Serum anti–T cell receptor (TCR) Ab’s are involved in immune regulation directed against pathogenic T cells in experimental models of autoimmune diseases. Our identification of a dominant T cell population expressing the Vβ5.1 TCR gene (TCRBV5-1), which is responsible for the production of pathogenic anti-acetylcholine receptor (AChR) autoantibodies in HLA-DR3 patients with early-onset myasthenia gravis (EOMG), prompted us to explore the occurrence, reactivity, and regulatory role of anti-TCR Ab’s in EOMG patients and disease controls with clearly defined other autoantibodies. In the absence of prior vaccination against the TCR, EOMG patients had elevated anti-Vβ5.1 Ab’s of the IgG class. This increase was restricted largely to EOMG cases with HLA-DR3 and with less severe disease, and it predicted clinical improvement in follow-up studies. EOMG patient sera containing anti-TCR Ab’s bound specifically the native TCR on intact Vβ5.1-expressing cells and specifically inhibited the proliferation and IFN-γ production of purified Vβ5.1-expressing cells to alloantigens in mixed lymphocyte reaction and the proliferation of a Vβ5.1-expressing T cell clone to an AChR peptide, indicating a regulatory function for these Ab’s. This evidence of spontaneously active anti-Vβ5.1 Ab’s in EOMG patients suggests dynamic protective immune regulation directed against the excess of pathogenic Vβ5.1-expressing T cells. Though not sufficient to prevent a chronic, exacerbated autoimmune process, it might be boosted using a TCR peptide as vaccine.
Florence Jambou, Wei Zhang, Monique Menestrier, Isabelle Klingel-Schmitt, Olivier Michel, Sophie Caillat-Zucman, Abderrahim Aissaoui, Ludovic Landemarre, Sonia Berrih-Aknin, Sylvia Cohen-Kaminsky
Submitter: J. Edwin Blalock | Blalock@uab.edu
Univ of Alabama at Birmingham
Published August 11, 2003
The recent publication by Jambou et al. reports the very interesting finding that early onset myasthenia gravis (EOMG) patients (particularly HLA-DR3) contain regulatory autoantibodies against a dominant T cell population that is involved in the production of pathogenic antibodies (Ab) to the acetylcholine receptor (AChR). The regulatory autoAb actually recognize the VB5.1 TCR gene product on the T cell population and higher levels of such autoAb was associated with less severe disease and predicted clinical improvement (1).
These findings would seem to bode well for the eventual clinical testing of an experimental technique that is effective in the rodent model experimental autoimmune (EA) MG (2), and that was overlooked by Jambou et al. Specifically, we have described an algorithm for the design of antigen receptor mimetic (ARM) peptides which when used as vaccines cause the production of anti-clonotypic T cell receptor Ab that specifically recognize autoreactive T cells (3). One advantage in terms of specificity in the ARM approach as opposed to the TCR peptide vaccination suggested by Jambou et al. is that the later usually targets CDR2 while the former targets CDR3 (2,4). In the Lewis rat model of MG, the dominant T cell response is against AChR alpha-100-116 and is mediated via VB15+ TCR. Ab to ARM in this system recognize VB15 on autoreactive T cells, inhibits such T cell proliferation, and alters cytokine profiles (i.e., inhibits IFN-gamma and increases IL-10). As a consequence, ARM vaccination or Ab to ARM peptides prevents and reverses EAMG by lowering pathogenic AChR Ab levels and preserving AChR levels at the neuromuscular junction (2,5).
A particularly interesting parallel between our animal model results and the clinical findings of Jambou et al. is that in both systems an Ab response to only a subpopulation of autoreactive T cells can markedly impair a polyclonal autoAb response to the AChR. Thus it seems likely that a regulatory T cell response may be involved. Whether or not this is the case, the collective results suggest that polyclonality and epitope spreading may not be as intractable a problem for treatment of autoimmune diseases as first suspected. The results certainly suggest that TCR peptide and ARM peptide vaccines for MG should be evaluated in humans. In a broader sense, the ARM approach may be useful in other autoimmune diseases since it has been shown to ameliorate models of multiple sclerosis (6-8) and Guillain Barre syndrome (4) as well as facilitate the diagnosis of systemic lupus erythematosus and Sjogren's syndrome (9).
Conflict of interest: The author is a paid consultant for CuraVac, Inc.
References
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