The ability of leucocytes to enter infected tissues is a prerequisite of a successful immune response against invading pathogens. Usually a complex inflammatory response is initiated locally, which optimally leads to the elimination of the intruding pathogen and the initiation of tissue repair. However, in organs like the brain with a high content of postmitotic, non-renewable cells immune surveillance could provoke some disastrous collateral damage, which in certain situations may represent a serious threat to the survival of the host (Thomsen 2009). Probably for this reason, certain crucial organs like the brain, the eye, the testicles or the uterus, when carrying a foetus, seem to be particularly well protected against an overzealous immune attack by a series of characteristics, which confers them the title “immune-privileged”.
This immune-privilege, however, does not mean immunological absence.
Inflammatory processes take place in the brain as it is the case in the demyelating disease multiple sclerosis (MS), where encephalolitogenic CD4+ T cells drive the deleterious immune response against oligodendrocytes, and also the neurologic dysfunction in HAD (HIV-associated dementia), which is characterized by cognitive and motor abnormalities, seems to be a consequence of microglial infection and activation. In the latter case, several neurotoxic immunomodulatory factors are released from infected and activated microglia, leading to a neurotoxic cytokine environment that result in altered neuronal function, synaptic and dendritic degeneration, and neuronal apoptosis (Garden 2002).
A limited immune surveillance as immune privilege is better called, also has negative implications: The longevity of many cells and the relative inaccessibility of this tissue to components of the immune system make the brain and spinal cord particularly susceptible to persistent virus infection. In response to tumors of astrocytes, the immune system also seems to be inadequate to protect the host, and in the context of Alzheimer´s disease the inflammatory response might be insufficient to clear noxious material. So, the immune-privileged status of the brain implies a delicate balance between protection and immunopathologic damage and thus can be beneficial or detrimental to the host.
The immune privilege has mainly been attributed to two morphological pecularities:
the absence of classical lymphatic vessels and the blood-brain/ blood-CSF barrier.
Immunoproteasome assembly in the brain of LCMV-infected mice Introduction
Anatomically, there are no defined lymphatics in the brain however it is clear now, that antigens efficiently drain into cervical nodes by the movement of CSF through the brain and Virchow-Robin spaces to sites where it crosses into anatomically identifiable lymphatics beneath the cribriform plate and perineural sheath of cranial nerves (Cserr et al. 1992; Cserr and Knopf 1992; Kida et al. 1995; Knopf et al. 1995). Similar routes are assumed for antigen presenting cells (Hatterer et al. 2006). However, the importance of such indirect connections to the immune systems remains controversial and needs further investigation.
Taken together, the concept of immune privilege has greatly evolved since the last decade, and now it is widely accepted that the special anatomy clearly provides the cells of the CNS with a certain protective status but that the CNS is not excluded from immunological surveillance. Additional factors further have shifted the picture of the immune privileged status of the brain to a more dynamic scenario, in which immune tolerance is actively maintained by several mechanisms, which are tightly controlled by the activation status of local antigen presenting cells (Kwidzinski et al. 2003). 1.7 Blood brain barrier (BBB)
Apart from the absence of classic lymphatic vessels, the immune privileged status of the brain is mainly - but not exclusively - established by the blood-brain barrier (Galea et al. 2007). It consists of a complex layer of brain capillary cells, astroglia, pericytes and perivascular macrophages within the basal lamina. Together with the blood-cerebrospinal fluid barrier located at the ependymal cells of the choroids plexus it maintains brain homeostasis and acts as a barrier for virtually all molecules, except those that are small and lipophilic (Bart et al. 2000). There are, however, sets of small and large hydrophilic molecules that can enter the brain, and they do so by active transport (Rowland LP 1992). For essential nutrients, such as glucose and certain amino acids, specific membrane transporting proteins exist in relatively high concentrations in brain endothelial cells. One of these transporters suspected to be involved in maintaining the integrity of the blood- brain barrier is P-glycoprotein (P-gp), which is a well-known ABC-transporter primarily discovered to be upregulated in multi-drug restistence tumors (Juliano and Ling 1976). Apart from these tumors it is expressed in the brain at the luminal side of capillary endothelial cells (Tsuji 1998) and in several other
Immunoproteasome assembly in the brain of LCMV-infected mice Introduction
epithelial and endothelial tissues with homeostatic functions. P-glycoprotein works in opposite direction generally transporting back into the blood a variety of lipophilic molecules that enter the endothelial cells or penetrate into the brain. It is a functional part of the barrier, since P-glycoprotein knockout mice show an enhanced influx of circulating drugs and potential toxins into the brain (Schinkel et al. 1994; Schinkel et al. 1996). Furthermore, it should be mentioned that there is an inherent level of IgG, but not IgA and IgM present in the cerebrospinal fluid (Bart et al. 2000). Although the blood-brain barrier excludes molecules the size of cytokines or LPS and no transport mechanisms has been identified for these moieties so far, they can activate cells behind the BBB (Hickey et al. 1992) resulting in an up-regulation of MHC expression and eicosinoid synthesis a few hours after this substances are found in the circulation
(Hickey and Kimura 1987; Hickey et al. 1992) (Elmquist et al. 1997). As reviewed by Abbott et al.
(Abbott and Revest 1991) and Rubin et al. (Rubin and Staddon 1999), the functionality of the blood brain barrier to most hydrophilic substances largely depends on the tight junctions and adherent junctions. In contrast to peripheral endothelial cells, the tight junctions of the brain endothelial cells are continuous and show no hiatuses.
Pinocytic activity and transcellular transport in brain endothelial cells is rare and further limits the entrance of large molecules into the brain. It further has been shown that the integrity of the blood brain barrier is influenced and maintained by glial cells, especially astrocytes (Broadwell et al. 1994; Kuchler-Bopp et al. 1999; Akiyama et al. 2000). Figure 4 summarizes the described properties of the blood brain barrier:
expressed at the luminal side of the ECs and is actively ejecting certain undesired
Immunoproteasome assembly in the brain of LCMV-infected mice Introduction