Strain differences in the autoimmune response of mice to acetylcholine receptors

Fuchs, Sara; Nevo, Daniela; Tarrab‐Hazdai, Rebeca; Yaar, Israel

doi:10.1038/263329a0

Cited by 122 publications

(40 citation statements)

References 15 publications

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“…Our studies are compatible with the results of Fulpius et al (29) in that BALB/c mice appear to be a low EMG-susceptibility strain and exhibit a high serum concentration of anti-AChR antibodies. Our studies are consistent with those of Fuchs et al (30) to the extent that susceptibility to EMG is strain dependent, but differ in that mice possessing the H-2 q and H-2 s haplotypes were not found to be resistant to the induction of EMG. On the contrary, SJL mice which possess the H-2 s haplotype appear to be a high-susceptibility strain.…”

Section: Discussionsupporting

confidence: 91%

Experimental myasthenia gravis. A murine system.

Berman¹,

Patrick²

1980

The Journal of Experimental Medicine

139

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Mice from eight inbred strains were immunized with acetylcholine receptor (AChR) purified from Torpedo californica. All mice developed high concentrations of serum antibodies (10(-6) M) against the immunogen and approximately 80% possessed antibodies reactive with mouse nicotinic AChR. 33% of the mice immunized (n = 236) developed muscular weakness and flaccid paralysis. Behavioral, electrophysiological, and pharmacological similarities were found between the experimentally induced muscular weakness and the disease myasthenia gravis. Susceptibility to experimental myasthenia was found to be strain dependent in that the frequency of paralysis was much greater in some strains than others. The occurrence of muscular weakness and flaccid paralysis did not correlate with the concentration of antibodies reactive with T. californica or mouse AChR. Anti-receptor antibodies which increased the rate of AChR degradation on the mouse muscle cell line, BC3H-1, were found in the serum of both myasthenic and nonmyasthenic mice. 40% of the mice tested possessed antibodies reactive with antigenic determinants present on mouse receptor but not T. californica receptor. The occurrence of antibodies unique to mouse receptor did not correlate with myasthenia. Thus, myasthenia in the mouse does not occur simply as a consequence of the presence of antibodies directed against cell surface antigenic determinants of AChR. If anti-AChR antibodies are both necessary and sufficient for the induction of myasthenia, then these studies suggest that populations of a particular structure and/or specificity are required. It is anticipated that the mouse model of myasthenia gravis will permit the regulation of the anti-receptor immune response to be studied in detail.

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Section: Discussionsupporting

confidence: 91%

Experimental myasthenia gravis. A murine system.

Berman¹,

Patrick²

1980

The Journal of Experimental Medicine

139

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“…The WT mice are relatively resistant to EMG: after multiple TAChR immunizations, only 7-40% of WT mice develop EMG (22,23). They express the H-2 d haplotype, which correlates with resistance to EMG (23,24,29).…”

Section: Discussionmentioning

confidence: 99%

“…They express the H-2 d haplotype, which correlates with resistance to EMG (23,24,29). The epitope repertoire of their anti-TAChR CD4 ϩ T cells does not overlap with that of anti-TAChR CD4 ϩ T cells of H-2 b strains (like C57BL/6 mice), which usually are susceptible to EMG (1,22,23). The EMG resistance of BALB/c mice has been attributed to the constraints imposed by their H-2 class II molecules on the recognition of TAChR epitopes by the CD4 ϩ cells (29,30).…”

Section: Discussionmentioning

confidence: 99%

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The Susceptibility to Experimental Myasthenia Gravis of STAT6−/− and STAT4−/− BALB/c Mice Suggests a Pathogenic Role of Th1 Cells

Wang

Ostlie

Conti‐Fine

et al. 2004

The Journal of Immunology

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Autoantibodies to the muscle acetylcholine receptor (AChR) cause the symptoms of human and experimental myasthenia gravis (EMG). AChR-specific CD4+ T cells permit development of these diseases, but the role(s) of the Th1 and Th2 subsets is unclear. The STAT4 and STAT6 proteins, which mediate intracellular cytokine signaling, are important for differentiation of Th1 and Th2 cells, respectively. Wild-type (WT) BALB/c mice, which are prone to develop Th2 rather than Th1 responses to Ag, are resistant to EMG. We have examined the role of Th1 and Th2 cells in EMG using STAT4 (STAT4−/−)- or STAT6 (STAT6−/−)-deficient BALB/c mice. After AChR immunization, STAT6−/− mice were susceptible to EMG: they developed more serum anti-AChR Ab, and had more complement-fixing anti-AChR IgG2a and 2b and less IgG1 than WT or STAT4−/− mice. The susceptibility to EMG of STAT6−/− mice is most likely related to the Th1 cell-induced synthesis of anti-AChR Ab, which trigger complement-mediated destruction of the neuromuscular junction. CD4+ T cells of the STAT6−/− mice had proliferative responses to the AChR comparable to those of WT and STAT4−/− mice, and recognized similar AChR epitopes. STAT6−/− mice had abundant AChR-specific Th1 cells, which were nearly absent in WT and STAT4−/− mice. Spleen and lymph nodes from STAT6−/− mice contained cells that secreted IL-4 when cultured with AChR: these are most likely STAT6-independent cells, stimulated in a non-Ag-specific manner by the cytokines secreted by AChR-specific Th1 cells.

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“…The abnormality in MG is a deficiency of acetylcholine receptors at neuromuscular junctions caused by the antibody-mediated autoimmune attack (1)(2)(3)(4). The current treatment of MG is nonspecific, and, although immunosuppressive drugs are usually beneficial in MG, they result in generalized suppression of the immune system.…”

mentioning

confidence: 99%

Altered peptide ligands act as partial agonists by inhibiting phospholipase C activity induced by myasthenogenic T cell epitopes

Faber-Elmann

Paas-Rozner

Sela

et al. 1998

Proc. Natl. Acad. Sci. U.S.A.

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Myasthenia gravis (MG) is a T cellregulated, antibody-mediated autoimmune disease. Two peptides representing sequences of the human acetylcholine receptor ␣-subunit, p195-212 and p259-271, previously were shown to stimulate the proliferation of peripheral blood lymphocytes of patients with MG and were found to be immunodominant T cell epitopes in SJL and BALB͞c mice, respectively. Single amino acid-substituted analogs of p195-212 and p259-271, as well as a dual analog composed of the tandemly arranged two single analogs, were shown to inhibit, in vitro and in vivo, MG-associated autoimmune responses. Stimulation of T cells through the antigen-specific T cell receptor activates tyrosine kinases and phospholipase C (PLC). Therefore, in attempts to understand the mechanism of action of the analogs, we first examined whether the myasthenogenic peptides trigger tyrosine phosphorylation and activation of phospholipase C. For that purpose, we measured generation of inositol phosphates and tyrosine phosphorylation of PLC after stimulation of the p195-212-and p259-271-specific T cell lines with these myasthenogenic peptides. Both myasthenogenic peptides stimulated generation of inositol phosphates as well as tyrosine phosphorylation of PLC. However, the single and dual analogs, although inducing tyrosine phosphorylation of PLC, could not induce PLC activity. Furthermore, the single and dual analogs inhibited the induced PLC activity whereas they could not inhibit tyrosine phosphorylation of PLC that was caused by the myasthenogenic peptides. Thus, the altered peptides and the dual analog act as partial agonists. The down-regulation of PLC activity by the analogs may account for their capacity to inhibit in vitro MG-associated T cell responses.Myasthenia gravis (MG) is a T cell-regulated, antibodymediated autoimmune disease. The abnormality in MG is a deficiency of acetylcholine receptors at neuromuscular junctions caused by the antibody-mediated autoimmune attack (1-4). The current treatment of MG is nonspecific, and, although immunosuppressive drugs are usually beneficial in MG, they result in generalized suppression of the immune system. Ideally, treatment should inhibit specifically the immune response to acetylcholine receptors. Previous work in our laboratory has shown that two peptides representing sequences of the human acetylcholine receptor ␣-subunit, p195-212 and p259-271, were able to stimulate peripheral blood lymphocytes of patients with MG and to serve as immunodominant T cell epitopes of SJL and BALB͞c mice, respectively (5, 6). Altered myasthenogenic peptides, which are single amino acid-substituted analogs of p195-212 (Ala-207) and p259-271 (Lys-262), as well as a dual analog composed of the tandemly arranged two single analogs (Lys-262-Ala-207), were synthesized and were shown to inhibit the proliferative responses of both p195-212-and p259-271-specific T cell lines in vitro as well as the in vivo priming to the myasthenogenic peptides (7-9). Furthermore, the dual analog could reverse myasthenog...

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Strain differences in the autoimmune response of mice to acetylcholine receptors

Cited by 122 publications

References 15 publications

Experimental myasthenia gravis. A murine system.

Experimental myasthenia gravis. A murine system.

The Susceptibility to Experimental Myasthenia Gravis of STAT6−/− and STAT4−/− BALB/c Mice Suggests a Pathogenic Role of Th1 Cells

Altered peptide ligands act as partial agonists by inhibiting phospholipase C activity induced by myasthenogenic T cell epitopes

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