotection and this action seems
to be time-dependent. Acutely activated microglia produces inflammatory mediators that recruit other
activated immune cells, amplifying the inflammatory damage, but chronically activated microglia may
have a neuroprotective effect supporting the growth and survival of neural progenitor stem cells [31,36] .
On oligodendrocyte precursor cells microglia seems to have always direct protective action, being the
[37]
detrimental action mediated by astrocytes .
The neuroprotective function of microglia is mediated by different mechanisms such as debris clearance,
production of growth factors (overall BDNF), production of the immunosuppressive cytokine IL-10 and
neuronal circuit-shaping [27,38] .

TGF-beta secretion and CTLA-4 expression produced by neurons induce CD4+CD25-effector T
cells to take regulatory phenotype that exerts bystander suppression in experimental autoimmune