Can infections trigger post-infectious autoimmunity through molecular mimicry?

Infections initiate necessary immune defenses, but structural similarities between microbial and host antigens can inadvertently misdirect this response.

Molecular mimicry and cross-reactivity

• Pathogen-directed antibodies can cross-react with self-proteins due to sequence or structural homologies. For example, antibodies against Treponema pallidum, Acinetobacter species, and rubella E2 glycoprotein cross-react with myelin oligodendrocyte glycoprotein (MOG).
• SARS-CoV-2 nonstructural proteins share structural similarities with NMDA receptor subunits (GluN1 and GluN2A), prompting cross-reactive antibody binding.
• In the vasculature, antibodies target endothelial and vascular self-proteins, potentially involving candidates like the endothelin A receptor, GRP78, and RAGE.

Mechanisms of sustained autoimmunity

• Binding of cross-reactive antibodies to neural targets directly drives pathology. For instance, HSV-1-induced anti-NMDA receptor encephalitis occurs when pathogen-directed IgG antibodies bind GluN1 subunits, causing receptor internalization and neuroinflammation.
• In demyelinating conditions, molecular mimicry involving MOG and myelin basic protein (MBP) drives persistent myelin destruction.
• These auto-aggressive responses are further amplified and sustained through non-mimicry pathways, specifically the bystander activation of silent autoreactive lymphocytes and epitope spreading secondary to local inflammatory tissue damage.

Bottom line

• Bottom line: Infections can trigger chronic post-infectious autoimmunity through molecular mimicry, where cross-reactive antibodies target key neural and vascular proteins, with pathology further sustained by bystander activation and epitope spreading.