Experimental Autoimmune Encephalomyelitis (EAE) is the most widely used animal model for studying human autoimmune diseases of the central nervous system (CNS). This induced condition mimics many of the pathological and clinical features observed in Multiple Sclerosis (MS), a chronic, debilitating disease of the brain and spinal cord. EAE is primarily studied in rodents, such as mice and rats, to understand how the body’s own immune system mistakenly attacks the protective covering of nerve fibers (myelin). The model allows researchers to investigate the complex mechanisms of autoimmune neuroinflammation and to test the efficacy of new therapeutic compounds.
The Mechanism of EAE Induction
The “Experimental” nature of EAE stems from its precise induction in a laboratory setting, forcing the immune system to break its natural tolerance to CNS components. The process, known as active immunization, involves injecting an animal with a specific myelin protein. The most common antigen used is a peptide fragment of Myelin Oligodendrocyte Glycoprotein (MOG), typically the MOG\(_{35-55}\) peptide.
This myelin antigen is emulsified with Complete Freund’s Adjuvant (CFA), a powerful immune stimulant. CFA contains inactivated Mycobacterium tuberculosis bacteria, which acts as a robust danger signal to hyperactivate the animal’s immune system. The combination of the antigen and the adjuvant ensures that immune cells are primed to recognize the myelin protein as a threat.
In most rodent models, Pertussis Toxin (PTX) is also administered shortly after immunization. PTX provides an additional inflammatory stimulus and helps temporarily disrupt the blood-brain barrier (BBB). This disruption allows myelin-specific T-cells to migrate from the bloodstream into the CNS tissue, initiating the autoimmune attack.
Once inside the CNS, these autoreactive T-cells, primarily CD4+ T-helper cells, recognize the animal’s own myelin as the target. This misguided attack leads to inflammation, demyelination, and the subsequent neurological symptoms characteristic of EAE. This procedure reliably induces the disease in susceptible strains of mice, such as C57BL/6 mice, within nine to sixteen days.
EAE as a Model for Multiple Sclerosis
EAE is used extensively in MS research because it successfully recapitulates several pathological hallmarks of the human disease. The model features a pronounced infiltration of inflammatory cells, including T-cells and macrophages, which cross the compromised blood-brain barrier to enter the spinal cord and brain. This influx forms perivascular cuffs, mirroring the inflammatory lesions seen in MS patients.
The immune-mediated attack results in the destruction of the myelin sheath (demyelination), which slows or blocks nerve signal transmission. The chronic inflammatory environment in EAE also causes direct damage to the underlying nerve fibers (axonal damage or loss), which is believed to drive long-term disability in MS.
The ability to control the timing and severity of the disease allows scientists to isolate specific stages of the pathology for study. EAE has been indispensable in identifying the role of specific immune cell subsets, such as T-helper 1 (Th1) and T-helper 17 (Th17) cells, in driving CNS inflammation. Many currently approved MS treatments, including glatiramer acetate and fingolimod, were initially tested using EAE models.
Clinical Assessment and Disease Progression
Researchers closely monitor EAE progression using a standardized clinical scoring system to quantify the severity of neurological deficits. This scoring typically uses a scale ranging from 0 to 5, allowing for objective, reproducible measurement of the disease course and the effectiveness of experimental drugs. Animals are observed daily, and intermediate scores (e.g., 0.5 or 1.5) are often used to capture subtle changes. This method allows for the tracking of disease onset, peak severity, and the subsequent recovery or chronic phase, providing clear data on drug efficacy.
The scoring system tracks disease progression from health to severe paralysis:
- Score 0: Healthy animal with no signs of disease.
- Score 1: Limp tail, indicating a loss of tail tone.
- Score 2: Weak hind limbs or partial paralysis, often observed as a wobbly gait or mild dragging of a foot.
- Score 3: Complete paralysis of both hind limbs; the animal cannot move them forward to walk.
- Score 4: Complete paralysis of the hind limbs and partial paralysis of the forelimbs.
- Score 5: Moribund or euthanized due to the severity of the paralysis.
Key Differences Between EAE and Human MS
Despite its utility, EAE is an induced condition and exhibits several differences from naturally occurring human MS, which limits its direct translational power. The most significant difference is the typical disease course: many EAE models are acute and monophasic, meaning the disease peaks and then resolves. While relapsing-remitting and chronic progressive EAE models exist, human MS is typically a chronic relapsing-remitting or progressive disease over decades.
The location of inflammation also varies. EAE lesions are often concentrated primarily in the spinal cord, accounting for the prominent tail and hind limb paralysis observed. Human MS lesions, conversely, are more broadly distributed throughout the brain, optic nerve, and spinal cord.
EAE is induced in genetically uniform, inbred animals under controlled conditions, resulting in a predictable and uniform disease onset. Human MS is a heterogeneous condition influenced by genetic and environmental factors, with a variable and unpredictable onset.
Some common EAE models are T-cell driven and do not require B-cells for disease induction. B-cells and the antibodies they produce are recognized as having a much more prominent role in human MS pathology than is represented in these specific EAE models.