Autoimmune Encephalitis pathophysiology
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Julinka Auta Fernandes
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Autoimmune Encephalitis Microchapters |
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Differentiating Autoimmune Encephalitis from Other Conditions |
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Diagnosis |
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Treatment |
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Case Studies |
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Autoimmune Encephalitis On the Web |
Overview
Autoimmune encephalitis results from immune responses against neuronal antigens that disturb synaptic signaling, alter network excitability, and, in some forms, cause neuronal destruction. The relative contributions of antibodies, T cells, complement, and other inflammatory cells differ among syndromes.[1]
In anti-NMDA receptor encephalitis, antibody-induced receptor redistribution and internalization can produce marked neuronal dysfunction without requiring extensive neuronal death. In encephalitis associated with intracellular antigens such as Hu or Ma2, cytotoxic T-cell-associated neuronal injury is more prominent.[2][3]
Pathogenesis
Autoimmune encephalitis involves failure of immune tolerance followed by antigen-specific humoral and/or cellular immune responses. An initiating trigger is not identified in every patient.[1]
Initiation of the Immune Response
Autoimmune encephalitis can develop in association with tumor antigen expression, infection-associated immune activation, or disruption of immune regulation.
- Tumor-associated immune activation: Ovarian teratomas associated with anti-NMDAR encephalitis may contain neural tissue expressing the receptor and organized lymphoid structures supporting local antibody production. Studies of teratomas and cervical lymph nodes demonstrate sites of NMDAR-specific B-cell responses.[4]
- Postinfectious immune activation: Herpes simplex encephalitis can be followed by newly developing neuronal antibodies, including NMDAR antibodies, and an autoimmune neurological relapse. The precise steps by which infection breaks immune tolerance remain incompletely defined.[5]
- Treatment-associated immune dysregulation: Immune checkpoint inhibitors can precipitate neurological immune-related adverse events, including encephalitis, and may exacerbate pre-existing antitumor-associated neural autoimmunity.[6]
Peripheral and Intrathecal Immunity
Autoimmune encephalitis can involve both peripheral and central nervous system immune compartments. In anti-NMDAR encephalitis, antibody-secreting plasma cells and plasmablasts have been identified in perivascular and interstitial brain compartments, supporting local antibody production.[7]
Studies of LGI1- and CASPR2-associated disease have identified enriched antigen-reactive B cells in cerebrospinal fluid with features consistent with peripheral maturation. These findings support a model involving peripheral immune activation, immune-cell trafficking across CNS barriers, and intrathecal antibody production; the relative contribution of each compartment varies.[8]
Antibody-Mediated Synaptic Dysfunction
Autoimmune encephalitis associated with neuronal surface or extracellular synaptic antigens can impair receptor trafficking, receptor function, or interactions between synaptic proteins. The mechanisms below have been demonstrated principally in neuronal cultures, antibody-transfer models, or other experimental systems; their contribution in individual patients may differ.
| Antigen | Molecular or cellular effect | Functional significance |
|---|---|---|
| NMDAR: GluN1 subunit | Antibodies cross-link surface receptors and promote receptor internalization, reducing synaptic NMDAR density and NMDAR-mediated currents. | Impaired glutamatergic transmission and synaptic plasticity. Receptor loss is reversible after antibody removal in experimental systems.[2] |
| LGI1 | Antibodies interfere with LGI1 interactions with ADAM22/ADAM23 and alter the organization of synaptic AMPA receptors and Kv1.1 potassium channels. | Disturbed excitability, synaptic transmission, plasticity, and memory.[9][10] |
| CASPR2 | Patient antibodies can inhibit CASPR2–contactin-2 binding without causing substantial CASPR2 internalization in the tested models. | Disruption of axonal protein interactions is a proposed contributor to central and peripheral hyperexcitability; the complete downstream mechanism remains under investigation.[11] |
| AMPAR: GluA1/GluA2 subunits | Antibodies reduce the synaptic localization and number of AMPA receptors in neuronal cultures. | Altered excitatory synaptic transmission; receptor localization can recover after antibody removal.[12] |
| GABAA receptor | Patient antibodies reduce synaptic GABAA receptor clusters in experimental systems. | Loss of inhibitory synaptic function provides a mechanism for severe seizures and status epilepticus.[13] |
| GABAB receptor | Experimental patient IgG altered receptor-dependent network activity without detectable receptor internalization in one study. | Functional modulation appears possible, but the precise relationship between experimental network effects and human seizure generation remains incompletely resolved.[14] |
| DPPX | Antibodies reduce neuronal DPPX and its associated Kv4.2 potassium-channel protein in culture; these effects can reverse after antibody removal. | Altered regulation of neuronal excitability. DPPX-associated disease often combines cognitive symptoms, hyperexcitability, and gastrointestinal symptoms.[15] |
| mGluR5 | Patient antibodies decrease neuronal surface mGluR5 clusters. | Disruption of metabotropic glutamate receptor availability provides a potential mechanism for the associated cognitive and neuropsychiatric syndrome.[16] |
| Neurexin-3α | Antibodies reduce neurexin-3α clusters and synapse formation in developing neuronal cultures. | Experimental disruption of synaptic development; effects depend on the model and neuronal maturity.[17] |
T-Cell-Associated Neuronal Injury
Autoimmune encephalitis associated with intracellular Hu or Ma2 antigens often shows neuronal loss and granzyme-B-positive CD8 T cells apposed to neurons. The associated antibodies generally mark this cellular immune response.[3][18]
GAD65 is an intracellular enzyme involved in GABA synthesis. The direct pathogenic contribution of GAD65 antibodies remains uncertain. In a selected surgical cohort of GAD-associated temporal lobe epilepsy, investigators demonstrated cytotoxic T-cell-associated neuronal injury and subsequent hippocampal sclerosis, supporting a cellular contribution to persistent epilepsy.[19][20]
Complement and Other Inflammatory Effector Mechanisms
Autoimmune encephalitis does not have one uniform complement-dependent injury mechanism. An early anti-NMDAR tissue series did not detect terminal complement-mediated brain injury despite the ability of patients' antibodies to bind complement in vitro.[7]
A 2025 tissue study identified C3-associated synaptic engulfment by central nervous system phagocytes in selected neuronal-surface-antibody cases. Intracellular-antigen cases showed a stronger neuronal pSTAT1 and cytotoxic T-cell signature. Complement-associated synapse elimination should therefore be distinguished from terminal membrane-attack-complex-mediated neuronal lysis.[21]
In LGI1 encephalitis, potentially complement-activating IgG subclasses were associated with hippocampal sclerosis in a small 2024 cohort; this association does not by itself establish the complete injury pathway.[22] A study published online in September 2026 demonstrated antibody-dependent cellular phagocytosis and cytotoxicity in cell-based assays using LGI1/CASPR2 patient antibodies. Their precise contribution to neuronal injury in patients remains to be established.[23]
Functional Consequences
Autoimmune encephalitis can disrupt neuronal networks through altered receptor availability and synaptic plasticity even when widespread neuronal destruction is absent. Passive transfer of NMDAR-antibody-containing patient CSF to mice produced memory and behavioral abnormalities that improved as antibody effects subsided, supporting a direct functional role for the antibodies.[24]
Persistent deficits may also reflect structural neuronal injury. In GAD-associated temporal lobe epilepsy, established tissue damage and ongoing seizures can persist after the more active inflammatory phase.[20]
Antibody-Negative Disease
Autoimmune encephalitis meeting appropriate clinical criteria may occur without an identified neural antibody. This category does not establish a single pathogenic mechanism. Unrecognized antigenic targets or limitations of available testing may contribute, but antibody-negative results alone do not demonstrate autoimmune pathogenesis.[25][1]
Genetics
Autoimmune encephalitis is generally acquired. Reported genetic associations concern susceptibility and immune recognition rather than a single Mendelian inheritance pattern for the entire disease group.
| Syndrome | Reported genetic association | Pathophysiological interpretation |
|---|---|---|
| LGI1-antibody disease | Strong association with HLA-DRB1*07:01 and related class II haplotypes in studied populations. | Supports a role for antigen presentation and antigen-specific immune responses.[26] |
| CASPR2-antibody disease | Association with HLA-DRB1*11:01 in a predominantly European-ancestry cohort. | Indicates a susceptibility profile distinct from LGI1-associated disease.[26] |
| Anti-NMDAR encephalitis | A 2024 Chinese Han genome-wide association study identified associations involving IFIH1 and HLA-DQB1*05:02, among other HLA variants. | Implicates innate immune/interferon pathways and antigen presentation in susceptibility within the studied population.[27] |
These are susceptibility associations, not diagnostic findings. Their magnitude and generalizability can vary across populations.[26][27]
Associated Conditions
Autoimmune encephalitis is associated with several conditions that may initiate or accompany the immune response; the pattern depends on the antigen and clinical syndrome.
| Associated condition | Relationship to autoimmune encephalitis |
|---|---|
| Ovarian teratoma | Neural antigen expression and intratumoral antibody production provide an immune link to anti-NMDAR encephalitis.[4] |
| Other neoplasms | Important associations include small-cell lung cancer with Hu- or GABAB-receptor-associated syndromes, thymoma with CASPR2-associated disease, and Hodgkin lymphoma with mGluR5-associated encephalitis. Tumor associations vary among antibodies.[18] |
| Herpes simplex encephalitis | Can precede a secondary neuronal autoimmune response and autoimmune neurological relapse.[5] |
| Immune checkpoint inhibitor exposure | Can trigger encephalitis as a neurological immune-related adverse event or exacerbate pre-existing neural autoimmunity.[6] |
| Overlapping demyelinating disease | A minority of anti-NMDAR patients have concurrent or separate demyelinating syndromes, sometimes with MOG or AQP4 antibodies. This indicates overlapping immune disorders rather than identical antigenic mechanisms.[28] |
| Type 1 diabetes mellitus and GAD65 autoimmunity | GAD65 antibodies may occur in diabetes as well as neurological autoimmunity. Their presence, particularly at low serum concentrations, requires clinical interpretation and is not proof of encephalitis.[19] |
Gross Pathology
Autoimmune encephalitis has no single defining macroscopic appearance. Chronic limbic injury may produce hippocampal atrophy; associated hippocampal sclerosis is characterized microscopically by neuronal loss and gliosis. Structural studies in selected LGI1- and GAD-associated disease document hippocampal damage, but these changes are not specific to autoimmune encephalitis.[22][20]
Severe synaptic dysfunction can occur with relatively limited destructive neuronal pathology, particularly in anti-NMDAR encephalitis. Structural appearance therefore does not uniformly reflect the severity of neuronal dysfunction.[3][2]
Microscopic Pathology
Autoimmune encephalitis shows heterogeneous microscopic findings depending on the antigenic target, disease duration, and sampled region. Tissue studies support several overlapping patterns.
| Disease pattern | Reported tissue findings | Pathophysiological significance |
|---|---|---|
| Anti-NMDAR encephalitis | Perivascular and interstitial lymphocytes and CD138-positive antibody-secreting cells; relatively limited destructive neuronal pathology in some studied cases. | Supports intrathecal humoral immunity and substantial functional disturbance without obligatory widespread neuronal loss.[7][3] |
| Hu- or Ma2-associated encephalitis | Cytotoxic CD8-positive T cells apposed to neurons, granzyme B expression, neuronal loss, and reactive tissue changes. | Supports a prominent T-cell-associated destructive process.[3] |
| GAD-associated temporal lobe epilepsy | Active-stage T-cell and plasma-cell infiltrates, cytotoxic lymphocytes near neurons, and later hippocampal neuronal loss and sclerosis in surgical specimens. | Suggests an inflammatory neuronal injury phase followed by persistent structural epileptogenic damage in the studied cohort.[20] |
| Synaptic injury in recent tissue studies | Neuronal pSTAT1-associated changes were prominent in intracellular-antigen disease; C3-associated synaptic engulfment by phagocytes was observed in selected neuronal-surface-antibody cases. | Demonstrates that immune-mediated synapse loss may accompany receptor dysfunction and that tissue mechanisms vary between disease groups.[21] |
Findings vary with disease subtype and sampling.[3]
References
- ↑ 1.0 1.1 1.2 Hahn C, Budhram A, Alikhani K, et al. Canadian consensus guidelines for the diagnosis and treatment of autoimmune encephalitis in adults. Can J Neurol Sci. 2024;51(6):734–754. doi:10.1017/cjn.2024.16. PMID:38312020.
- ↑ 2.0 2.1 2.2 Hughes EG, Peng X, Gleichman AJ, et al. Cellular and synaptic mechanisms of anti-NMDA receptor encephalitis. J Neurosci. 2010;30(17):5866–5875. doi:10.1523/JNEUROSCI.0167-10.2010. PMID:20427647.
- ↑ 3.0 3.1 3.2 3.3 3.4 3.5 Bien CG, Vincent A, Barnett MH, et al. Immunopathology of autoantibody-associated encephalitides: clues for pathogenesis. Brain. 2012;135(5):1622–1638. doi:10.1093/brain/aws082. PMID:22539258.
- ↑ 4.0 4.1 Al-Diwani A, Theorell J, Damato V, et al. Cervical lymph nodes and ovarian teratomas as germinal centres in NMDA receptor-antibody encephalitis. Brain. 2022;145(8):2742–2754. doi:10.1093/brain/awac088. PMID:35680425.
- ↑ 5.0 5.1 Armangue T, Leypoldt F, Málaga I, et al. Herpes simplex virus encephalitis is a trigger of brain autoimmunity. Ann Neurol. 2014;75(2):317–323. doi:10.1002/ana.24083. PMID:24318406.
- ↑ 6.0 6.1 Guidon AC, Burton LB, Chwalisz BK, et al. Consensus disease definitions for neurologic immune-related adverse events of immune checkpoint inhibitors. J Immunother Cancer. 2021;9(7):e002890. doi:10.1136/jitc-2021-002890. PMID:34281989.
- ↑ 7.0 7.1 7.2 Martinez-Hernandez E, Horvath J, Shiloh-Malawsky Y, et al. Analysis of complement and plasma cells in the brain of patients with anti-NMDAR encephalitis. Neurology. 2011;77(6):589–593. doi:10.1212/WNL.0b013e318228c136. PMID:21795662.
- ↑ Theorell J, Harrison R, Williams R, et al. Ultrahigh frequencies of peripherally matured LGI1- and CASPR2-reactive B cells characterize the cerebrospinal fluid in autoimmune encephalitis. Proc Natl Acad Sci U S A. 2024;121(7):e2311049121. doi:10.1073/pnas.2311049121. PMID:38319973.
- ↑ Ohkawa T, Fukata Y, Yamasaki M, et al. Autoantibodies to epilepsy-related LGI1 in limbic encephalitis neutralize LGI1-ADAM22 interaction and reduce synaptic AMPA receptors. J Neurosci. 2013;33(46):18161–18174. doi:10.1523/JNEUROSCI.3506-13.2013. PMID:24227725.
- ↑ Petit-Pedrol M, Sell J, Planagumà J, et al. LGI1 antibodies alter Kv1.1 and AMPA receptors changing synaptic excitability, plasticity and memory. Brain. 2018;141(11):3144–3159. doi:10.1093/brain/awy253. PMID:30346486.
- ↑ Patterson KR, Dalmau J, Lancaster E. Mechanisms of Caspr2 antibodies in autoimmune encephalitis and neuromyotonia. Ann Neurol. 2018;83(1):40–51. doi:10.1002/ana.25120. PMID:29244234.
- ↑ Lai M, Hughes EG, Peng X, et al. AMPA receptor antibodies in limbic encephalitis alter synaptic receptor location. Ann Neurol. 2009;65(4):424–434. doi:10.1002/ana.21589. PMID:19338055.
- ↑ Petit-Pedrol M, Armangue T, Peng X, et al. Encephalitis with refractory seizures, status epilepticus, and antibodies to the GABAA receptor. Lancet Neurol. 2014;13(3):276–286. doi:10.1016/S1474-4422(13)70299-0. PMID:24462240. Article title abbreviated.
- ↑ Nibber A, Mann EO, Pettingill P, et al. Pathogenic potential of antibodies to the GABAB receptor. Epilepsia Open. 2017;2(3):355–359. doi:10.1002/epi4.12067. PMID:29588966.
- ↑ Hara M, Ariño H, Petit-Pedrol M, et al. DPPX antibody-associated encephalitis: Main syndrome and antibody effects. Neurology. 2017;88(14):1340–1348. doi:10.1212/WNL.0000000000003796. PMID:28258082.
- ↑ Spatola M, Sabater L, Planagumà J, et al. Encephalitis with mGluR5 antibodies: Symptoms and antibody effects. Neurology. 2018;90(22):e1964–e1972. doi:10.1212/WNL.0000000000005614. PMID:29703767.
- ↑ Gresa-Arribas N, Planagumà J, Petit-Pedrol M, et al. Human neurexin-3α antibodies associate with encephalitis and alter synapse development. Neurology. 2016;86(24):2235–2242. doi:10.1212/WNL.0000000000002775. PMID:27170573.
- ↑ 18.0 18.1 Graus F, Vogrig A, Muñiz-Castrillo S, et al. Updated diagnostic criteria for paraneoplastic neurologic syndromes. Neurol Neuroimmunol Neuroinflamm. 2021;8(4):e1014. doi:10.1212/NXI.0000000000001014. PMID:34006622.
- ↑ 19.0 19.1 Muñoz-Lopetegi A, et al. Neurologic syndromes related to anti-GAD65: Clinical and serologic response to treatment. Neurol Neuroimmunol Neuroinflamm. 2020;7(3):e696. doi:10.1212/NXI.0000000000000696. PMID:32123047.
- ↑ 20.0 20.1 20.2 20.3 Tröscher AR, Mair KM, Verdú de Juan L, et al. Temporal lobe epilepsy with GAD antibodies: neurons killed by T cells not by complement membrane attack complex. Brain. 2023;146(4):1436–1452. doi:10.1093/brain/awac404. PMID:36314080.
- ↑ 21.0 21.1 Di Liberto G, Egervari K, Vogrig A, et al. Neuronal pSTAT1 hallmarks synaptic pathology in autoimmune encephalitis against intracellular antigens. Acta Neuropathol. 2025;149(1):35. doi:10.1007/s00401-025-02882-7. PMID:40278930.
- ↑ 22.0 22.1 Bien CG, Rada A, Mertens M, et al. LGI1 encephalitis: potentially complement-activating anti-LGI1-IgG subclasses 1/2/3 are associated with the development of hippocampal sclerosis. J Neurol. 2024;271:6325–6335. doi:10.1007/s00415-024-12594-9.
- ↑ Businaro P, Masciocchi S, Scaranzin S, et al. Antibody-dependent cellular phagocytosis and cytotoxicity in patients with LGI1 and CASPR2 encephalitis. Neurol Neuroimmunol Neuroinflamm. 2026;13(6):e200646. Published online September 23, 2026. doi:10.1212/NXI.0000000000200646. PMID:42777167.
- ↑ Planagumà J, Leypoldt F, Mannara F, et al. Human N-methyl D-aspartate receptor antibodies alter memory and behaviour in mice. Brain. 2015;138(1):94–109. doi:10.1093/brain/awu310. PMID:25392198.
- ↑ Graus F, Titulaer MJ, Balu R, et al. A clinical approach to diagnosis of autoimmune encephalitis. Lancet Neurol. 2016;15(4):391–404. doi:10.1016/S1474-4422(15)00401-9. PMID:26906964.
- ↑ 26.0 26.1 26.2 Binks S, Varley J, Lee W, et al. Distinct HLA associations of LGI1 and CASPR2-antibody diseases. Brain. 2018;141(8):2263–2271. doi:10.1093/brain/awy109. PMID:29788256.
- ↑ 27.0 27.1 Liu X, Zheng X, Shu Y, et al. Genome-wide association study identifies IFIH1 and HLA-DQB1*05:02 loci associated with anti-NMDAR encephalitis. Neurol Neuroimmunol Neuroinflamm. 2024;11(3):e200221. doi:10.1212/NXI.0000000000200221. PMID:38579189.
- ↑ Titulaer MJ, Höftberger R, Iizuka T, et al. Overlapping demyelinating syndromes and anti-N-methyl-D-aspartate receptor encephalitis. Ann Neurol. 2014;75(3):411–428. doi:10.1002/ana.24117. PMID:24700511.