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Differential recognition of heat-shock protein dnaJ–derived epitopes by effector and Treg cells leads to modulation of inflammation in juvenile idiopathic arthritis

  1. Margherita Massa1,
  2. Maristella Passalia1,
  3. Silvia Magni Manzoni2,
  4. Rita Campanelli1,
  5. Laura Ciardelli2,
  6. Gisella Puga Yung3,
  7. Sylvia Kamphuis4,
  8. Angela Pistorio5,
  9. Valentina Meli6,
  10. Alessandro Sette7,
  11. Berent Prakken4,†,
  12. Alberto Martini8,
  13. Salvatore Albani9,†,*

Article first published online: 27 APR 2007

DOI: 10.1002/art.22567

Issue

Arthritis & Rheumatism

Arthritis & Rheumatism

Volume 56, Issue 5, pages 1648–1657, May 2007

Additional Information

How to Cite

Massa, M., Passalia, M., Manzoni, S. M., Campanelli, R., Ciardelli, L., Yung, G. P., Kamphuis, S., Pistorio, A., Meli, V., Sette, A., Prakken, B., Martini, A. and Albani, S. (2007), Differential recognition of heat-shock protein dnaJ–derived epitopes by effector and Treg cells leads to modulation of inflammation in juvenile idiopathic arthritis. Arthritis & Rheumatism, 56: 1648–1657. doi: 10.1002/art.22567

Author Information

  1. 1

    Fondazione IRCCS Policlinico San Matteo, Pavia, Italy, and EUREKA Institute for Translational Medicine, Siracusa, Italy

  2. 2

    Fondazione IRCCS Policlinico San Matteo, Pavia, Italy

  3. 3

    University of California, San Diego, La Jolla, California, and EUREKA Institute for Translational Medicine, Siracusa, Italy

  4. 4

    University Medical Center Utrecht, Utrecht, The Netherlands, and EUREKA Institute for Translational Medicine, Siracusa, Italy

  5. 5

    IRCCS G. Gaslini, Genoa, Italy

  6. 6

    Androclus Therapeutics, Milan, Italy, and EUREKA Institute for Translational Medicine, Siracusa, Italy

  7. 7

    La Jolla Institute for Allergy and Immunology, La Jolla, California

  8. 8

    IRCCS G. Gaslini, University of Genoa, Genoa, Italy, and EUREKA Institute for Translational Medicine, Siracusa, Italy

  9. 9

    University of California, San Diego, La Jolla, California, Androclus Therapeutics, Milan, Italy, and EUREKA Institute for Translational Medicine, Siracusa, Italy

  1. †

    Drs. Prakken and Albani are coinventors of concepts and sequences, patents for which are owned by University of California, San Diego.

*University of California at San Diego, Departments of Medicine and Pediatrics, 9500 Gilman Drive, La Jolla, CA 92093-0731

Publication History

  1. Issue published online: 27 APR 2007
  2. Article first published online: 27 APR 2007
  3. Manuscript Accepted: 24 JAN 2007
  4. Manuscript Received: 20 DEC 2005

Funded by

  • “Ricerca Corrente” grants from the IRCCS Policlinico San Matteo, Pavia, Italy

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Abstract

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.

Conclusion

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.

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