Lps

0 Lipoproteins bacteria

0 Lipotalcholc acid 0 Tefchoic actd 0 Peptidogtycan

0 Llpopeptfdas 0 Porin

Q Lipoarablnomannan 0 My col y I arabinogalactan Q Mannophosphoinoiiitirift

Figure I PAMPs in bacterial cell walls The ecll wall of Grant-positive bacteria consists, or several layers of peptidog-lycan (PGN) where proteins and carbohydrates like teichoic acids are covalently attached. Lipoieichoic acids (LTA) arc inserted into the bacterial ccll membrane together with other glycolipids and lipoproteins. An outer membrane eovets the thin PGN layer of Gram-negative bacteria. Ltpopolysaccharide (LPS) is anchored in the outer membrane together with various proteins and lipoproteins. The mycobacterial cell wall consists of several lipids, lipoproteins and glycolipids like lipoarabinontannan [LAM). Mycoplasma are special in that they do not have a cell wall, hut they have lipoproteins and lipopiptides, such as MALP-2, inserted into their plasma membrane.

fly Droxophila, and the horseshoe crab Lima I us. pathogens in the hacmolymph arc recognized by soluble FRRs that trigger proteolytic cascades that ultimately result in an immune response (reviewed in [9,101). Similarly, the complement pathways in mammals are initiated by solubie PRRs that trigger proteolytic cascades that are central to host defence. Additional soluble PRRs used by the mammalian host to limit infection include the collccims and LPS-binding proteins. These molecules function as adaptors that facilitate the binding of pathogen components to innate immune receptors.

The mechanism by which the central nervous system (CNS) senses and responds to circulating microbial components is largely unknown. One explanation could be that activated endothelial ceils produce proinflammatory mediators that further activate perivascular macrophages behind the blood-brain barrier, ll is clear, however, that ceils of the immune system are capable of crossing the barrier, and that they do so much more efficiency when PAMPs, or PAMP-induced cytokines are circulating in the blood or are generated in the CNS [3]. For infections originating in the CNS one can assume that microglia would recognise palhogen-derived molecules directly through PRRs. However, as the microglia are quiescent compared to other tissue macrophages, the threshold for activation and initiation of inflammation may also be higher. In addition to being involved in pathogen recognition, microglia are also involved in CNS disorders where they might recognise distorted self-structures formed during disease processes. Il is tempting to speculate that neurodegenerative diseases result, in part, through the activation of proinflammatory responses that iead to neuronal destruction. For example, microglial cells are known to aggregate around the neurofibrillary tangles that form in senile plaques during Alzheimer's disease [II].

The discovery of the role of the Toll-like receptor (TLR) family in regulating the activation of macrophages by microbes has opened a new [¬°eld, demonstrating a remarkable specificity in microbial recognition by these pattern-recognition receptors. TLR transcripts are demonstrated

Table I Exogenous TLR ligands*.
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