Profile of the continuous antigenic regions on the extracellular part of the alpha chain of an acetylcholine receptor.

Mulac‐Jeričević, Biserka; Kurisaki, Jun‐ichi; Atassi, M. Zouhair

doi:10.1073/pnas.84.11.3633

Cited by 42 publications

(9 citation statements)

References 51 publications

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“…Different sequence segments were recognized by different strains, and two of them (residues 152-167 and 172-205) overlapped epitope sequences identified here. Other studies investigated the response of lymphocytes from different mouse strains, immunized with TAChR, to synthetic peptides corresponding to the proposed extracellular domain of TAChR a subunit (residues 1-210) [26,44]. C57BL/6 mice, the only strain tested in both our and those studies, in agreement with our results, recognized peptides a 148-160 and a 184-196 [26].…”

Section: Cross-reactivity With Syngeneic Achr Sequencessupporting

confidence: 93%

Experimental myasthenia gravis in congenic mice. Sequence mapping and H‐2 restriction of T helper epitopes on the α subunits of Torpedo californica and murine acetylcholine receptors

et al. 1991

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Immunization of mice with nicotinic acetylcholine receptor from Torpedo electric organ (TAChR) causes a disease similar to human myasthenia gravis (experimental autoimmune myasthenia gravis, EAMG). Susceptibility to EAMG correlates with the H-2 haplotype. In this study we used overlapping synthetic peptide corresponding to the complete sequences of the alpha subunits from TAChR and murine muscle AChR (MAChR) to map T helper epitopes in congenic murine strains of different H-2 haplotype. C57BL/6 and BALB/B mice (highly susceptible to EAMG) and BALB/c and CB17 mice (less susceptible to EAMG), immunized with TAChR, developed similar anti-TAChR antibody titers and L3T4+ (T helper) cell sensitization. Different sequence segments of the TAChR alpha subunit were recognized by L3T4+ cells from strains of H-2b and H-2d haplotype. The sequence segments recognized by the H-2d strains have the highest predicted propensity to form amphipatic alpha helices, while those recognized by the H-2b strains do not. We investigated whether in EAMG T helper cells cross-react with autologous AChR sequences, and a true break of the tolerance occurs. Overlapping synthetic peptides, corresponding to the complete sequence of MAChR alpha subunit, were used to test L3T4+ cell from mice immunized with TAChR. L3T4+ cell strains did not cross-react with any murine peptide sequence, while L3T4+ cells from H-2d mice were strongly stimulated by the peptide sequence Ma alpha 304-322, which is very similar to the homologous Torpedo peptide.

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Section: Cross-reactivity With Syngeneic Achr Sequencessupporting

confidence: 93%

Experimental myasthenia gravis in congenic mice. Sequence mapping and H‐2 restriction of T helper epitopes on the α subunits of Torpedo californica and murine acetylcholine receptors

et al. 1991

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“…Epitope mapping of antibodies in the sera of animals immunized witb ACbR revealed the presence of several immu-nogenic epitopes (73,223). However, as previously mentioned, the immune response to the intact AChR results mainly in the production of antibodies to discontinuous epitopes.…”

Section: In Immunized Animalsmentioning

confidence: 76%

Anatomy of the antigenic structure of a large memberane autoantigen, the muscle‐type nicotinic acetylcholine receptor

Tzartos

Barkas²,

Cung

et al. 1998

Immunological Reviews

198

171

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The neuromuscular junction nicotinic acetylcholine receptor (AChR), a pentameric membrane glycoprotein, is the autoantigen involved in the autoimmune disease myasthenia gravis (MG). In animals immunized with intact AChR and in human MG, the anti-AChR antibody response is polyclonal. However, a small extracellular region of the AChR alpha-subunit, the main immunogenic region (MIR), seems to be a major target for anti-AChR antibodies. A major loop containing overlapping epitopes for several anti-MIR monoclonal antibodies (mAbs) lies within residues alpha 67-76 at the extreme synaptic end of each alpha-subunit: however, anti-MIR mAbs are functionally and structurally quite heterogeneous. Anti-MIR mAbs do not affect channel gating, but are very effective in the passive transfer of MG to animals; in contrast, their Fab or Fv fragments protect the AChR from the pathogenic effects of the intact antibodies. Antibodies against the cytoplasmic region of the AChR can be elicited by immunization with denatured AChR and the precise epitopes of many such mAbs have been identified; however, it is unlikely that such antibodies are present in significant amounts in human MG. Antibodies to other extracellular epitopes on all AChR subunits are present in both experimental and human MG; these include antibodies to the acetylcholine-binding site which affect AChR function in various ways and also induce acute experimental MG. Finally, anti-AChR antibodies cross-reactive with non-AChR antigens exist, suggesting that MG may result from molecular mimicry. Despite extensive studies, many gaps remain in our understanding of the antigenic structure of the AChR; especially in relation to human MG. A thorough understanding of the antigenic structure of the AChR is required for an in-depth understanding, and for possible specific immunotherapy, of MG.

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“…Because of the critical role of the MIR in the pathogenesis of myasthenia gravis, its localization on the AChR molecule and the elucidation of its structure are goals of an intense investigation. AChR peptides (proteolytic, biosynthetic, or synthetic) have been used for this purpose (Ratnam et al, 1 9 8 6~; Barkas et al, 1987Barkas et al, , 1988Mulac-Jericevic et al, 1987;Ralston et al, 1987;Tzartos et al, 1988~). Binding of polyclond anti-AChR antisera to synthetic peptides did not succeed in localizing the MIR (Mulac-Jericevic et al, 1987;Ralston et al, 1987).…”

mentioning

confidence: 99%

“…AChR peptides (proteolytic, biosynthetic, or synthetic) have been used for this purpose (Ratnam et al, 1 9 8 6~; Barkas et al, 1987Barkas et al, , 1988Mulac-Jericevic et al, 1987;Ralston et al, 1987;Tzartos et al, 1988~). Binding of polyclond anti-AChR antisera to synthetic peptides did not succeed in localizing the MIR (Mulac-Jericevic et al, 1987;Ralston et al, 1987). The use of mAbs and proteolytic or biosynthetic peptides has recently restricted MIR localization to residues 46-120 of the Torpedo (Ratnam et al, 1986a), 6-85 and 37-85 of mammalian muscle (Barkas et al, 1987), and 61-76 of Torpedo (Barkas et al, 1988) a-subunit.…”

mentioning

confidence: 99%

Main Immunogenic Region of Torpedo Electroplax and Human Muscle Acetylcholine Receptor: Localization and Microheterogeneity Revealed by the Use of Synthetic Peptides

Tzartos

Loutrari

Tang

et al. 1990

Journal of Neurochemistry

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Most anti-nicotinic acetylcholine receptor (AChR) antibodies in myasthenia gravis are directed against an immunodominant epitope or epitopes [main immunogenic region (MIR)] on the AChR alpha-subunit. Thirty-two synthetic peptides, corresponding to the complete Torpedo alpha-subunit sequence and to a segment of human muscle alpha-subunit, were used to map the epitopes for 11 monoclonal antibodies (mAbs) directed against the Torpedo and/or the human MIR and for a panel of anti-AChR mAbs directed against epitopes on the alpha-subunit other than the MIR. A main constituent loop of the MIR was localized within residues alpha 67-76. Residues 70 and 75, which are different in the Torpedo and human alpha-subunits, seem to be crucial in determining the binding profile for several mAbs whose binding to the peptides correlated very well with their binding pattern to native Torpedo and human AChRs. This strongly supports the identification of the peptide loop alpha 67-76 as the actual location of the MIR on the intact AChR molecule. Residues 75 and 76 were necessary for binding of some mAbs and irrelevant for others, in agreement with earlier suggestions that the MIR comprises overlapping epitopes. Structural predictions for the sequence segment alpha 67-76 indicate that this segment has a relatively high segmental mobility and a very strong turning potential centered around residues 68-71. The most stable structure predicted for this segment, in both the Torpedo and human alpha-subunits, is a hairpin loop, whose apex is a type I beta-turn and whose arms are beta-strands. This loop is highly hydrophilic, and its apex is negatively charged. All these structural properties have been proposed as characteristic of antibody binding sites. We also localized the epitopes for mAbs against non-MIR regions. Among these, the epitope for a monoclonal antibody (mAb 13) that noncompetitively inhibits channel function was localized within residues alpha 331-351.

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Profile of the continuous antigenic regions on the extracellular part of the alpha chain of an acetylcholine receptor.

Cited by 42 publications

References 51 publications

Experimental myasthenia gravis in congenic mice. Sequence mapping and H‐2 restriction of T helper epitopes on the α subunits of Torpedo californica and murine acetylcholine receptors

Experimental myasthenia gravis in congenic mice. Sequence mapping and H‐2 restriction of T helper epitopes on the α subunits of Torpedo californica and murine acetylcholine receptors

Anatomy of the antigenic structure of a large memberane autoantigen, the muscle‐type nicotinic acetylcholine receptor

Main Immunogenic Region of Torpedo Electroplax and Human Muscle Acetylcholine Receptor: Localization and Microheterogeneity Revealed by the Use of Synthetic Peptides

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