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Keywords:

  • antigen presentation;
  • autoantibody;
  • heat shock protein;
  • inflammation

ABSTRACT

  1. Top of page
  2. ABSTRACT
  3. HSP as a molecular chaperone
  4. Mechanisms of HSP release from cells
  5. Fate of HSP-peptide complex internalized with HSP-peptide receptors
  6. HSP receptors
  7. CD91/LRP/α2-macroglobulin receptor
  8. LOX-1
  9. TLR and CD14
  10. CD40
  11. Effect of anti-HSP autoantibodies on immunomodulatory activities of HSP
  12. Concluding remarks
  13. References

HSP are groups of stress-inducible proteins which contribute to quality control by assisting the correct folding of both nascent and denatured proteins, and promoting the degradation of unrecoverable denatured proteins. HSP also help to maintain cellular homeostasis and protect from cell death through a mechanism called thermotolerance. Cells subjected to mild stress induce HSP which then protect them against subsequent stress. However, in cells subjected to severe stress, HSP promote apoptosis. Besides these intracellular events, HSP also exist in extracellular fluids, and have been shown to contribute to immunomodulation. In innate immunity extracellular HSP, like various microbial substances, induce various proinflammatory cytokines. In acquired immunity they interact with antigenic polypeptides and assist in antigen presentation. The extracellular HSP are so-called adjuvant. Release of HSP from cells is triggered by stress and trauma, and is thus regarded as an immunological “danger signal”. In addition, anti-HSP autoantibodies are frequently found in patients with autoimmune diseases and inflammatory disorders, and these autoantibodies can modulate the “danger signal” triggered by extracellular HSP.

List of Abbreviations: 
APC

antigen presenting cell

CIDP

chronic inflammatory demyelinating polyneuropathy

CSF

cerebrospinal fluids

DC

dendritic cell

E. coli

Escherichia coli

ER

endoplasmic reticulum

FLS

fibroblast-like synoviocytes

GBS

Guillain-Barre syndrome

GRP

glucose-regulated protein

HSP

heat shock protein

IL

interleukin

LAMP

lysosomal-associated membrane protein

LDL

low-density lipoproteins

LOX-1

lectin-like oxidized low density lipoprotein receptor-1

LPS

lipopolysaccharide

LRP

low-density lipoprotein receptor-related protein 1

MBP

myelin basic protein

MHC

major histocompatibility complex

MS

multiple sclerosis

NF-κB

nuclear factor kappa-light-chain-enhancer of activated B cells

PAMP

pathogen-associated molecular pattern(s)

PBMC

peripheral blood mononuclear cell

SREC-1

scavenger receptor expressed by endothelial cells 1

TLR

Toll-like receptor

TNF-α

tumor necrosis factor-α

HSP are induced in both eukaryotic and prokaryotic cells by stresses which result in the denaturing of cellular proteins, such as heat shock, heavy metal ions, toxic chemicals, and ultraviolet rays. Furthermore, various pathophysiological events such as hypoxia, ischemia, inflammation, and infection can also induce HSP expression. Various families of HSP exist within the different cellular organelles (cytosol, ER, and mitochondria), and are characterized by their molecular mass (Table 1).

Table 1.  HSP family proteins in eukaryotes and prokaryotes
FamilyEukaryotesProkaryotes
CytosolEndoplasmic reticulumMitochondria
HSP10  HSP10/Cpn10GroES
HSP27 (small HSP)HSP27 α-crystallin β-crystallin  IbpA IbpB
HSP40Hsdj1/Hdj2 HSP40/Hdj1 Rdj2/mDj3 mmDjA4 auxillin  etc……..Mtj1 hDj9/HedjhTid1DnaJ CbpA/RcsG/DjlA
HSP60 (chaperonin)CCT/TRiC MKKS HSP60/Cpn60GroEL
HSP70HSP70/HSP72 HSC70/HSC73Grp78/BipGrp75/Pbp74DnaK Hsc66
HSP90HSP90α HSP90βGrp94/gp96 HtpG
HSP110HSP110/105 HSP70RY/HSP70h APG1/OSP94Grp170/Orp150  

It is recognized that the primary function of HSP is to act as a “molecular chaperone” which assists protein folding. In addition, HSP have been shown to share diverse functions such as control of protein degradation, protection from cell death (thermotolerance) (1–3), immunomodulation, and regulation of development and evolution (4) (Table 2). HSP usually reside in a given organelle as shown in Table 1. However, HSP are also found in extracellular fluids under a certain condition. Extracellular HSP have been shown to share immunomodulatory activities similar to adjuvants and proinflammatory cytokines. So they are sometimes referred to as “danger signals”, which signify certain invasion, and are a trigger for immune responses. In this review, we focus on the immunomodulatory activity of extracellular HSP.

Table 2.  Functions of stress proteins
Stress ProteinsFunction
IntracellularExtracellular
  1. This table is cited from (79) with some modifications.

HSP27Chaperone, anti-deathAnti-inflammatory
HSP60Mitochondria chaperoninPro-inflammatory
HSP70Chaperone, anti-deathImmunoregulatory (adjuvant), pro-inflammatory, neuronal agonist
HSP90Chaperone, evolutional modulatorPro-immune
HSP110Chaperone, co-chaperonePro-immune
BiP/GRP78ER chaperoneAnti-inflammatory
gp96/GRP94ER chaperoneImmunoregulatory (adjuvant)
GRP170ER chaperonePro-immune

HSP as a molecular chaperone

  1. Top of page
  2. ABSTRACT
  3. HSP as a molecular chaperone
  4. Mechanisms of HSP release from cells
  5. Fate of HSP-peptide complex internalized with HSP-peptide receptors
  6. HSP receptors
  7. CD91/LRP/α2-macroglobulin receptor
  8. LOX-1
  9. TLR and CD14
  10. CD40
  11. Effect of anti-HSP autoantibodies on immunomodulatory activities of HSP
  12. Concluding remarks
  13. References

An important function of HSP is that of a “molecular chaperone” which facilitates the folding of both nascent, de novo synthesized proteins and proteins denatured by stress. Therefore, HSP are ubiquitously expressed within cells under normal conditions, additional expression being induced by stressful conditions. HSP also promote the degradation of unrecoverable and needless proteins. Thus HSP carry out “quality control” with regard to the production, recycling and disposal of proteins within cells.

Cells under severe or strong stress die through the processes of necrosis or apoptosis. In contrast, cells experiencing mild degrees of stress respond by upregulating their expression of HSP. It is known that cells expressing increased amounts of HSP, especially HSP70 and HSP27, are more resistant to stresses that induce apoptosis (1–3). This is known as “thermotolerance”. HSP70 suppresses activation of the c-Jun N-terminal kinase pathway, and both HSP70 and HSP27 suppress various steps in the mitochondrial pathway for apoptosis.

Mechanisms of HSP release from cells

  1. Top of page
  2. ABSTRACT
  3. HSP as a molecular chaperone
  4. Mechanisms of HSP release from cells
  5. Fate of HSP-peptide complex internalized with HSP-peptide receptors
  6. HSP receptors
  7. CD91/LRP/α2-macroglobulin receptor
  8. LOX-1
  9. TLR and CD14
  10. CD40
  11. Effect of anti-HSP autoantibodies on immunomodulatory activities of HSP
  12. Concluding remarks
  13. References

As described above, HSP undertake quality control of proteins within cells to maintain cellular homeostasis and provide protection from stress. Because HSP do not have leader signal sequences that direct their secretion, they are considered to be intracellular proteins. However, extracellular HSP in body fluids have been identified and suggested to play physiological roles. Increased concentrations of serum HSP60 are associated with the early presentation of cardiovascular disease, and with physiological stress in women (5, 6), whereas increased concentrations of serum HSP70 are related to the severity of chronic heart failure, myocardial infarction, atherosclerosis, and both peripheral and renal vascular diseases (7–10).

One mechanism by which HSP may be released from cells is via accidental release of intracellular materials from necrotic cells (11, 12). Another mechanism is active secretion by viable cells. For examples, HSP70 is secreted via secretary vesicles or lysosomal endosomes (11, 13, 14), and the exosomes are positive for HSP27, HSC70, HSP70 and HSP90, as well as other recognized exosomal markers such as MHC class I, CD81, and LAMP-2. HSP70 release involves transit through the endolysosomal compartment and is inhibited by lysosomotropic compounds. In addition, the rate of HSP70 secretion correlates well with the appearance of the lysosomal marker LAMP-1 on the cell surface. These secretion systems are also known to be IL-1β secretion machinery (15–17).

Fate of HSP-peptide complex internalized with HSP-peptide receptors

  1. Top of page
  2. ABSTRACT
  3. HSP as a molecular chaperone
  4. Mechanisms of HSP release from cells
  5. Fate of HSP-peptide complex internalized with HSP-peptide receptors
  6. HSP receptors
  7. CD91/LRP/α2-macroglobulin receptor
  8. LOX-1
  9. TLR and CD14
  10. CD40
  11. Effect of anti-HSP autoantibodies on immunomodulatory activities of HSP
  12. Concluding remarks
  13. References

Some HSP bind directly to both monocyte-derived and myeloid DC (18, 19). They also bind to other antigen presenting cells such as macrophages, monocytes, and B cells (20, 21). Cell surface glycoproteins called scavenger receptors (which interact with various types of hydrophobic, structurally unrelated, compounds such as LDL, and bacterial components such as LPS and lipoteichoic acids), are some of the most important receptors for HSP. These receptors recognize HSP by “pattern recognition”. They also recognize apoptotic cells via exposed intracellular membrane phospholipids (e.g., phosphatidylserine) and take these apoptotic cells up via receptor internalization. HSP preferentially interact with denatured proteins, which have exposed hydrophobic regions, and carry these polypeptides (as HSP-polypeptide complexes) to the scavenger receptors. HSP are believed to have the potential to bind hydrophobic substances. Based on the analogy that HSP interact with unfolded proteins, the formation of hydrophobic interaction with scavenger receptors seems reasonable.

What is the fate of internalized HSP-peptide complexes? Because some cytosolic HSP form part of the ubiquitin-proteasome system, polypeptides chaperoned by HSP are degraded. The degraded peptide fragments are then transported into the ER, loaded onto MHC class I molecules, and presented to the cells of the immune system (Fig. 1). In this way, HSP chaperone and facilitate the presentation of antigenic polypeptides. The most characteristic example is the presentation of tumor antigens. Several human melanoma antigens (such as melanoma antigen recognized by T-cell 1/melanoma antigen A, tyrosinase, and gp100) associate with gp96 and HSP70 (22–24). The peptides derived from these antigens are then presented via HLA-A2. A colon carcinoma antigen, carcino-embryonic antigen/epithelial cell adhesion molecule, can also associate with HSP70, this association enhancing antigen presentation (25). These complexes and conjugates of HSP with tumor antigens are being studied as potential cancer vaccines. Some viral antigens associated with gp96 and their peptides are also presented. These include vesicular stomatitis (26), bovine herpes 1 (27), influenza (28), and hepatitis B (29) viruses.

image

Figure 1. Immunomodulatory activities of extracellular HSP on antigen presenting cells.

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HSP70 also interacts with auto-antigens such as MBP, myelin proteolipid protein, and myelin oligodendrocyte protein (30), thus contributing to the etiology of MS. MBP complexed with HSP70 is taken up at higher rates by APC than MBP alone, resulting in enhanced immunological responses against MBP which cause demyelination (31).

Other stress proteins also contribute to the enhancement of antigen presenting activity through their interaction with polypeptides. Srivastava et al. have proposed the “presentosome”, an efficient carrying system of peptides for antigen presentation which forms around the ER membrane within the cells (32, 33). The presentosome contains sub-populations of proteasome, antigen presentation system proteins (transporters associated with antigen processing, tapasin, and MHC class I), cytosolic stress proteins (HSP70, HSP90, and HSP110), and ER stress proteins (gp96, calreticulin, calnexin, and GRP170). The cytosolic and ER stress proteins act as “chaperones”, namely they efficiently deliver antigenic polypeptides from degradation machines to presentation machines.

HSP receptors

  1. Top of page
  2. ABSTRACT
  3. HSP as a molecular chaperone
  4. Mechanisms of HSP release from cells
  5. Fate of HSP-peptide complex internalized with HSP-peptide receptors
  6. HSP receptors
  7. CD91/LRP/α2-macroglobulin receptor
  8. LOX-1
  9. TLR and CD14
  10. CD40
  11. Effect of anti-HSP autoantibodies on immunomodulatory activities of HSP
  12. Concluding remarks
  13. References

HSP can interact with HSP receptors on the surface of immune cells. Some of the resulting complexes, namely HSP-polypeptide complexes, play a role in the internalization of ligands. On the other hand, HSP can act like proinflammatory cytokines and microbial substances, interacting with signaling receptors such as TLR. We will now take a closer look at some examples of these HSP receptors.

CD91/LRP/α2-macroglobulin receptor

  1. Top of page
  2. ABSTRACT
  3. HSP as a molecular chaperone
  4. Mechanisms of HSP release from cells
  5. Fate of HSP-peptide complex internalized with HSP-peptide receptors
  6. HSP receptors
  7. CD91/LRP/α2-macroglobulin receptor
  8. LOX-1
  9. TLR and CD14
  10. CD40
  11. Effect of anti-HSP autoantibodies on immunomodulatory activities of HSP
  12. Concluding remarks
  13. References

CD91/LRP is the receptor for oxidized LDL on APC and other cell types. It has been reported to interact with various HSP, such as gp96, HSP70, HSP90, and calreticulin (34, 35). Binder et al. have shown that, in APC, transfection of small interfering RNA specific for gp96 suppresses the re-presentation of peptide antigen chaperoned by gp96 (36). This ability to re-present peptide antigens is well correlated with the degree of expression of CD91. Also, the interaction of HSP70 with immune cells, such as DC and PBMC, is competitively inhibited by α2-macroglobulin, a ligand for CD91 (37). However, Theriault et al. have suggested that the interaction between CD91/LRP and HSP70 has a relatively weak affinity, or even that it may have been indirectly deduced from biochemical examinations (38).

LOX-1

  1. Top of page
  2. ABSTRACT
  3. HSP as a molecular chaperone
  4. Mechanisms of HSP release from cells
  5. Fate of HSP-peptide complex internalized with HSP-peptide receptors
  6. HSP receptors
  7. CD91/LRP/α2-macroglobulin receptor
  8. LOX-1
  9. TLR and CD14
  10. CD40
  11. Effect of anti-HSP autoantibodies on immunomodulatory activities of HSP
  12. Concluding remarks
  13. References

Delneste et al. have identified LOX-1, which is a scavenger receptor, as an HSP receptor (39, 40). Complexes between HSP70 and polypeptides internalized by APC via LOX-1 and the derived peptides undergo antigen cross-presentation.

Furthermore, other scavenger receptors, such as SREC-1, are thought to interact with HSP70 and calreticulin (41–43). Gp96 and calreticulin can also bind and internalize via scavenger receptor A (44) and SREC-1(38).

TLR and CD14

  1. Top of page
  2. ABSTRACT
  3. HSP as a molecular chaperone
  4. Mechanisms of HSP release from cells
  5. Fate of HSP-peptide complex internalized with HSP-peptide receptors
  6. HSP receptors
  7. CD91/LRP/α2-macroglobulin receptor
  8. LOX-1
  9. TLR and CD14
  10. CD40
  11. Effect of anti-HSP autoantibodies on immunomodulatory activities of HSP
  12. Concluding remarks
  13. References

TLR are pattern recognition molecules for microbial substances (45, 46). TLR transduce cellular signals resulting in activation of the transcription factor NF-κB, which plays a critical role in inflammatory reactions and in the production of interferons. The human genome codes for more than 10 TLR.

TLR4, which cooperates with MD2 and CD14, recognizes the LPS of Gram-negative bacteria. TLR2 recognizes mycoplasma lipoproteins, peptidoglycan, and various other microbial macromolecules. TLR5 recognizes bacterial flagella. TLR3, TLR7 and TLR8 recognize viral RNA and are located intracellularly within the endosomes. TLR9, which is also located in the endosomes, recognizes DNA containing a CpG motif.

It has also been suggested that several host proteins act as TLR agonists. For example, TLR2 and/or TLR4 act as receptors for HSP, which have been suggested to host endogenous ligands of TLR. Asea et al. reported that HSP70 transduces signals via TLR4 and TLR2, facilitated by CD14 (47), and Vabulas et al. reported that HSP70 activates MAP kinase cascades and NF-κB via TLR4 and TLR2 (48). Using LPS-non-responder mice (C3H/HeJ), Dybdahl et al. have shown that inflammatory reactions induced by coronary artery bypass grafting with the use of cardiopulmonary bypass are initiated by extracellular HSP70 via TLR4 signaling (49). Chen et al. reported that heat stress induces release of HSP70 from tumor cells which, in turn, activate tumor cells to produce chemokines via the TLR4 signaling pathway (50). These chemokines subsequently attract DC and T cells to the tumor site. Luo et al. reported that Hsp70 is actively released from FLS in rheumatoid arthritis in response to heat shock or TNF-α, and that it downregulates the production of IL-6, TNF-α, and monocyte chemotactic protein 1 by FLS through negative feedback (51). Also, extracellular HSP70 may be a major paracrine/autocrine inducer of IL-10 production in FLS via TLR4 (52). Ohashi et al. have indicated that HSP60 is also a ligand for TLR4 (53).

However, contradictory reports also exist. Tsan and Gao have published numerous reports showing that LPS or other bacterial substances contained in HSP60 and HSP70 preparations as contaminants are the true ligands for TLR (54–58). These studies were based mainly on the murine macrophage cell line, RAW264.7. However, Yokota et al. have shown that RAW264.7 do not respond to HSP60 and HSP70, whereas human monocytic cell lines (THP-1 and U937) and human PBMC do (59). Species or cell-type differences may exist in the interactions between HSP and TLR. Bausinger et al. reported that HSP70 preparations containing low concentrations of endotoxin (<10 IU/ml) do not induce cytokine production in human monocyte-derived DC (60). Ye and Gan reported that recombinant bacterial HSP70 expressed in E. coli stimulates both Jurkat cells and primary human T cells via TLR5, and that this response is due to contamination of flagellin proteins derived from E. coli (61). Thus some controversy still exists as to whether HSP are true TLR agonists.

In addition, CD14, which comprises part of the TLR4 complex, also contributes to the agonistic activity of HSP for TLR. However, the reports are conflicting. Some reports suggest that CD14, a cofactor for both TLR4 and TLR2, can interact directly with HSP. Asea et al. showed that HSP70-induced TNF-α production and NF-κB activation are enhanced when cell lines (U373 and HEK293) are transfected with CD14 (62, 63). However, Delneste et al. showed that the binding of HSP70 to human primary DC and macrophages is not inhibited by anti-CD14 antibodies (39), while Kol et al. showed that HSP60-induced IL-6 production by human PBMC is suppressed by anti-CD14 monoclonal antibody, but not by the LPS-neutralizing antibiotic, polymyxin B (64).

CD40

  1. Top of page
  2. ABSTRACT
  3. HSP as a molecular chaperone
  4. Mechanisms of HSP release from cells
  5. Fate of HSP-peptide complex internalized with HSP-peptide receptors
  6. HSP receptors
  7. CD91/LRP/α2-macroglobulin receptor
  8. LOX-1
  9. TLR and CD14
  10. CD40
  11. Effect of anti-HSP autoantibodies on immunomodulatory activities of HSP
  12. Concluding remarks
  13. References

CD40 is a member of the TNF receptor family, and contributes to the maturation of APC through binding to its counter receptor, CD40L, on activated T cells (65). Wang et al. have shown that mycobacterial, but not human, HSP70 can bind avidly to CD40 and induce production of CC chemokines, such as CCL3, CCL4, and CCL5 (66). Becker et al. reported that human HSP70 can interact with, and that HSP70-peptide complexes are internalized via, CD40 (21). Millar et al. suggest that CD40 expression by bone marrow-derived DC is necessary for Hsp70-induced CTL activation resulting in autoimmune responses (67).

Effect of anti-HSP autoantibodies on immunomodulatory activities of HSP

  1. Top of page
  2. ABSTRACT
  3. HSP as a molecular chaperone
  4. Mechanisms of HSP release from cells
  5. Fate of HSP-peptide complex internalized with HSP-peptide receptors
  6. HSP receptors
  7. CD91/LRP/α2-macroglobulin receptor
  8. LOX-1
  9. TLR and CD14
  10. CD40
  11. Effect of anti-HSP autoantibodies on immunomodulatory activities of HSP
  12. Concluding remarks
  13. References

Anti-HSP60 autoantibodies are often found in patients with various immunological disorders such as rheumatic autoimmune diseases, atherosclerosis, and cardiovascular diseases (68–70). Autoantibodies against other HSP families, such as HSP70 and HSP90, have also been reported in these immunological disorders (71, 72). However, the pathophysiology of these diseases is still unclear in regard to the mechanism underlying autoantibody formation. Because of high sequence homology at the amino acid level (approximately 50 to 60%), molecular mimicry between host and bacterial HSP is considered to be important for autoantibody formation. However, Yokota et al. reported that the anti-mitochondrial HSP60 autoantibodies found in patients with rheumatic autoimmune disease cross-react not only with bacterial HSP60 (E. coli GroEL and mycobacterial HSP65), but also with the cytosolic chaperonin CCT/TRiC (73). CCT/TRiC is a group 2 chaperonin (this group also contains the archeal chaperonins), which shares weak (15 to 20%) amino acid sequence identity with group 1 chaperonins (which include mitochondrial HSP60 and bacterial HSP60). Anti-HSP60 autoantibodies seem to recognize conformational epitope(s) rather than sequence-specific epitope(s). Anti-bacterial HSP60 antibodies in human sera contain both those recognizing sequence-specific epitope(s) specific for bacterial HSP60, and those recognizing the conformational epitope(s) common to the HSP60 families including human HSP60 and CCT/TRiC.

Several pieces of evidence supporting the pathological role of anti-HSP autoantibodies have been found. Wick and colleagues showed that anti-HSP60 autoantibodies are cytotoxic to endothelial cells, as stressed endothelium expresses HSP60 on the cell surface (type II allergy) (74, 75). This cytotoxicity may be a causative factor in atherosclerosis. On the other hand, immune complexes formed between soluble HSP and anti-HSP antibodies could cause an Arthus reaction (type III allergy).

Yokota et al. reported that murine anti-HSP monoclonal antibodies, including those against HSP60 and HSP70, can enhance HSP-induced proinflammatory cytokine and chemokine production via TLR signaling in human monocytic cells lines and human PBMC (59). The phenomenon was observed for both HSP60/anti-HSP60 and HSP70/anti-HSP70 antibody complexes. Because the effect is seen when using divalent F(ab’)2 fragments, but not when using monovalent Fab fragments, this enhancement is probably due to cross-linking of HSP, which are ligands for TLR, by autoantibodies (Fig. 2). The Fc portions of the antibodies do not contribute to this effect, because F(ab’)2 fragment lacking the Fc region still have enhancing activity. Thus Fc receptors on the surface of monocytic cells are unlikely to contribute to the enhancing effect. Similar enhancing effects are observed using sera containing anti-HSP60 autoantibodies derived from rheumatic autoimmune diseases such as rheumatoid arthritis, systemic lupus erythematosus, and Sjögren's syndrome.

image

Figure 2. Effect of anti-HSP autoantibodies on extracellular HSP-induced immunomodulatory activity.

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Yonekura et al. identified anti-HSP autoantibodies in CSF from patients with inflammatory neuropathies (76). Significantly higher autoantibody titers against various families of HSP, including HSP60, HSP70, HSP90, and HSP27, were found in CSF, but not in sera, of patients with GBS and CIDP. Chiba et al. also reported anti-HSP70 autoantibodies in CSF from MS patients (77). In this case, the autoantibodies were HSP70-specific. The anti-HSP70 autoantibodies found in CSF from MS patients are also able to enhance HSP70-induced cytokine production by monocytic cells (78), this phenomenon probably being the result of cross-linking of HSP70. However, this effect is not seen for anti-HSP autoantibodies (whose specificities are low) found in CSF from patients with GBS and CIDP.

Concluding remarks

  1. Top of page
  2. ABSTRACT
  3. HSP as a molecular chaperone
  4. Mechanisms of HSP release from cells
  5. Fate of HSP-peptide complex internalized with HSP-peptide receptors
  6. HSP receptors
  7. CD91/LRP/α2-macroglobulin receptor
  8. LOX-1
  9. TLR and CD14
  10. CD40
  11. Effect of anti-HSP autoantibodies on immunomodulatory activities of HSP
  12. Concluding remarks
  13. References

Molecular chaperones (HSP and stress proteins) were originally thought to be exclusively located intracellularly, where they function as a quality control of proteins and cells. However, these molecular chaperones can be released from cells into the body fluids by either physiological or accidental mechanisms. Bacterial and viral pathogens are recognized by host pattern recognition molecules such as TLR, RIG-I-like receptors, and NOD-like receptors via their PAMP. Extracellular HSP are considered to be PAMP by the host immune system, and so these extracellular molecular chaperones can act as “a self adjuvant”. Thus, they are able to activate both innate and acquired immune systems, including inducing production of proinflammatory cytokines, cell adhesion molecules, and co-stimulatory molecules within the innate immune system, and enhancing antigen presentation within the acquired immune system (Fig. 1).

The accidental release of HSP into the systemic circulation occurs via necrotic cells, for example, in injured tissues. This is called a “danger signal”. Physiological release occurs via an active secretion system, similar to that observed for IL-1β in response to LPS and extracellular ATP (15–17). It is very interesting that these extracellular molecular chaperones and an important proinflammatory cytokine utilize the same secretion systems. Furthermore, anti-HSP autoantibodies, which are occasionally found in the body fluids of patients with immunological disorders, may enhance the cytokine- and adjuvant-like activities of HSP. Cross-linking of HSP, and probably HSP receptors, by anti-HSP autoantibodies is the probable mechanism for enhancement of HSP signaling (Fig. 2).

References

  1. Top of page
  2. ABSTRACT
  3. HSP as a molecular chaperone
  4. Mechanisms of HSP release from cells
  5. Fate of HSP-peptide complex internalized with HSP-peptide receptors
  6. HSP receptors
  7. CD91/LRP/α2-macroglobulin receptor
  8. LOX-1
  9. TLR and CD14
  10. CD40
  11. Effect of anti-HSP autoantibodies on immunomodulatory activities of HSP
  12. Concluding remarks
  13. References
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