Antigenic Recognition by the Brain: The Brain as an Immunocompetent Organ - New Insights to Neuroimmune Biology - page 136

microglia need to be able to respond quickly to both endogenous and exogenous
threats. The function of neuronal TLRs in the innate immune response has not yet
been identified [6-8] .
Apart from viral or bacterial infection of the brain, TLRs binding to antigenic
homologous epitopes (homotopes) have little role to play in most neuropathologies.
This suggests that they have important roles in physiological regulation. Recent stud-
ies indicate that there are many endogenous ligands for TLRs [9-11] . Understanding
the role of these receptors in brain injury and pathology without pathogen or infiltrat-
ing macrophages is of utmost importance [6] .
It has been suggested that TLRs are stress receptors, as they bind to heat shock
protein (HSP) mRNA [12] and to heparin sulfate [13] . The currently identi-
fied endogenous ligands of TLRs may be divided into two categories: those that
alter development, particularly of dendritic cells, and those that result from cel-
lular damage. It is primarily the detection of damage and subsequent activation of
inflammatory mediators that link TLRs to most neuropathologies. The pro- or anti-
inflammatory response to this damage can be beneficial, detrimental, or even both,
depending on the time scale over which the response is activated [6] . For instance,
although TLR3 responds to viral infection in a pro-survival manner, it may help West
Nile virus to cross into the CNS [14] .
It is important to note that both the activation of TLRs and the regulation of
inflammation are understood as constituting a fine level of control that can tip an
inflammatory event from being beneficial to being detrimental. Evidence is mount-
ing for the role of TLRs in inflammation and regeneration that occurs following spi-
nal cord injury, and further investigations may lead to therapeutic options to optimize
both the initial response and ongoing treatment [6] .
7.2.2 Innate Immune Defense in the CNS
Innate or natural immunity (NATIM) plays an important role in defending the fetus
in utero; it remains active in self-defense and also participates in the physiology of
the host for life. This system is ready to act instantaneously at any time, immuniza-
tion is not necessary, and we never lose our natural immune defense—it is there till
our last moment [15,16] .
Because the blood-brain barrier (BBB) protects the CNS from invasion by immune/
inflammatory cells and even from macromolecules [17] , the brain relies heavily on
its NATIM system for defense during homeostasis. It appears that all cells in the
brain, including neurons and nerves, express innate immune receptors, and are capa-
ble of responding to homologous epitopes, which are recognized by innate antigen
receptors [6] . Within the CNS, the choroid plexus participates in acute phase responses
and is able to produce acute phase proteins (APP) [18] . If, however, this system is
incapable of handling the insult, there are mechanisms to admit the cells of adaptive
immunity (e.g., macrophages, T and B cells, and other leukocytes) into the CNS [19] .
Initially NATIM was considered to be nonspecific immunity. However, recently
it has become clear that innate antigen receptors do have specificity and recognize
evolutionarily highly preserved homologous epitopes ( homotopes ; also known as