Self epitopes shared between human skeletal myosin and Streptococcus pyogenes M5 protein are targets of immune responses in active juvenile dermatomyositis.
OBJECTIVE
To identify self T cell epitopes associated with proinflammatory immune responses and clinically active juvenile dermatomyositis (juvenile DM). The target of our search for relevant epitopes was represented by amino acid sequences shared between human skeletal myosin and Streptococcus pyogenes M5 protein. The long-term objective of the project is to identify suitable targets for immunotherapy of the disease.


METHODS
We used computerized algorithms to identify putative agretopes on both the human myosin and Streptococcus M5 proteins. Direct binding assays for homolog peptides were used to confirm such predictions. Antigenicity and functional cross-reactivity were evaluated by cytotoxicity assays and by measurement of cytokine levels. Specific T cells were isolated by T cell capture, and T cell receptor (TCR) V(beta) gene usage was identified by reverse transcriptase-polymerase chain reaction.


RESULTS
We identified peptides that are targets of disease-specific cytotoxic T cell responses. T cell reactivity against the self peptides correlates with clinical signs of early, active myositis. Such reactivity is accompanied by production of proinflammatory cytokines, which may contribute to the damage. T cell cross-recognition of bacterial and human homologs was shown functionally as well as by sorting peptide-specific T cells and identifying oligoclonal and largely overlapping TCR V(beta) gene usage.


CONCLUSIONS
These findings represent the first identification of a self epitope in juvenile DM, providing a potential candidate for antigen-specific immune therapy.
Massa
Margherita
M
IRCCS Policlinico San Matteo, Pavia, Italy.
Costouros
Nick
N
Mazzoli
Federica
F
De Benedetti
Fabrizio
F
La Cava
Antonio
A
Le
Tho
T
De Kleer
Isme
I
Ravelli
Angelo
A
Liotta
Margaret
M
Roord
Sarah
S
Berry
Charles
C
Pachman
Lauren M
LM
Martini
Alberto
A
Albani
Salvatore
S
D001426:Bacterial Proteins / Q000276:immunology*; D002648:Child; D003429:Cross Reactions; D003882:Dermatomyositis / Q000276:immunology* / Q000628:therapy; D000939:Epitopes / Q000276:immunology*; D006801:Humans; D007167:Immunotherapy / Q000379:methods; D009218:Myosins / Q000276:immunology*; D013297:Streptococcus pyogenes / Q000276:immunology*; D013602:T-Lymphocytes, Cytotoxic
D001426:Bacterial Proteins; D000939:Epitopes; D009218:Myosins