**2.3 Particularities of inflammation in the central nervous system**

In the central nervous system (CNS), the same inflammatory mechanism previously described remains valid. However, because of the blood–brain barrier, the actors and kinetic of inflammation in the CNS are particular [9]. Furthermore, in the CNS, the immune reactions are molded by the presence of cellular and molecular factors slowing the immune response [9]. In the physiologic conditions, the blood–brain barrier is not permeable to blood constitutes including immune cells. This immune isolation of the CNS brings up the question about the actors implicated in an inflammatory reaction in this particular organ. Many studies prove that the microglial cells located in the periventricular spaces express the class II molecules of the major histocompatibility complex (class II MHC) and can play the role of macrophages in the initiation and amplification of inflammation [9, 10]. Hence, microglial cells can be activated in CNS by three ways: pathogen-associated molecular patterns (PAMPs), missing self, or danger-associated molecular patterns (DAMPs) [11, 12]. This microglial cell activation leads to phagocytosis, antigen presentation, and production of pro-inflammatory cytokines [13]. Furthermore, the active microglial cells express the co-stimulant molecules including CD45, B7–1, B7–2, LFA-1, CD40, ICAM-1, and VCAM-1 which increase the permeability of the blood–brain barrier resulting in the penetration of immune cells in the CNS [9, 13]. It is possible for the active T lymphocytes to cross the blood–brain barrier and penetrate into the brain parenchyma [14]. If these infiltrated T lymphocytes recognize their specific antigen, they will produce pro-inflammatory cytokines that further increase the permeability of the blood–brain barrier [9]. However, this inflammatory activity caused by activated microglial cells or activated T lymphocyte in the CNS remains strongly modulated and inhibited by many cells and molecular immunosuppressing factors present in the CNS.

In the CNS, they are unappropriated conditions for the development and amplification of an inflammatory reaction. Indeed, we observe in the CNS a reduction of the expression of class I and class II molecules of the major histocompatibility complex on the cells, a local production of anti-inflammatory cytokines and a continuous elimination, by apoptosis, of the active T lymphocytes that have crossed the blood– brain barrier [9]. This apoptotic elimination of infiltrated T lymphocyte is the result of an interaction between receptors Fas/Apo-1 (CD95) on the active T lymphocytes and ligands FasL (CD95L) on the CNS cells [15, 16]. This "inflammo-resistance" state of the CNS is not necessarily an advantage. Indeed, low expression of class I molecules of the major histocompatibility complex on the CNS cells leads to two potential consequences. Firstly, it may be possible for the active immune cells if they cross the blood–brain barrier to attack the self CNS cells following the "missing self" principle [11]. Secondly, it may be difficult for active cytotoxic T lymphocyte when they cross the blood–brain barrier to destroy infected CNS cells in the case of CNS viral infection [17]. These consequences make the CNS particularly susceptible to persistent inflammatory states once the pathogen or other cause of inflammation has circumvented all the anti-inflammatory processes present in CNS [17]. Furthermore, even if apoptotic elimination of infiltrated active T lymphocytes leads to a modulation of inflammation in the CNS, it also delays the elimination of the cause of inflammation and therefore prolongs the inflammatory state in the CNS. Apoptosis of infiltrated active T lymphocytes also leads to the release, in the CNS parenchyma, of anti-inflammatory cytokines notably IL-10 and TGFβ which inhibit the cytotoxic activity of active T lymphocytes and thus might perpetuate an eventual CNS viral infection [18, 19]. It appears that it is difficult for an inflammatory process to begin in the CNS, but if for one reason or the other an inflammatory process does begin in the CNS, it becomes very difficult to avert it completely and rapidly.
