Biomedical Engineering Reference
In-Depth Information
response design, including innate immunity and readiness for an adaptive
immune response, if necessary.
Dendritic cells respond to two types of signals: direct recognition of
pathogens (through specific pattern-recognition receptors) and ''danger sig-
nals,'' an indirect sensing of infection and
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or injury (through inflammatory
cytokines, internal cellular compounds, and ongoing specific immune res-
ponses) (57). In response to these signals, DCs are activated to enter an
integrated developmental program called maturation, which transforms
immature DC into efficient APCs and T-cell stimulators, and are, therefore,
responsible for the development of an adaptive immune response. (see
Reference 53 for a full review.)
The stimulation of a variety of surface receptors in the DC are known
to trigger DC (53) maturation and antigen presentation: pathogenic com-
pounds, inflammatory mediators such as TNF-a,IL-lb, PGE-2, GM-CSF,
immunoglobulins, T-cell derived signals mainly CD40L, and cell death, both
necrotic and apoptotic (53,58-60). Heat shock proteins released by necrotic
and injured cells are also important inducers of DC maturation (57). The
innate immune reaction in smokers has been shown to be accompanied by
many of the inflammatory mediators listed here, and could easily provide
the necessary costimulation for DC maturation.
B.
Heat Shock Proteins
The HSPs are reviewed here in some detail because they could have a
primordial role in COPD, being responsible for the abundance of CD8
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T-cells in the disease, and the development of autoimmunity (61,62).
Genes that encoded HSPs were identified serendipitously in fruit flies
that were inadvertently exposed to high temperature (63). These genes, and
the proteins encoded by them, are present in all cells in all forms of life. The
HSPs can be classified into 10 families with 1-5 closely related proteins in
each. They constitute up to 5% of the total intracellular proteins; however,
under stresses like exposure to high temperatures, toxins, oxidative condi-
tions, etc., their intracellular levels can rise to 15% or more (57). Heat shock
proteins are not normally present in the blood or other body fluids, nor are
they expressed on the cell surface under normal conditions. Therefore, the
presence of HSPs in the extracellular milieu would act as an excellent mes-
sage that alerts the immune system to physical damage in the tissue, whether
as a consequence of bacterial, chemical, mechanical, or oxidative injury.
This chain of events would also explain the presence of a surface receptor
for HSPs, which are normally intracellular, in APCs (57).
The immunological functions of HSPs began to emerge in the 1980s
when it was observed that certain HSPs isolated from cancer cells elicited
immunity to cancers where corresponding preparations from normal tissues
did not (64). Immunogenicity of tumor-derived HSPs was the result of the
