Clinical/ Immunopathological Presentations and Antigen-specific CD8+T Cell Responses in Paraneoplastic Autoimmune KLHL11 Encephalitis

Objective: To describe phenotypic presentations, outcomes and histopathological features and T cell responses in Kelch-like protein 11 (KLHL11) encephalitis.\n\nBackground: KLHL11-IgG is a newly identified biomarker of paraneoplastic encephalitis.\n\nDesign/Methods: Clinical features and outcomes of KLHL11-IgG seropositive cases identified in the Mayo Clinic Neuroimmunology Laboratory (confirmed by transfected-cell and tissue-based immunofluorescence assays) were reviewed. Peripheral blood mononuclear cells (PBMCs) from two KLHL11-IgG-seropositive patients were exposed in vitro to KLHL11 recombinant protein and T cell activation was analyzed by flow cytometry.\n\nResults: Thirty-eight KLHL11-IgG-seropositive patients were identified, all men. Initial clinical presentations were: ataxia (81%), diplopia (55%), vertigo (50%), hearing loss (39%), tinnitus (34%), dysarthria (30%) and seizures (23%). Hearing loss or tinnitus preceded other neurological deficits by 1–8 months in 10 patients (26%). Among patients screened for malignancy, testicular germ-cell tumors (63%) or testicular microlithiasis and fibrosis (16%) were found. In another two patients, lymph node biopsy yielded different cancer diagnoses (metastatic lung adenocarcinoma and chronic lymphocytic leukemia). Initial brain MRIs revealed T2-hyperintensities in temporal lobe (10), cerebellum (7), brainstem (3) or diencephalon (4). A biopsied gadolinium-enhancing temporal lobe lesion demonstrated T cell-predominant inflammation and non-necrotizing granulomas. Cerebellar biopsy (patient with chronic ataxia) and two autopsied brains demonstrated Purkinje neuronal loss and Bergmann gliosis, supporting early stage active inflammation and later extensive neuronal loss. Compared to non-autoimmune control PBMCs, CD8+ and CD4+ T cells were significantly activated (surface-CD69 upregulation) when patient PBMCs were cultured with KLHL11 protein. Most patients (59%) benefitted from immunotherapy and/or cancer treatment (neurological disability stabilized [11] or improved [9]). Kaplan-Meier curve demonstrated significantly higher probability of wheelchair dependence among patients without detectable testicular cancer.\n\nConclusions: KLHL11-IgG is a biomarker of paraneoplastic encephalitis that is highly associated with testicular germ-cell tumors. Neuropathological findings and the demonstrated KLHL11 specific T-cell responses support a CD8+-T cell-mediated cytotoxic pathogenesis.\n\nDisclosure: Dr. Dubey has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Consulted for UCB and Astellas. All compensation for consulting activities is paid directly to Mayo Clinic.. Dr. Dubey has received research support from Research support from Grifols and Center of Multiple Sclerosis and Autoimmune Neurology, Center for Clinical and Translational Science. Patent pending for KLHL11 as a marker of neurological autoimmunity.. Dr. Wilson has received research support from Roche, GenentechDr. Giannini has nothing to disclose. Dr. Gandhi has nothing to disclose. Dr. Cheville has nothing to disclose. Dr. Lennon has received royalty, license fees, or contractual rights payments from Royalty payments from RSR/Kronus. Dr. Clarkson has nothing to disclose. Dr. Eggers has nothing to disclose. Dr. Devine has nothing to disclose. Dr. Mandel-Brehm has nothing to disclose. Dr. Kryzer has nothing to disclose. Dr. Andrews has nothing to disclose. Dr. Hales has nothing to disclose. Dr. Kattah has nothing to disclose. Dr. Eaton has nothing to disclose. Dr. Jitprapaikulsan has nothing to disclose. Dr. Mills has nothing to disclose. Dr. Flanagan has received research support from Medimmune/Viela Bio. Dr. Zekeridou has received research support from patent pending on PDE10A-IgG as a biomarker of paraneoplastic autoimmunity. Dr. Leibovich has nothing to disclose. Dr. Fryer has nothing to disclose. Dr. Hinson has nothing to disclose. Dr. Torre has nothing to disclose. Dr. Kaufman has nothing to disclose. Dr. Thoreson has nothing to disclose. Dr. Sagen has nothing to disclose. Dr. Linnoila has nothing to disclose. Dr. DeRisi has nothing to disclose. Dr. McKeon has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Grifols, Medimmune, and Euroimmun. Dr. McKeon has received royalty, license fees, or contractual rights payments from Pending patents: MAP1B, Kelch-like-protein 11, GFAP and MAP1B. Dr. McKeon has received research support from Medimmune, Euroimmun but has not received personal compensation.. Dr. Pittock has received personal compensation from Alexion, Grifols, Euroimmun, MedImmune/Viela Bio Dr. Pittock has received research support from Alexion, Grifols, Euroimmun, MedImmune/Viela Bio