While much of the research on stroke has focused on the immediate inflammatory processes that occur during the ischaemia and reperfusion phase, clinically, one of the most important secondary factors affecting mortality is post-stroke infection (Roth et al., 2001; Vargas et al., 2006). The severity of the infection in most cases correlates with the severity of the stroke, but it is difficult to determine which is cause and which is effect. It is unclear whether a large infarct causes a subsequent large suppression of the immune system and more serious consequences of an infection, or if a serious infection will significantly inhibit neuronal recovery resulting in a more severe infarct. An initial increase in immune cell numbers in the first 24 h after stroke (Offner et al., 2006a) is followed by a significant decrease in immune function in the days following stroke (Offner et al., 2006b; Liesz et al., 2009a), which is matched with an increase in Tregs. The Tregs are thought to cause spleen atrophy and drastically decrease the number of circulating immune cells. However, once again there is uncertainty, as splenic atrophy could be caused by neural stimulation from the damaged brain and the apparent increase in Tregs could be a symptom of their ability to survive splenic atrophy, causing further dampening of the immune system. Considering however, that immune suppression may in itself be a contributing factor to the severity of stroke, perhaps an increase in Tregs in the days and weeks, rather than hours, following stroke should be considered a factor to be modulated to provide optimum protection from infection and minimization of infarct. Systemic infection following stroke can lead to an increased core temperature, increased acidosis and contribute to excitotoxicty, all leading to a larger infarct (Reith et al., 1996).
Clinically, it is quite difficult to determine if the stroke causes increases infection severity or if a severe infection increases stroke damage. It is becoming accepted that the ischaemia, reperfusion and subsequent neural damage causes, at first a heightened immune response and secondarily to that, immune suppression. When put in the context of the possibility of autoimmunity, this hypothesis appears to have a better fit. As a result of the stroke, immune cells have access to the usually off-limits CNS and in order to prevent the development of autoimmunity, the immune system is suppressed. It is rare to find a stroke patient who subsequently develops autoimmune disease, however, multiple clinical studies have shown the presence of brain-specific antibodies following stroke (Bornstein et al., 2001; Gromadzka et al., 2001; Dambinova et al., 2003). It has also been shown in experimental models of multiple sclerosis that astrocytes are responsible for stimulating T cells to become regulatory and limit autoimmunity (Trajkovic et al., 2004). However, this has not been extended to the paradigm of stroke. In experimental neural trauma, the autoimmune reaction can be modulated to produce a better outcome. Mice that were tolerant to myelin basic protein (MBP) prior to MCAO and had concurrent LPS treatment suffered a smaller infarct than those unexposed to MBP and autoimmunity was prevented (Gee et al., 2008). It was also shown that pre-treatment with LPS dampened the cellular immune response to stroke, but this may be more to do with preconditioning the TLRs in both the CNS and immune system, thus obscuring the precise reason for neuroprotection (Rosenzweig et al., 2004). Many studies have suggested that autoimmunity is detrimental in stroke, as mice with B and T cells removed suffer a smaller infarct (Hurn et al., 2007). However, this approach does not account for the different stages of inflammation, nor does it account for the contribution of different types of T cells. Both the CNS and peripheral response could be co-ordinated by TLR signalling, in the immediate response of the microglia and also the delayed response of the various immune cells. TLR ligands are present immediately following the infarct and are secreted into the periphery following BBB breakdown. TLRs are currently being targeted for various immune therapies, including autoimmune disease states (Gomariz et al., 2010) and the link between these receptors and the autoimmune consequences of stroke could provide potential therapies to minimize secondary damage following stroke. The current situation appears to be that autoimmunity can be developed after stroke and unless there is a subsequent infection, the consequences are minimal. As far as clinical treatments go, however, understanding the underlying mechanisms that control the immune reaction to the CNS will need to be known in greater detail in order facilitate pharmacological development in this area. One signalling system that appears to play a role in both the CNS and the peripheral response to stroke are the TLRs. Given the potential for these receptors to be involved as a bridge between the CNS and the periphery during ischaemic insult, a brief overview of TLR signalling will follow.