The conformation of the main immunogenic region on the α‐subunit of muscle acetylcholine receptor is affected by neighboring receptor subunits

Fostieri, Efrosini; Beeson, David; Tzartos, Socrates J.

doi:10.1016/s0014-5793(00)01980-3

Cited by 13 publications

(7 citation statements)

References 27 publications

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“…Examples of titrations of the Fabs are shown in Figure 2 (b and c); the efficient binding by monomeric Fabs of soluble AChR (at ‫005ف‬ pM final concentration) indicates a high affinity. The muscle extracts used for screening and precipitations were from amputees with ischemic disease; although these have a preponderance of fetal compared with adult AChR (Vincent and Newsom-Davis, 1985), antibodies to the ␣, ␤, or ␦ subunits bind similarly to both isoforms (Fostieri et al, 2000;Tzartos et al, 1998). We therefore tested the Fabs against AChR extracted from TE671 cells that express only fetal AChR or from a TE671 subline that expresses predominantly (Ͼ90%) adult AChR (Beeson et al, 1996).…”

Section: Specificity Of Amc-m Fabs For Fetal Achrmentioning

confidence: 99%

“…is thought to be the target of the majority of AChR antibodies in MG (Tzartos et al, 1998); although some may have a preference for the fetal isoform (Fostieri et al, 2000), they should also have been able to bind adult AChR and to compete with the anti-MIR mAb. In fact, the almost exclusive recognition of fetal, rather than adult, AChR contrasts sharply with Fabs cloned from the thymus of a more typical nonparous young female MG patient under the same conditions.…”

Section: H/k ----------------------T----2 H/k ---------------------Ftmentioning

confidence: 99%

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Antibodies to Acetylcholine Receptor in Parous Women with Myasthenia: Evidence for Immunization by Fetal Antigen

Matthews

Sims

Ledwidge

et al. 2002

Laboratory Investigation

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SUMMARY:The weakness in myasthenia gravis (MG) is mediated by autoantibodies against adult muscle acetylcholine receptors (AChR) at the neuromuscular junction; most of these antibodies also bind to fetal AChR, which is present in the thymus. In rare cases, babies of mothers with MG, or even of asymptomatic mothers, develop a severe developmental condition, arthrogryposis multiplex congenita, caused by antibodies that inhibit the ion channel function of the fetal AChR while not affecting the adult AChR. Here we show that these fetal AChR inhibitory antibodies are significantly more common in females sampled after pregnancy than in those who present before pregnancy, suggesting that they may be induced by the fetus. Moreover, we were able to clone high-affinity combinatorial Fab antibodies from thymic cells of two mothers with MG who had babies with arthrogryposis multiplex congenita. These Fabs were highly specific for fetal AChR and did not bind the main immunogenic region that is common to fetal and adult AChR. The Fabs show strong biases to VH3 heavy chains and to a single V1 light chain in one mother. Nevertheless, they each show extensive intraclonal diversification from a highly mutated consensus sequence, consistent with antigen-driven selection in successive steps. Collectively, our results suggest that, in some cases of MG, initial immunization against fetal AChR is followed by diversification and expansion of B cells in the thymus; maternal autoimmunity will result if the immune response spreads to the main immunogenic region and other epitopes common to fetal and adult AChR. (Lab

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Section: Specificity Of Amc-m Fabs For Fetal Achrmentioning

confidence: 99%

Section: H/k ----------------------T----2 H/k ---------------------Ftmentioning

confidence: 99%

Antibodies to Acetylcholine Receptor in Parous Women with Myasthenia: Evidence for Immunization by Fetal Antigen

Matthews

Sims

Ledwidge

et al. 2002

Laboratory Investigation

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“…Its exact epitope on both the Torpedo and human AChR has been identified (α67–76) [5], while Fostieri et al . [15] have recently shown that it binds to both adult and embryonic AChRs, but it prefers the adult isoform [15]. Intact mAb198 causes antigenic modulation of AChRs in muscle cell cultures, whereas its Fab or Fv fragments do not cause modulation but rather they inhibit the modulation activity of the intact mAb198 [4,16].…”

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confidence: 99%

Crystal structure of Fab198, an efficient protector of the acetylcholine receptor against myasthenogenic antibodies

Poulas

Eliopoulos

Vatzaki

et al. 2001

European Journal of Biochemistry

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The crystal structure of the Fab fragment of the rat monoclonal antibody 198, with protective activity for the main immunogenic region of the human muscle acetylcholine receptor against the destructive action of myasthenic antibodies, has been determined and refined to 2.8 A Ê resolution by X-ray crystallographic methods. The mouse anti-lysozyme Fab D1.3 was used as a search model in molecular replacement with the amore software. The complementarity determining regions (CDR)-L2, CDR-H1 and CDR-H2 belong to canonical groups. Loops CDR-L3, CDR-H2 and CDR-H3, which seem to make a major contribution to binding, were analyzed and residues of potential importance for antigen-binding are examined. The antigen-binding site was found to be a long crescent-shaped crevice. The structure should serve as a model in the rational design of very high affinity humanized mutants of Fab198, appropriate for therapeutic approaches in the model autoimmune disease myasthenia gravis.

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“…Many of the antibodies bind to a region of the extracellular domain of the chain, the main immunogenic region or MIR. Its conformation is affected by the ↔ interchange, as demonstrated by the observation that some antibodies bind better to the MIR of the fetal AChR than the adult form, even though the and subunits do not contribute directly to the MIR (Fostieri, Beeson, & Tzartos, 2000). Titres of MIR antibodies vary considerably between patients and other antibodies may play an equally important role in some individuals.…”

Section: Structure and Epitopes Of The Acetylcholine Receptormentioning

confidence: 99%

The Ectopic Germinal Centre Response in Autoimmune Disease and Cancer

Stott¹,

McIntyre²

2011

Autoimmune Disorders - Current Concepts and Advances From Bedside to Mechanistic Insights

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The conformation of the main immunogenic region on the α‐subunit of muscle acetylcholine receptor is affected by neighboring receptor subunits

Abstract: Myasthenia gravis (MG) is caused by autoantibodies to the acetylcholine receptor (AChR).

Cited by 13 publications

References 27 publications

Antibodies to Acetylcholine Receptor in Parous Women with Myasthenia: Evidence for Immunization by Fetal Antigen

Antibodies to Acetylcholine Receptor in Parous Women with Myasthenia: Evidence for Immunization by Fetal Antigen

Crystal structure of Fab198, an efficient protector of the acetylcholine receptor against myasthenogenic antibodies

The Ectopic Germinal Centre Response in Autoimmune Disease and Cancer

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