ArticlesTolerogenic immune responses to novel T-cell epitopes from heat-shock protein 60 in juvenile idiopathic arthritis
Introduction
Much attention has focused on the role of T-regulatory cells in the control of inflammation and autoimmunity.1 The antigens that lead to the activation of these cells are not known. Cohen and Young2 postulated that heat-shock proteins (HSP) could be part of the immunological homunculus, which includes a few dominant self antigens encoded in a cellular regulatory network that comprises the immune system's picture of self. As such, HSP are candidate antigens to trigger the activation of T regulatory cells.3, 4, 5, 6 Indeed a regulatory role has been ascribed to HSP in several autoimmune and inflammatory diseases,6, 7, 8, 9, 10, 11 and immunotherapy with peptides derived from HSP has induced a favourable antigen-specific immune deviation in patients with type I diabetes and rheumatoid arthritis.12, 13, 14
Juvenile idiopathic arthritis is a heterogeneous autoimmune disease characterised by chronic inflammation of one or more joints.15 Different subtypes of the disease exist; the persistent oligoarticular subtype in general has a benign clinical course, whereas the polyarticular subtypes are non-remitting in many cases and need aggressive immunosuppressive treatment. Notably, only in the oligoarticular subtype does the presence of T-cell responses to self HSP60 predict disease remission.16, 17 The induced T cells have a regulatory phenotype and as such might contribute to disease remission.10
Antigen-specific immunotherapy with HSP60 epitopes could represent a novel treatment option for specific modulation of the immune system in patients with juvenile idiopathic arthritis, instead of aspecific suppression of the immune system as with standard treatments. However, the HSP60 epitopes recognised by T cells of patients with juvenile idiopathic arthritis are not known, mainly because the polymorphic nature of MHC molecules in patients with the disease necessitates identification of epitopes that have the potential to bind a diverse range of MHC molecules. Computer algorithms that predict potential pan-DR epitopes are now available.18, 19 These algorithms have been successfully used for the identification of specific epitopes in infectious-disease and cancer settings, but their use to identify pan-DR epitopes applicable to autoimmune diseases has not been addressed.20
We used a computer algorithm for the identification of potential pan-DR HSP60 epitopes to find potential targets for HSP60 immunotherapy in juvenile idiopathic arthritis and to assess whether immune responses to these epitopes contribute to the distinct clinical outcome in this disease.
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Participants
We took blood from 57 patients with juvenile idiopathic arthritis who met the diagnostic criteria of oligoarticular or polyarticular (including extended oligoarticular) onset subtypes of the disease.21 Table 1 shows the patients' characteristics. Disease duration at the time of sampling was defined as the time since the first disease-related symptom (arthritis). The presence of joint swelling or limitation of movement with either pain on movement or tenderness defined active disease. The
Results
We detected positive T-cell responses (T-cell proliferation or cytokine production) for all eight HSP60 peptides in most PBMC from patients with juvenile idiopathic arthritis. T-cell proliferative responses in PBMC from patients with juvenile idiopathic arthritis differed significantly from those induced in PBMC from healthy controls for the peptides p1–p5 (p1, p<0·0001; p2, p=0·005; p3, p=0·002; p4, p=0·017; p5, p<0·0001; figure 1). We were surprised that PBMC from most children with type 1
Discussion
We identified many HSP60 epitopes originating from human and microbial HSP60 and recorded T-cell recognition of these HSP60 epitopes in PBMC from patients with juvenile idiopathic arthritis irrespective of MHC genotype. Previous studies have suggested HSP60 as a candidate for antigen-specific immunotherapy in various human autoimmune diseases, including juvenile idiopathic arthritis.3, 5, 24 These studies did not identify candidate epitopes of HSP60 that could be recognised in most patients,
Glossary
- T-regulatory cells
- T lymphocytes that suppress activity of other T cells. This process can be either beneficial (eg, prevention of T–cell activation that could cause disease), or deleterious (eg, suppression of T cells that kill cancer cells). Several different regulatory T cell types have been described, including those positive for CD4 and CD25, and interleukin-10-producing T cells. Treg cells play an important part in control of inflammation and autoimmunity.
- Heat-shock proteins (HSP)
- Highly
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