Biomedical Engineering Reference
In-Depth Information
subsequently been shown to be widely distributed in other insects, animals,
and plants. In mammals, they are referred to as Toll-like receptors (TLRs)
because of their similarities to the original Toll receptors (56). The extracel-
lular domains of these receptors detect specific components of bacterial, fun-
gal, and viral pathogens that serve as ligands for the TLRs. The interaction
between ligand and receptor initiates the production of the cytokines that
control the innate inflammatory immune response. The mammalian TLR
family continues to grow and currently has 10 recognized members. They
are expressed on a wide variety of inflammatory immune cells including
monocyte
=
macrophages, dendritic and mast cells. They are also expressed
on the epithelial cells of the airway and are located on the lateral surface
below the tight junctions in the gastrointestinal mucosa (56). This requires
that microbes breach the epithelial barrier and invade the paracellular space
from the apical surface before they interact with a TLR and elicit a
response.
The chromosomal location of each of the 10 known genes for human
TLRs is established and ligands recognized by TLR1,2,3,4,5,7 and 9 have
been identified (56). These ligands include components of fungi (TLR2),
gram positive bacteria (TLR2), gram negative bacteria (TLR4), mycobac-
teria (TLR1), bacterial flagella (TLR5), mycoplasma (TLR6) and viruses
(TLR3) (56). Activation of the TLRs by these ligands initiates an intracellu-
lar signaling pathway that is similar to the mammalian IL-1 pathway. The
close association between the Drosophila Toll and mammalian IL-1 recep-
tor is highly conserved and is referred to as the Toll
=
IL-1 receptor (TIR)
domain. Both TLRs and IL-1R associate with an intracellular adaptor
protein MyD 88 which has a TIR domain and this interaction leads to
the activation of both the JNK and NF-kB signaling pathways that regulate
the expression of a many genes associated with the innate inflammatory
immune response (56). The distribution of the toll receptors in the human
lung is only beginning to be studied and should provide some novel insights
into COPD.
C. Adaptive Immunity
In contrast to the innate immune system which responds quickly to many
stimuli and mounts a nonspecific response that lacks specificity and has
no memory the adaptive immune response develops more slowly, is very
specific to individual antigens and has exquisite memory for previous expo-
sure. The development of an adaptive response requires an interaction
between T cells and B lymphocytes that have recognized the same antigen
but the chance of this happening in the peripheral blood where only one
in every 10
5
or 10
6
lymphocytes demonstrate such specificity is very remote.
Local lymphatic collections in the regional lymph nodes and bronchial
mucosa greatly increase the opportunity for this type of interaction. Because
