Soluble CD4 suppress the antigen driven proliferative response of certain T cell clones specific for mycobacteria and for peptides by mycobacterial heat shock proteins

Abstract Heat shock proteins (HSP) have been implicated in autoimmune diseases such as type I diabetes mellitus, systemic lupus erythematosus, and multiple sclerosis, in which T cell proliferative responses or autoantibodies towards endogenous HSP have been detected (Journal of Autoimmunity2003;20:313). HSP70 can function as an endogenous ‘danger’ signal, acting on antigen-presenting cells and critically influencing the decision between induction of tolerance and immunity upon antigen encounter (Millar et al. Nature Medicine2003; 9:1469). We studied T-cell proliferative responses and auto-antibodies to human HSP60, HSP70 and HSP90 proteins in 20 newly diagnosed aplastic anemia patients, peripheral blood was obtained (11 females, 9 males; age average 36.1±19 years). A non-isotopic immunoassay was used for BrdU incorporation into proliferative T cells and ELISA to measure HSP antibody titer. T cell proliferation was measured as the Eu-fluorescence in a time-resolved fluorometer. A positive result was defined as > 2 standard deviations (SD) from the mean of the controls. T-cell responses to HSP70 in the patient group (N=20; mean±SD Eu-fluorescence= 47,129±36,248) were significantly greater than those of the control group (N=18 healthy adult; mean Eu-fluorescence= 23,941±12,996; p=0.01). Fifty percent of the patients showed increased T cell proliferation after HSP70 stimulation compared to 5% in the control group (p=0.03). T-cell responses of the patient group to HSP90 and HSP60 were similar to those of the control group. Twenty percent of patients showed increased T cell proliferation to HSP 60 and HSP 90 stimulation compared to 5% in the control group (p=0.363). HSP antibody (IgG/A/M) seropositivity was 25% to HSP60, 50% to HSP70, and 5% to HSP90 in patients and 8% to HSP60, 0% to HSP70, and 0% to HSP90 in controls. Heightened autoimmunity to HSP70, but not to HSP60 and HSP90, is a feature of acquired aplastic anemia at presentation.

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T-Cell Responses to Heat Shock Proteins in Rheumatoid Arthritis

Stress Proteins in Medicine ◽

10.1201/9781003067474-8 ◽

2020 ◽

pp. 131-145

Author(s):

Harald G. Wiker ◽

Morten Harboe ◽

Jacob B. Natvig

Keyword(s):

Rheumatoid Arthritis ◽

T Cell ◽

Heat Shock ◽

Heat Shock Proteins ◽

T Cell Responses ◽

Cell Responses ◽

Shock Proteins

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Recognition of a mycobacteria-specific epitope in the 65-kD heat-shock protein by synovial fluid-derived T cell clones.

Journal of Experimental Medicine ◽

10.1084/jem.171.3.831 ◽

1990 ◽

Vol 171 (3) ◽

pp. 831-841 ◽

Cited By ~ 126

Author(s):

J S Gaston ◽

P F Life ◽

P J Jenner ◽

M J Colston ◽

P A Bacon

Keyword(s):

Amino Acids ◽

T Cell ◽

Heat Shock ◽

Synovial Fluid ◽

Heat Shock Protein ◽

Mononuclear Cells ◽

Cell Clone ◽

T Cell Clones ◽

Cell Clones ◽

T Cell Clone

Adjuvant arthritis in rats is induced by a T cell clone specific for amino acids 180-188 of the mycobacterial 65-kD heat-shock protein, and synovial T cell responses to this same Ag have been noted in human arthritis. We have isolated 65-kD Ag-specific T cell clones from synovial fluid mononuclear cells of a patient with acute arthritis, which, unlike the corresponding PBMC, showed a marked proliferative response to the 65-kD Ag. Using synthetic peptides corresponding to the whole sequence of the 65-kD Ag, all the clones were shown to recognize an epitope present in the first NH2-terminal peptide (amino acids 1-15), with no response to the adjacent peptide (amino acids 6-22) or to any other peptide. The complete dominance of this epitope in the response to the 65-kD Ag was shown by documenting responses to the peptide in PBMC obtained after recovery from the arthritis. This epitope, like that recognized by the rat arthritogenic T cell clone, is in a portion of the 65-kD sequence that is not conserved between bacteria and eukaryotes, so that in this case, joint inflammation could not be attributed to bacteria-induced T cell clones cross-reacting with the self 65-kD Ag.

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Proliferative response to conserved epitopes of the Chlamydia trachomatis and human 60-kilodalton heat-shock proteins by lymphocytes from women with salpingitis

American Journal of Obstetrics and Gynecology ◽

10.1016/0002-9378(94)90282-8 ◽

1994 ◽

Vol 171 (2) ◽

pp. 455-460 ◽

Cited By ~ 35

Author(s):

Steven S. Witkin ◽

Jan Jeremias ◽

Miklos Toth ◽

William J. Ledger

Keyword(s):

Heat Shock ◽

Chlamydia Trachomatis ◽

Heat Shock Proteins ◽

Proliferative Response ◽

Shock Proteins

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Immune Recognition of Heat Shock Proteins Provides a Molecular Basis for the “Hygiene Hypothesis” Linking High Prevalence of Immune Disorders to Lack of Cell Stress Eliciting Events

ISRN Immunology ◽

10.5402/2012/826863 ◽

2012 ◽

Vol 2012 ◽

pp. 1-13

Author(s):

W. van Eden

Keyword(s):

T Cell ◽

Heat Shock ◽

Heat Shock Proteins ◽

Molecular Basis ◽

Hygiene Hypothesis ◽

Cell Stress ◽

Host Cells ◽

Immune Recognition ◽

Shock Proteins ◽

Old Friends

A modern interpretation of the hygiene hypothesis proposes the so-called “old friends” to trigger tolerogenic responses through innate receptors of dendritic cells (DC). Tolerogenic DCs would drive regulatory T-cell polarization through induction of old-friend-specific Treg. In the tissues of the gut that are besieged by our old friends, these cells are held to produce a continuous bystander regulation. However, such local bystander regulation in the gut may be difficult to reconcile with suppression of responses to airway allergens or autoimmune antigens present in distant body tissues. Alternatively, the regulatory Tregs may be triggered through recognition of stress proteins or heat shock proteins (HSP). Microbial HSP are immunodominant and evolutionary conserved with homologs present in mammalian cells. Microbial HSP are now known to induce Tregs that cross-recognize mammalian HSP. In addition, microbial exposures, both friendly and nonfriendly, cause cell stress and, consequently, HSP upregulation in host cells. Also such upregulated HSP can activate HSP-specific Tregs that target the upregulated HSP at sites of inflammatory stress wherever in our body. Under inflammatory conditions, cell stress-associated HSP are abundant and therefore easy targets for cognate T-cell interactions. Herewith, they provide a molecular basis for the hygiene hypothesis.

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