Autoimmune encephalitis (AE) is a group of conditions defined by brain inflammation, occurring when the body’s immune system mistakenly attacks healthy brain cells. This immune response primarily targets proteins on the surface of neurons, causing dysfunction in signaling within the central nervous system. AE is a collective term for various syndromes sharing the common feature of self-directed brain inflammation. Understanding this complex condition requires identifying the diverse triggers that set the immune system on this course.
Post-Infectious Activation
A common pathway initiating Autoimmune Encephalitis is a preceding infection (viral, bacterial, or parasitic). AE symptoms often emerge days to weeks after the infection has cleared, suggesting a delayed reaction rather than direct pathogen invasion. This mechanism is explained by molecular mimicry.
Molecular mimicry occurs when the immune system generates antibodies against a pathogen, but a component of that pathogen structurally resembles a protein found in the brain. Although effective against the invader, the resulting antibodies cross-react with the similar self-protein, mistakenly labeling brain cells as a threat. For example, Herpes Simplex Virus (HSV) is a well-established trigger, particularly for anti-NMDAR encephalitis cases following an HSV infection.
Other common pathogens, including influenza or SARS-CoV-2, have been implicated as potential triggers due to this cross-reactivity. The immune system’s defense against external threats inadvertently primes it to attack neuronal structures.
Malignancies and Paraneoplastic Causes
A distinct trigger for AE is an underlying malignancy, known as a paraneoplastic syndrome. Here, the immune response is initiated by a tumor rather than an external pathogen. This AE type arises because certain cancer cells express proteins normally found only in the brain.
The immune system recognizes these “onconeural” proteins on the tumor as foreign and attacks the cancer cells. However, the resulting antibodies cannot distinguish between the proteins on the tumor and the identical proteins expressed on healthy neurons. This misidentification causes the immune system to attack the nervous system.
Common malignancies associated with paraneoplastic AE include small-cell lung cancer, testicular tumors (seminomas), ovarian teratomas, and thymomas. Neurological symptoms often develop acutely, frequently preceding the tumor diagnosis by weeks or months. For example, anti-NMDAR encephalitis is strongly associated with ovarian teratomas, while anti-GABA-B receptor encephalitis is often linked to small-cell lung cancer.
Autoimmune Predisposition and Risk Factors
While infections and tumors are direct triggers, an individual’s underlying susceptibility determines who develops AE. Genetic factors significantly influence this predisposition by affecting immune system function. The human leukocyte antigen (HLA) system, which helps distinguish self from non-self, is the most studied genetic factor.
Specific HLA types are strongly associated with certain forms of AE, suggesting a reduced threshold for the immune system to launch an attack. For instance, anti-LGI1 encephalitis has a strong association with the HLA-DRB107:01 subtype. This genetic linkage suggests some individuals are more prone to misidentifying neuronal proteins as foreign when faced with a trigger.
A personal or family history of other systemic autoimmune diseases, such as lupus or Hashimoto’s thyroiditis, also increases the likelihood of developing AE. These conditions indicate a pre-existing tendency for immune system dysregulation. These underlying vulnerabilities allow an infectious or paraneoplastic event to initiate the attack on the brain.
The Immune Response Mechanism
Once a trigger initiates the process, the immune attack involves generating pathogenic antibodies that target specific neuronal components. These antibodies are directed against proteins on the surface of nerve cells, interfering with normal brain signaling. The type of AE is often defined by the specific neuronal protein the antibodies target.
For instance, in anti-NMDAR encephalitis, antibodies target the N-methyl-D-aspartate receptor, which regulates synaptic transmission. Antibody binding causes receptors to be internalized and removed from the neuron’s surface, silencing communication between nerve cells. Conversely, in anti-LGI1 encephalitis, antibodies attack the Leucine-rich glioma-inactivated 1 protein, which regulates potassium channels.
These antibodies must cross the blood-brain barrier, a selective membrane protecting the central nervous system. Once across, they bind to neuronal targets, causing inflammation and disrupting the balance of signals necessary for brain function. This action explains the severe neurological and psychiatric symptoms characterizing Autoimmune Encephalitis.