Biomedical Engineering Reference
In-Depth Information
association of HSPs molecules with peptides that were generated by the
degradation of proteins expressed by the cells from which the HSPs were
purified (65-68). This suggests that the HSPs chaperone the peptide finger-
print, which includes the antigenic fingerprint, of the cells from which they
are isolated and these complexes have the capability of eliciting MHC Class
I restricted antigen-specific CD8
รพ
T-cell responses, a phenomenon called
cross-priming or cross-presentation (69).
It is now clearly established that the HSPs, as well as the major histo-
compatibility (MH) molecules, are peptide-binding proteins, with HSPs
being more promiscuous than MHC, the difference in promiscuity having
important physiological consequences. The difference in the stringency of
requirements for peptide binding by the two make it possible for one (the
HSPs) to bind to any available peptide and to render them presentable to
the other (the MHC). The ability of the HSPs to scan the entire repertoire
of intracellular proteins allows them to have a key role as informers of
the MHC molecules (and therefore of the T-cells) with respect to intracellu-
lar pathogens (or pathogenic events). Thus, the HSPs carry peptides gener-
ated within cells, mediating transfer to the MHC Class I molecules of that
cell (normal or ''intrinsic'' MHC I antigen presentation); if the cell is lysed,
the HSPs within the cell are released and carry the chaperoned peptides, to
the MHC molecules of the neighboring DCs: cross-presentation (or ''extrin-
sic'' presentation), to MHC I (57) (see below).
In addition to the targeting of chaperoned peptides for presentation,
the interaction of HSPs (without peptides) with APCs leads to peptide-inde-
pendent activation of innate immune mechanisms (61). Acting through toll
receptors TLR2, TLR4, and CD14 (70-75), they can induce secretion of
inflammatory cytokines TNF-
a
, IL-1
b
, IL-12, and GM-CSF by macro-
phages (70); induction of inducible nitric oxide synthase (iNOS) and produc-
tion of NO by macrophages and DCs (76); secretion of chemokines such as
monocyte chemoattractant protein-1 (MCP-1), macrophage inflammatory
protein-2 (MIP-2), and RANTES by T-cells (77,78); maturation of dendritic
cells, as measured by enhanced expression of MHC Class II, CD886 and
CD40 (70,79-81); migration of DCs to draining lymph nodes (82) and trans-
location of nuclear factor-
k
B (NF-
k
B) into the nuclei of macrophage and
DCs (70) perhaps the proximal event that mediates many of the events
listed. In many of these activities, HSPs are strikingly reminiscent of bacter-
ial lipopolysaccharides (LPS) or endotoxins, which exert powerful effects on
APCs (57) (Fig. 3).
The presence of HSPs in the extracellular milieu would, therefore, act
as an excellent message that alerts the DCs to physical damage of the sur-
rounding cells, whether as a consequence of bacterial, viral, mechanical,
or any other type of injury, and might therefore confer an immunological,
and hence survival advantage to the organism. However, under special cir-
cumstances, HSPs have the potential to promote autoimmunity by serving
