Myasthenia Gravis

Myasthenia gravis is a T cell-dependent, antibody-mediated autoimmune disease. A dual altered peptide ligand (APL) that is composed of the tandemly arranged two single amino acid analogs of two myasthenogenic peptides, p195–212 and p259–271, was demonstrated to down-regulate in vitro and in vivo myasthenia gravis-associated autoreactive responses. The aims of this study were to demonstrate the suppressive properties and to elucidate the mechanism of action of the dual APL on a T cell line specific to the myasthenogenic peptide p195–212. We demonstrate here that incubation of cells of the line with the dual APL resulted in the inhibition of proliferation and secretion of IL-2 and IFN-γ triggered by p195–212. In contrast, secretion of TGF-β and IL-10 was upregulated. The dual APL induced the generation of CD4+CD25+ cells that were characterized by the expression of CD45Rblow, cytotoxic T lymphocyte-associated antigen-4, TGF-β, CD62L, Foxp3, and neuropilin. In addition, the dual APL-treated cells were capable of inhibiting the proliferation response of the line when the two sets of cells were cocultured. The role of CD4+CD25+ cells was further confirmed by demonstrating that the suppression was abrogated by blocking/neutralization of CD25. Thus, the dual APL acts by inducing the formation of CD4+CD25+ regulatory cells. By using a T cell line, we could show that the immunosuppressive CD4+CD25+ cells were indeed induced by the dual APL and are not part of the naturally occurring regulatory cells

“…MG and experimental autoimmune MG (EAMG) are characterized by weakness and fatigability of voluntary muscles (1,2). The ␣-subunit of the AChR is predominant for T cell epitopes (3).…”

mentioning

confidence: 99%

Suppression of myasthenogenic responses of a T cell line by a dual altered peptide ligand by induction of CD4⁺CD25⁺regulatory cells

Aruna

Sela

Mozes

2005

“…Weakness and fatigability of voluntary muscles characterize both MG and experimental autoimmune MG (EAMG) (34). Although the symptoms of MG are caused by autoantibodies produced by B cells, there is ample evidence that T cells have a key role in the etiopathology of the disease in humans and animals (34)(35)(36)(37). Because the ␣-subunit of the AChR was shown to be predominant for T cell epitopes (36), we have used peptides representing different sequences of the human AChR ␣-subunit.…”

Section: Ms Preclinical Studiesmentioning

confidence: 99%

Therapeutic vaccines in autoimmunity

Sela

Mozes

2004

Similarly to prophylactic vaccines whose purpose is to prevent infectious diseases, therapeutic vaccines against autoimmune diseases are based on their similarity to the putative causes of the disease. We shall describe here two such examples: a copolymer of amino acids related to myelin basic protein, in the case of multiple sclerosis, and a peptide derived from the nicotinic acetylcholine receptor (

“…Weakness and fatigability of voluntary muscles characterize the disease (1,2). Two peptides representing sequences of the human AChR ␣-subunit, namely p195-212 and p259-271, were able to stimulate peripheral blood lymphocytes of patients with MG and were shown to be immunodominant T cell epitopes of SJL and BALB/c mice, respectively (3,4).…”

mentioning

confidence: 99%

A 50-kDa ERK-like protein is up-regulated by a dual altered peptide ligand that suppresses myasthenia gravis-associated responses

Ben-David¹,

Aruna²,

Seger

et al. 2006

Myasthenia gravis (MG) and its animal model, experimental autoimmune MG (EAMG), are T cell-dependent antibody-mediated autoimmune diseases. A dual altered peptide ligand (APL) that is composed of the tandemly arranged two single amino acid analogues of two myasthenogenic peptides, p195-212 and p259 -271, down-regulated in vitro and in vivo MG-associated autoreactive responses. The dual APL was shown to exert its beneficial effects by up-regulating ERK1,2 in CD4 ؉ CD25 ؉ regulatory cells. In this study, we investigated a novel 50-kDa ERK-like protein (ERK-50) that is up-regulated significantly in addition to ERK1,2 after treatment with the dual APL. We report here that ERK-50 was upregulated in LN cells and in LN-derived T cells of mice that were immunized with the myasthenogenic peptides and treated with the dual APL. Moreover, ERK-50 was up-regulated in dual-APLtreated mice that were immunized with the Torpedo acetylcholine receptor. ERK-50 was demonstrated to be recognized by antibodies directed against the C and N termini of ERK1, against the C terminus of ERK2, and against general ERK. The 50-kDa ERK was shown to be stimulated by Con A, and inhibition of MEK1 down-regulated the 50-kDa ERK as was shown for ERK1,2. However, 4␤-phorbol 12-myristate 13-acetate (TPA) did not stimulate ERK-50. Finally, the activated ERK-50 was up-regulated in the dual-APL-induced CD4 ؉ CD25 ؉ regulatory cells. Thus, ERK-50 is suggested to be a novel ERK isoform, being up-regulated in response to treatment with the dual APL.autoimmunity ͉ immunomodulation ͉ kinase