Adjuvanticity of α2-Macroglobulin, an Independent Ligand for the Heat Shock Protein Receptor CD91

Binder, Robert J.; Karimeddini, David; Srivastava, Pramod K.

doi:10.4049/jimmunol.166.8.4968

Cited by 79 publications

(53 citation statements)

References 16 publications

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“…Moreover, our results showing that ␣ 2 M present in RASF may be captured by CD91 (Fig. 6A) indicate that ␣ 2 M, which displays the capacity to chaperone Ags into DCs for T cell cross-priming (22), also contributes to the RA cross-priming process. Future studies might include determining the effects of specific inhibitors of hsp70 such as deosyspergualin (34) on hsp/DC-mediated crosspriming events in RA and other autoimmune diseases, assessing the interactions of other hsp family members, such as Ig H chain binding protein, and characterizing ␣ 2 M/DC interactions in the RA joint.…”

Section: Discussionmentioning

confidence: 91%

Aberrant Extracellular and Dendritic Cell (DC) Surface Expression of Heat Shock Protein (hsp)70 in the Rheumatoid Joint: Possible Mechanisms of hsp/DC-Mediated Cross-Priming

Martin

Carsons

Kowalewski

et al. 2003

The Journal of Immunology

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We describe, in rheumatoid arthritis (RA), abnormalities in the expression and distribution of heat shock protein (hsp) and dendritic cells (DCs) that are conducive to cross-priming and DC cross-talk. As detected by ELISA, inducible (i)hsp70 was dramatically increased in RA synovial fluid (RASF) vs normal human and RA sera and osteoarthritis and gout synovial fluid. Immunoblot analysis of fresh RASF cells revealed marked increases in ihsp70 and activation of its transcription factor heat shock factor-1, compared with fresh normal peripheral blood cells. Flow cytometry and microscopy demonstrated high levels of ihsp70 on the surface of RASF myeloid DCs (but not normal myeloid DCs) that occurred concurrently with hspRs (CD91/CD14). ihsp70 present in RASF exhibited chaperoning potential, as indicated by the capture of ihsp70 present in RASF on the surface of normal DCs. Binding was partially competitively inhibited by excess α2-macroglobulin, indicating that hspRs in addition to CD91 participate in the capture process. These data indicate that ihsp70 may chaperone autologous Ags into immature RASF DCs via hspRs, and that cross-talk between DCs coexpressing hsp/hspRs reflects a disease process in RA. The induction of surface ihsp70 on normal cells after sublethal heat stress and the release of ihsp70 from normal DCs after inflammatory stress also suggest that the pattern of ihsp70 expression in RASF occurs in response to sustained stress.

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Section: Discussionmentioning

confidence: 91%

Aberrant Extracellular and Dendritic Cell (DC) Surface Expression of Heat Shock Protein (hsp)70 in the Rheumatoid Joint: Possible Mechanisms of hsp/DC-Mediated Cross-Priming

Martin

Carsons

Kowalewski

et al. 2003

The Journal of Immunology

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“…The binding to hydrophobic molecules does not inhibit the trapping of proteases and is not known to be associated with any conformational changes (Barrett 1981). Previous work has indicated that α 2 M-polypeptide complexes are immunogenic (Chu and Pizzo 1993;Binder et al, 2001). α 2 M bound peptides are internalised by LRP and fragments of the peptide are subsequently re-presented on the cell surface.…”

Section: Haptoglobinmentioning

confidence: 99%

Extracellular Chaperones and Amyloids

Wilson¹,

Yerbury²,

Poon³

2008

Heat Shock Proteins and the Brain: Implications for Neurodegenerative Diseases and Neuroprotection

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The pathology of more than 40 human degenerative diseases is associated with fibrillar proteinaceous deposits called amyloid. Collectively referred to as protein deposition diseases, many of these affect the brain and the central nervous system. In many cases the amyloid deposits are extracellular and are found associated with newly identified abundant extracellular chaperones (ECs). Evidence is discussed which suggests an important regulatory role for ECs in amyloid formation and disposal in vivo. This is emerging as an exciting field. A model is presented in which it is proposed that, under normal conditions, ECs stabilize extracellular misfolded proteins by binding to them, and then guide them to specific receptors for uptake and subsequent degradation. In this scenario, EC receptors are a critical part of a quality control system which protects the brain against dangerously hydrophobic proteins/peptides. However, it also appears possible that in the presence of a high molar excess of misfolded protein, such as might occur during disease, the limited amounts of ECs available may actually exacerabate pathology. Further advances in understanding of the mechanisms that control extracellular protein folding are likely to identify new strategies for effective disease therapies. ABSTRACTThe pathology of more than 40 human degenerative diseases is associated with fibrillar proteinaceous deposits called amyloid. Collectively referred to as protein deposition diseases, many of these affect the brain and the central nervous system. In many cases the amyloid deposits are extracellular and are found associated with newly identified abundant extracellular chaperones (ECs). Evidence is discussed which suggests an important regulatory role for ECs in amyloid formation and disposal in vivo. This is emerging as an exciting field. A model is presented in which it is proposed that, under normal conditions, ECs stabilize extracellular misfolded proteins by binding to them, and then guide them to specific receptors for uptake and subsequent degradation. In this scenario, EC receptors are a critical part of a quality control system which protects the brain against dangerously hydrophobic proteins/peptides. However, it also appears possible that in the presence of a high molar excess of misfolded protein, such as might occur during disease, the limited amounts of ECs available may actually exacebate pathology. Further advances in understanding of the mechanisms that control extracellular protein folding are likely to identify new strategies for effective disease therapies.

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“…It is interesting to note that α2-macroglobulin, the originally described ligand for CD91, is also able to channel exogenous antigens into the endogenous pathway of antigen presentation via the same receptor (Ref. 157).…”

Section: Tumour Immunitymentioning

confidence: 99%

Heat shock proteins in health and disease: therapeutic targets or therapeutic agents?

Pockley

2001

Expert Rev. Mol. Med.

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Adjuvanticity of α2-Macroglobulin, an Independent Ligand for the Heat Shock Protein Receptor CD91

Cited by 79 publications

References 16 publications

Aberrant Extracellular and Dendritic Cell (DC) Surface Expression of Heat Shock Protein (hsp)70 in the Rheumatoid Joint: Possible Mechanisms of hsp/DC-Mediated Cross-Priming

Aberrant Extracellular and Dendritic Cell (DC) Surface Expression of Heat Shock Protein (hsp)70 in the Rheumatoid Joint: Possible Mechanisms of hsp/DC-Mediated Cross-Priming

Extracellular Chaperones and Amyloids

Heat shock proteins in health and disease: therapeutic targets or therapeutic agents?

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