Tolerogenic immune responses to novel T-cell epitopes from heat-shock protein 60 in juvenile idiopathic arthritis.
BACKGROUND
Juvenile idiopathic arthritis is a heterogeneous autoimmune disease characterised by chronic inflammation of one or more joints. In patients with this disease, T-cell reactivity to autologous heat-shock protein 60 (HSP60) is associated with a favourable prognosis. We sought to identify HSP60 T-cell epitopes to find potential targets for HSP60 immunotherapy and to assess whether immune responses to these epitopes contribute to the distinct clinical outcome of this disease.


METHODS
We identified eight potential epitopes using a computer algorithm from both self and microbial HSP60 binding to many HLA-DR molecules. We analysed the pattern of T-cell responses induced by these HSP60 peptides in peripheral-blood mononuclear cells (PBMC) of 57 patients with juvenile idiopathic arthritis, 27 healthy controls, and 20 disease controls. We undertook in-vitro MHC binding studies with the identified peptides, and HLA class II typing of a subset of patients with juvenile idiopathic arthritis.


RESULTS
Five of the eight peptides identified yielded proliferative T-cell responses in 50-70% of PBMC from patients with juvenile idiopathic arthritis irrespective of MHC genotype, but not in PBMC from healthy or disease controls. Although PBMC from both patients with juvenile idiopathic arthritis and healthy controls produced interferon gamma in response to these peptides, only PBMC from patients with the disease produced interleukin 10.


CONCLUSIONS
The recorded T-cell-induction in juvenile idiopathic arthritis is tolerogenic. In patients with oligoarticular disease, the immune responses to the HSP60 epitopes identified could contribute to disease remission.


CONCLUSIONS
The broad recognition of these HSP60 epitopes in a population of patients with polymorphic MHC genotypes opens the way for HSP60-peptide immunotherapy, representing a novel treatment option to specifically modulate the immune system in patients with juvenile idiopathic arthritis.
Department of Paediatric Immunology, IACOPO Institute for Translational Medicine, University Medical Centre Utrecht, Utrecht, The Netherlands.
Sylvia
S
Kamphuis
Wietse
W
Kuis
Wilco
W
de Jager
Gijs
G
Teklenburg
Margherita
M
Massa
Grace
G
Gordon
Marjolein
M
Boerhof
Ger T
GT
Rijkers
Cuno S
CS
Uiterwaal
Henny G
HG
Otten
Alessandro
A
Sette
Salvatore
S
Albani
Berent J
BJ
Prakken
D000293:Adolescent; D001171:Arthritis, Juvenile / Q000235:genetics / Q000276:immunology* / Q000628:therapy; D018834:Chaperonin 60 / Q000276:immunology*; D002648:Child; D002675:Child, Preschool; D016207:Cytokines / Q000378:metabolism; D018984:Epitopes, T-Lymphocyte / Q000276:immunology*; D005260:Female; D006801:Humans; D007108:Immune Tolerance; D016233:Immunotherapy, Active; D008213:Lymphocyte Activation; D008285:Major Histocompatibility Complex; D008297:Male; D011379:Prognosis; D013601:T-Lymphocytes / Q000276:immunology
D018834:Chaperonin 60; D016207:Cytokines; D018984:Epitopes, T-Lymphocyte