Adenylate kinase 5 autoimmunity in treatment refractory limbic encephalitis

Abstract

We report two men with limbic encephalitis (LE) refractory to corticosteroids, IVIg and plasma exchange. Both patients had serum/CSF antibodies that reacted with the cytoplasm of neurons. Probing of a hippocampal cDNA library resulted in the isolation of adenylate kinase 5 (AK5). Patients' antibodies, but not those of 111 controls, recognized AK5-expressing phage plaques. Human AK5-affinity purified antibodies reproduced the neuronal immunolabeling of patients' antibodies, and co-localized with a rabbit AK5 antibody, confirming that the brain autoantigen was AK5. Detection of antibodies to AK5 in LE patients carries a poor prognosis, and suggests the prompt use of aggressive immunosuppression.

Figure 1

Panel A: Section of rat temporal cortex immunolabeled with serum of Patient #1. Serum IgG shows intense neuronal cytoplasmic reactivity. Panel B: Nitrocellulose filter with mixed (∼50%) AK5-expressing bacteriophage plaques and irrelevant plaques, incubated with normal serum (N), Patients' sera (C1, C2), and a rabbit polyclonal AK5 antibody (AK5). Normal serum shows no reactivity with AK5 plaques, whereas the patients' sera and anti-AK5 antibody show strong reactivity with AK5-expressing plaques. Irrelevant plaques are barely visible in C1 and C2, but are seen in AK5 producing mild non-specific background signal. Panel C: Section of rat temporal cortex immunolabeled with a polyclonal rabbit anti-AK5 antibody. Note that the cytoplasmic reactivity is similar to that seen with the patient's serum (panel A). Panel D: Section of rat temporal cortex immunolabeled with patient' IgG eluted from filters containing 100% AK5-expressing plaques. Note that the cytoplasmic reactivity is similar to that produced by patient's serum (panel A), and co-localizes with the polyclonal AK5 rabbit antibody using a double immunolabeling assay (inset with yellow cytoplasmic immunolabeling). Panel E: Section of rat temporal cortex incubated with patient's IgG eluted from irrelevant plaques produces no reactivity. Similar negative results were obtained with the IgG from normal individuals eluted from AK5-expressing plaques. Panels A, B, D, E ×400, avidin-biotin-peroxidase technique with mild hematoxylin counterstaining. Inset in D, immunofluorescence, double immunolabeling, × 400.