Affinity maturation is required for pathogenic monovalent IgG4 autoantibody development in myasthenia gravis.
J Exp Med
; 217(12)2020 12 07.
Article
en En
| MEDLINE
| ID: mdl-32820331
ABSTRACT
Pathogenic muscle-specific tyrosine kinase (MuSK)-specific IgG4 autoantibodies in autoimmune myasthenia gravis (MG) are functionally monovalent as a result of Fab-arm exchange. The development of these unique autoantibodies is not well understood. We examined MG patient-derived monoclonal autoantibodies (mAbs), their corresponding germline-encoded unmutated common ancestors (UCAs), and monovalent antigen-binding fragments (Fabs) to investigate how affinity maturation contributes to binding and immunopathology. Mature mAbs, UCA mAbs, and mature monovalent Fabs bound to MuSK and demonstrated pathogenic capacity. However, monovalent UCA Fabs bound to MuSK but did not have measurable pathogenic capacity. Affinity of the UCA Fabs for MuSK was 100-fold lower than the subnanomolar affinity of the mature Fabs. Crystal structures of two Fabs revealed how mutations acquired during affinity maturation may contribute to increased MuSK-binding affinity. These findings indicate that the autoantigen drives autoimmunity in MuSK MG through the accumulation of somatic mutations such that monovalent IgG4 Fab-arm-exchanged autoantibodies reach a high-affinity threshold required for pathogenic capacity.
Texto completo:
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Base de datos:
MEDLINE
Asunto principal:
Autoanticuerpos
/
Inmunoglobulina G
/
Afinidad de Anticuerpos
/
Miastenia Gravis
Límite:
Humans
Idioma:
En
Revista:
J Exp Med
Año:
2020
Tipo del documento:
Article