Differential recognition of heat-shock protein dnaJ-derived epitopes by effector and Treg cells leads to modulation of inflammation in juvenile idiopathic arthritis.
OBJECTIVE
To identify epitopes on Escherichia coli heat-shock protein (HSP) dnaJ or on homologous human HSP dnaJ involved in the induction/modulation of autoimmune inflammation in patients with oligoarticular juvenile idiopathic arthritis (JIA).


METHODS
We used a proliferation assay and cytokine production to evaluate the immune responses of synovial fluid mononuclear cells (SFMCs) to pan-HLA-DR binder peptides derived from either homologous or nonhomologous regions on bacterial and human HSP dnaJ. Cytofluorometric analysis was performed in order to phenotype and sort Treg cells. Sorted cells were then analyzed for the expression of the forkhead box P3 (FoxP3) transcription factor, and their regulatory capacity was tested in coculture assays.


RESULTS
T cell responses to E coli HSP dnaJ-derived peptides were eminently proinflammatory. Conversely, peptides derived from human HSP dnaJ induced interleukin-10 (IL-10) production from SFMCs of patients with oligoarticular JIA. A positive correlation was found between disease with a better prognosis (persistent oligoarticular JIA) and recognition of 3 human HSP dnaJ-derived peptides. The recognition of the human peptide H134-148 also induced a significantly greater amount of IL-10 in patients with persistent oligoarticular JIA than in those with extended oligoarticular JIA (P = 0.0012). Incubation of SFMCs from patients with persistent oligoarticular JIA with this human epitope increased the percentage of Treg cells and FoxP3 expression. It also induced the recovery of suppressor activity by Treg cells.


CONCLUSIONS
This is the first description of a self-regulating immune modulator circuit active during autoimmune inflammation through recognition of HSP epitopes with different functional properties. These epitopes induce T cells with regulatory function. Such induction correlates with disease severity and prognosis.
Massa
Margherita
M
Fondazione IRCCS Policlinico San Matteo, Pavia, Italy.
Passalia
Maristella
M
Manzoni
Silvia Magni
SM
Campanelli
Rita
R
Ciardelli
Laura
L
Yung
Gisella Puga
GP
Kamphuis
Sylvia
S
Pistorio
Angela
A
Meli
Valentina
V
Sette
Alessandro
A
Prakken
Berent
B
Martini
Alberto
A
Albani
Salvatore
S
D000293:Adolescent; D000328:Adult; D000595:Amino Acid Sequence; D001171:Arthritis, Juvenile / Q000276:immunology* / Q000473:pathology; D016022:Case-Control Studies; D002478:Cells, Cultured; D002648:Child; D002675:Child, Preschool; D000939:Epitopes / Q000276:immunology*; D029968:Escherichia coli Proteins / Q000032:analysis / Q000276:immunology; D051858:Forkhead Transcription Factors / Q000378:metabolism; D050956:HSP40 Heat-Shock Proteins / Q000032:analysis / Q000276:immunology*; D006801:Humans; D007249:Inflammation / Q000276:immunology* / Q000473:pathology; D016753:Interleukin-10 / Q000378:metabolism; D018832:Molecular Chaperones / Q000032:analysis / Q000276:immunology*; D008969:Molecular Sequence Data; D011379:Prognosis; D012720:Severity of Illness Index; D013582:Synovial Fluid / Q000166:cytology / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000473:pathology
C107481:DNAJA1 protein, human; C494647:DNAJB1 protein, human; C121958:DNAJB2 protein, human; D000939:Epitopes; D029968:Escherichia coli Proteins; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D050956:HSP40 Heat-Shock Proteins; D018832:Molecular Chaperones; D016753:Interleukin-10