I recently spent time with a case report that, on first reading, appears to sit comfortably in the category of academic rarity. A woman in her forties develops autoimmune limbic encephalitis, tests positive for anti-LGI1 antibodies, and is incidentally found to have an early-stage breast cancer. The authors present it primarily as a possible paraneoplastic phenomenon, and in isolation, that framing seems reasonable.
But the more I read, the less comfortable I became with that conclusion.
Not because LGI1 encephalitis is unfamiliar, and not because autoimmune encephalitis itself is unusual. What caught my attention was the type of immune response involved, and the timing of its appearance. This was not an inflammatory, cytotoxic autoimmune process. It was an IgG4-mediated disease, developing shortly after a COVID infection. Once you take that seriously, the case stops looking rare and starts looking consequential.
Uribe, Maria Fernanda Niño, Gilles Van Cutsem, and Philippe Kerschen. "Leucine-rich glioma-inactivated protein 1 antibody-positive limbic encephalitis in a patient with an early-stage asymptomatic breast cancer." BMJ Case Reports CP 18.4 (2025): e261902.
Why IgG4 changes the interpretation completely
IgG4 antibodies are fundamentally different from the antibodies most clinicians think about when they hear the word “autoimmune.” They are poor activators of complement, weak recruiters of inflammatory cells, and are best understood as tolerance antibodies. Historically, IgG4 production has been associated with chronic antigen exposure: allergen desensitisation, parasitic infection, or the group of conditions we now call IgG4-related disease. In those contexts, IgG4 represents an immune system that has decided to stand down rather than fight.
Before COVID, IgG4 was not something we associated with post-viral syndromes or acute infection. In fact, it would have been considered biologically inappropriate in that setting. Acute viral immunity is classically dominated by IgG1 and IgG3, the subclasses designed for clearance and destruction. That is precisely why the appearance of IgG4 in post-COVID mRNA vaccine contexts should make us pause.
LGI1 encephalitis as a model of synaptic failure
LGI1 autoimmune encephalitis is an instructive example because it makes the mechanism visible. LGI1 is a synaptic organising protein, heavily expressed in the hippocampus and medial temporal lobes. Its role is not structural but regulatory: it stabilises synaptic signalling and helps maintain normal excitatory balance. IgG4 antibodies against LGI1 do not kill neurons, they interfere with communication between them.
