High-Affinity Human Germline and Mutated Autoantibodies Commonly Cross-React to Self-Antigens in 5 Subgroups of...

Antineuronal autoantibodies targeting surface membrane proteins are the hallmark of an increasing number of autoimmune encephalitides. The autoantibodies can be directly pathogenic and cause various symptoms ranging from epilepsy and psychosis to amnesia and autonomic dysfunction. It is largely unclear how the humoral autoimmune response is triggered and propagated.

We analyzed whether affinity maturation leads to increasing affinity of encephalitis-related autoantibodies to their receptors by determining the binding strength of patient-derived monoclonal autoantibodies and their germline ancestors from 11 patients with NMDAR, LGI1, mGluR5, CASPR2, and GABA_AR encephalitis. In addition, binding to foreign and self-antigens was assessed.

For most autoantibodies, affinity maturation generated or increased binding to neuronal surface antigens. However, high numbers of somatic hypermutations were not necessarily needed, as half of germline-encoded variants already recognized the respective antigen with strong binders in all groups. 10%-15% of reverted and mutated monoclonal autoantibodies recognized nuclear antigens, and one-third were reactive to mammalian tissues other than brain. Immunoprecipitation combined with mass spectrometry identified the nuclear antigen proteins major vault protein and translocated promotor region as targets of selected germline ancestors.

The findings suggest analogous immunologic mechanisms across 5 different encephalitides, with high-affinity autoantibodies already in the germline pool and frequent reactivity to nuclear antigens. Future studies should determine the contribution of immunologic checkpoint deficiencies, as seen in one patient with a pathogenic immune checkpoint mutation.