Mecanismos de reconocimiento del anticuerpo de esclerosis múltiple MS con los antígenos EBNA1 y GlialCAM mediante...

Multiple sclerosis (MS), a severe autoimmune disease of the central nervous system (CNS), is marked by detrimental demyelination and axonal destruction. High-affinity molecular mimicry exists between Epstein-Barr virus nuclear antigen 1 (EBNA1) and glial cell adhesion molecule (GlialCAM) in the CNS, leading to cross-reactivity of the cerebrospinal fluid-derived B-cell monoclonal antibody (mAb) MS39p2w174 with EBNA1 and GlialCAM. We aim to explore two interesting questions using molecular dynamics simulations in explicit solvent: How does molecular mimicry between the two antigens (Ags) contribute to the cross-reactivity of the immune response? What conformational changes occur in the complementarity-determining regions (CDRs) of the mAb upon binding? Remarkably, both Ags are best described by a combination of induced-fit and conformational-selection mechanisms according to local and global structure analysis and the Kolmogorov-Smirnov test, allowing the similar epitopes to be recognized by the same Ab. Conformational characterization suggests the CDR1 loop of the mAb light chain (CDR-L1) experiences significant changes. Binding-energy prediction proves the hydrogen bonds are critical for complex stability, and both CDR-L1 and CDR-H3 (heavy-chain CDR3 loop) are important interaction interfaces. The role of CDR-H3 has been verified by previous studies. Furthermore, the distinct binding characteristics for the two Ags and Ab are demonstrated. EBNA1 shows higher binding affinity, allowing a precise fit and greater complex stability. In contrast, GlialCAM undergoes more significant local conformational changes to achieve structural complementarity, compensating for its lower intrinsic affinity. These differences highlight varied molecular recognition strategies underlying antibody specificity and cross-reactivity. The findings provide a deep understanding of the molecular pathogenesis of MS caused by different Ags with high-affinity molecular mimicry, providing theoretical support for further research.