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inflammatory reaction, which could be life-threatening. However, allergy cannot be
transferred by IgE antibodies [70] , and serum IgE titers and skin reactions do not
always correlate with the severity of allergy [71,72] . In addition, asthma has two dis-
tinct etiological types: allergic asthma and idiopathic asthma [66] . These facts are
hardly compatible with the prevailing view that allergy and asthma are caused by IgE
antibodies. Given the fact that mast cells and inflammation are regulated by the CNS,
we suggest that allergy is the result of excessive up-regulation of mast-cell sensitivity
to the allergen by the nervous system. Bronchial hypersensitivity has the same etiol-
ogy. In the case of idiopathic asthma, mast cells function as nociceptors and respond
to nocuous stimulation by triggering an exaggerated inflammatory reaction.
Hyperactive SNMC pathways are involved in arthritis [73] , airway inflammation
[74] , and inflammatory conditions in the heart [75] . Bradykinin induces synovial
inflammation and also signals the hypothalamus [69,76] . Vagal sensory efferents
respond to pro-inflammatory cytokines (e.g., IL-1) in visceral organs and provide
inflammatory feedback signals to the hypothalamus [77] . Migraine headache is
caused by a maladjusted SNMC pathway [78] .
7.5.1.1 Alzheimer's Disease
In 2006, it was shown that the Asp299Gly mutation in TLR4 caused a decreased
inflammatory response and correlated with protection from late-onset Alzheimer's
disease (AD) [79] . The involvement of TLRs in AD is controversial. The innate
immune system is important in both the periphery and the CNS in combating AD.
Although TLR2 appears to be beneficial, the role of TLR4 is more controversial.
A consistent feature of neuropathological events is the activation of microglia by
TLRs. Activated microglia protect against invading pathogens and spinal cord injury;
decreased activation may lead to cancer and inappropriate activation to neuropathic
pain. TLRs are involved in both ischemia and reperfusion during stroke. It has also
been suggested that chronic TLR malfunction can lead to AD and that TLRs respond
to brain lesions [6] .
Although the brain is often considered to be an immunologically privileged site,
many of the pathological events are caused by invading cells. Such cells express
TLRs, which manage inflammation in the CNS and stimulate the production of
chemokines that regulate the invasion of cells into the CNS. The role of TLRs in
neuropathology has not been fully established, and further investigation is necessary
for better understanding. This receptor family offers therapeutic potential in the treat-
ment of such conditions as neuropathic pain, Alzheimer's disease, spinal cord injury,
and multiple sclerosis. A more complete understanding of their role is essential for
developing this potential [6] .
7.6 Conclusions
The expression of TLRs by neurons proves that the brain is able to sense infec-
tions and other pathological conditions directly, using innate immune receptors.
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