Limbic encephalitis (LE) with antibodies against adenylate kinase 5 (AK5) has been difficult to characterize because of its rarity. In this study, we identified 10 new cases and reviewed 16 previously reported patients, investigating clinical features, IgG subclasses, human leukocyte antigen (HLA), and CSF proteomic profiles. Patients with anti-AK5 LE were mostly men (20/26, 76.9%) of median age 66 years old (range 48-94). Predominant symptom was severe episodic amnesia in all patients, frequently associated with depression (17/25, 68.0%). Weight loss, asthenia, and anorexia were also highly characteristic, being present in 11/25 (44.0%) patients. Although epilepsy was always lacking at disease onset, seizures developed later in a subset of patients (4/25, 16.0%). All patients presented CSF abnormalities, such as pleocytosis (18/25, 72.0%), oligoclonal bands (18/25, 72.0%), and increased Tau (11/14, 78.6%). Temporal lobe hyper-intensities were almost always present at disease onset (23/26, 88.5%), evolving nearly invariably toward a severe atrophy in subsequent MRIs (17/19, 89.5%). This finding was in line with a poor response to immunotherapy, with only 5/25 (20.0%) patients responding. IgG1 was the predominant subclass, being the most frequently detected and the one with highest titres in nine CSF-serum paired samples. Temporal biopsy from one of our new cases showed massive lymphocytic infiltrates dominated by both CD4+ and CT8+ T-cells, intense granzyme B expression, and abundant macrophages/microglia. HLA analysis in 11 patients showed a striking association with HLA-B*08:01 (7/11, 63.6%; OR = 13.4, 95% CI [3.8-47.4]), C*07:01 (8/11, 72.7%; OR = 11.0, 95% CI [2.9-42.5]), DRB1*03:01 (8/11, 72.7%; OR = 14.4, 95% CI [3.7-55.7]), DQB1*02:01 (8/11, 72.7%; OR = 13.5, 95% CI [3.5-52.0]), and DQA1*05:01 (8/11, 72.7%; OR = 14.4, 95% CI [3.7-55.7]) alleles, which formed the extended haplotype B8-C7-DR3-DQ2 in 6/11 (54.5%) patients (OR = 16.5, 95% CI [4.8-57.1]). Finally, we compared the CSF proteomic profile of five anti-AK5 patients with that of 40 controls and 10 cases with other more common non-paraneoplastic LE (five with antibodies against leucine-rich glioma inactivated 1 and five against contactin-associated protein-like 2), as well as 10 cases with paraneoplastic neurological syndromes (five with antibodies against Yo and five against Ma2). These comparisons revealed, respectively, 31 and seven significantly up-regulated proteins in anti-AK5 LE, mapping to apoptosis pathways and innate/adaptive immune responses. These findings suggest that the clinical manifestations of anti-AK5 LE result from a distinct T-cell mediated pathogenesis, with major cytotoxicity-induced apoptosis leading to a prompt and aggressive neuronal loss, likely explaining the poor prognosis and response to immunotherapy.
