Background and Objectives Antibodies against LGI1 and CASPR2 (LGI1/CASPR2-IgG) associate with forms of autoimmune encephalitis (AE) that improve with immunotherapy but often show long-term residual disability. We aimed to investigate whether autoantibody effector functions contribute to pathogenic mechanisms and might act as prognostic biomarkers in patients with LGI1/CASPR2-AE. Methods We included patients with LGI1/CASPR2-AE, sufficient clinical information, and 1 serum sample available. We assessed the functional profile of LGI1/CASPR2-IgG using in vitro cell-based assays for complement-dependent cytotoxicity (CDC), antibody-dependent cellular phagocytosis (ADCP), and antibody-dependent cellular cytotoxicity (ADCC). Outcome was measured using the modified Rankin Scale (mRS) and the Clinical Assessment Scale in AE. Results We enrolled 55 patients (LGI1 = 31 and CASPR2 = 24). Coexistent ADCC and ADCP (ADCC+/ADCP+) were found in 28/55 patients (10/31 with LGI1 and 18/24 with CASPR2), while an isolated ADCP (ADCC-/ADCP+) was detected in 15 patients (12 with LGI1-IgG and 3 with CASPR2-IgG), and an isolated ADCC (ADCC+/ADCP-) was detected in 2 LGI1-IgG-positive patients. Because most patients (84%) showed a combination of IgG1/IgG3 and IgG4 subclass, no specific functional profiles could be identified according to the predominant subclass. Quantitative ADCP levels showed only a moderate correlation with CASPR2/LGI1-IgG titers (rho = 0.35, p = 0.02), while ADCC showed a moderate/strong correlation (rho = 0.54, p = 0.002). None of the patients showed CDC activation. In a multivariate logistic regression model (including functional profile, rituximab treatment, relapsing course, and cognitive impairment at onset), the ADCC+/ADCP + profile was the only predictor of poor outcome (mRS > 1, OR: 10.97 [95% CI 1.96-106.9]; p = 0.014). Discussion ADCC and ADCP, but not CDC, are common effector functions of LGI1/CASPR2-IgG, and their presence correlates with long-term poor outcome, suggesting that they might represent a useful prognostic biomarker and suggest additional pathogenic mechanisms. We provide the proof- of principle for a framework that could be applied to other autoantibody-mediated disorders.
Antibody-Dependent Cellular Phagocytosis and Cytotoxicity in Patients With LGI1 and CASPR2 Encephalitis / Businaro, P., Masciocchi, S., Scaranzin, S., Morandi, C., Zuliani, F., Malvaso, A., Cerne, D., Barone, P., Toriello, A., Arbasino, C., Cenciarelli, S., Volonghi, I., Casagrande, S., Nassani, S., Currò-Dossi, M., Micheli, S., Fattapposta, F., Bisecco, A., Leone, C., Marchioni, E., et al.. - In: NEUROLOGY® NEUROIMMUNOLOGY & NEUROINFLAMMATION. - ISSN 2332-7812. - 13:6(2026), p. e200646. [10.1212/NXI.0000000000200646]
Antibody-Dependent Cellular Phagocytosis and Cytotoxicity in Patients With LGI1 and CASPR2 Encephalitis
Casagrande, Silvia;Franciotta, Diego;
2026-01-01
Abstract
Background and Objectives Antibodies against LGI1 and CASPR2 (LGI1/CASPR2-IgG) associate with forms of autoimmune encephalitis (AE) that improve with immunotherapy but often show long-term residual disability. We aimed to investigate whether autoantibody effector functions contribute to pathogenic mechanisms and might act as prognostic biomarkers in patients with LGI1/CASPR2-AE. Methods We included patients with LGI1/CASPR2-AE, sufficient clinical information, and 1 serum sample available. We assessed the functional profile of LGI1/CASPR2-IgG using in vitro cell-based assays for complement-dependent cytotoxicity (CDC), antibody-dependent cellular phagocytosis (ADCP), and antibody-dependent cellular cytotoxicity (ADCC). Outcome was measured using the modified Rankin Scale (mRS) and the Clinical Assessment Scale in AE. Results We enrolled 55 patients (LGI1 = 31 and CASPR2 = 24). Coexistent ADCC and ADCP (ADCC+/ADCP+) were found in 28/55 patients (10/31 with LGI1 and 18/24 with CASPR2), while an isolated ADCP (ADCC-/ADCP+) was detected in 15 patients (12 with LGI1-IgG and 3 with CASPR2-IgG), and an isolated ADCC (ADCC+/ADCP-) was detected in 2 LGI1-IgG-positive patients. Because most patients (84%) showed a combination of IgG1/IgG3 and IgG4 subclass, no specific functional profiles could be identified according to the predominant subclass. Quantitative ADCP levels showed only a moderate correlation with CASPR2/LGI1-IgG titers (rho = 0.35, p = 0.02), while ADCC showed a moderate/strong correlation (rho = 0.54, p = 0.002). None of the patients showed CDC activation. In a multivariate logistic regression model (including functional profile, rituximab treatment, relapsing course, and cognitive impairment at onset), the ADCC+/ADCP + profile was the only predictor of poor outcome (mRS > 1, OR: 10.97 [95% CI 1.96-106.9]; p = 0.014). Discussion ADCC and ADCP, but not CDC, are common effector functions of LGI1/CASPR2-IgG, and their presence correlates with long-term poor outcome, suggesting that they might represent a useful prognostic biomarker and suggest additional pathogenic mechanisms. We provide the proof- of principle for a framework that could be applied to other autoantibody-mediated disorders.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione
