Experimental autoimmune encephalomyelitis

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Experimental autoimmune encephalomyelitis, sometimes experimental allergic encephalomyelitis (EAE), is an animal model of brain inflammation. It is an inflammatory demyelinating disease of the central nervous system (CNS). It is mostly used with rodents and is widely studied as an animal model of the human CNS demyelinating diseases, including multiple sclerosis (MS) and acute disseminated encephalomyelitis (ADEM). EAE is also the prototype for T-cell-mediated autoimmune disease in general.[ citation needed ]

Contents

EAE development was motivated by observations during the convalescence from viral diseases by Thomas M. Rivers, D. H. Sprunt and G. P. Berry in 1933. Their findings upon a transfer of inflamed patient tissue to primates was published in the Journal of Experimental Medicine . [1] [2] An acute monophasic illness, it has been suggested that EAE is far more similar to ADEM than to MS. [3]

Types of EAE

EAE can be induced in a number of species, including mice, rats, guinea pigs, rabbits and primates.

The most commonly used antigens in rodents are spinal cord homogenate (SCH), purified myelin, myelin protein such as MBP, PLP, and MOG, or peptides of these proteins, all resulting in distinct models with different disease characteristics regarding both immunology and pathology. [4] [5] It may also be induced by the passive transfer of T cells specifically reactive to these myelin antigens. [6]

Depending on the antigen used and the genetic make-up of the animal, rodents can display a monophasic bout of EAE, a relapsing-remitting form, or chronic EAE. The typical susceptible rodent will debut with clinical symptoms around two weeks after immunization and present with a relapsing-remitting disease. The archetypical first clinical symptom is weakness of tail tonus that progresses to paralysis of the tail, followed by a progression up the body to affect the hind limbs and finally the forelimbs.[ citation needed ]

However, similar to MS, the disease symptoms reflect the anatomical location of the inflammatory lesions, and may also include emotional lability, sensory loss, optic neuritis, difficulties with coordination and balance (ataxia), and muscle weakness and spasms. Recovery from symptoms can be complete or partial and the time varies with symptoms and disease severity. Depending on the relapse-remission intervals, rats can have up to three bouts of disease within an experimental period.[ citation needed ]

In mice

Demyelination is produced by injection of brain extracts, CNS proteins (such as myelin basic protein), or peptides from such protein emulsified in an adjuvant such as complete Freund's adjuvant. The presence of the adjuvant allows the generation of inflammatory responses to the protein/peptides. In many protocols, mice are coinjected with pertussis toxin to break down the blood-brain barrier and allow immune cells access to the CNS tissue. This immunisation leads to multiple small disseminated lesions of demyelination (as well as micro-necroses) in the brain and spinal cord and the onset of clinical symptoms.[ citation needed ]

Although sharing some features, mostly demyelination, this model, first introduced in the 1930s, differs from human MS in several ways. EAE either kills animals or leaves them with permanent disabilities; animals with EAE also suffer severe nerve inflammation, and the time course of EAE is entirely different from MS, being the main antigen (MBP) in charge. Some key differences between EAE in mice, and MS in humans include:

Secondary damage

Given that some conditions as MS show cortical damage together with the WM damage, there has been interest if this can appear as a secondary damage of the WM. [11]

Human Anti-MOG in mice

Anti-MOG associated encephalomyelitis can be passed from humans to mice, inducing MS type II demyelination (pattern II) [12]

Immunogenetic interactions

Deficiency of TBX21 or STAT4 provides resistance against EAE, while interferon-γ-, interferon-γ-receptor-, interleukin-12 subunit α-, interleukin 12 receptor, β 2 subunit-, and interleukin 18-deficiency exacerbated disease. [13]

In humans

Sometimes the human equivalent to EAE has been triggered in humans by accident or medical mistake. The reactions have been diverse according to the sources of the disease [14] [15] [16] The researchers in the last report have termed the condition "human autoimmune encephalitis" (HAE).

The damage in the second report fulfilled all pathological diagnostic criteria of MS and can therefore be classified as MS in its own right. The lesions were classified as pattern II in the Lucchinetti system. This case of human EAE also showed Dawson fingers. [16]

Using the confluent demyelination as barrier between MS and ADEM, [17] some other reports about EAE in humans classify its effects as ADEM but not always. In Japanese patients exposed to rabies vaccine that contained neural tissue, the clinical presentation resembled ADEM more than MS but the lesions were like acute multiple sclerosis (Uchimura and Shiraki, 1957). [18]

Anti-TNF demyelination

Recent problems with monoclonal antibodies point to an involvement of tumor necrosis factor alpha in the multiple sclerosis onset. Specifically, a monoclonal antibody against TNF-α (adalimumab) has been reported to induce a MS-like disease [19] [20]

Also some experimental therapies for other diseases has produced MS artificially in patients. Specifically, monoclonal antibodies treating cancer like pembrolizumab [21] and infliximab [22] have been reported to produce MS artificially.

Specific forms of EAE

Since the discovery of the four lucchinetti patterns, new EAE models have been published, specifically mimicking the patterns I and II. DTH-EAE for pattern I (T cell and macrophage-mediated delayed-type hypersensitivity) and fMOG-EAE for pattern II (antibody-mediated focal myelin oligodendrocyte glycoprotein-induced experimental autoimmune encephalitis) [23]

Also a model for pattern III lesions has been developed in which mitochondrial metabolism is impaired, resulting in a tissue energy deficiency, a mechanism later termed "virtual hypoxia". The demyelination, characterized by loss of myelin-associated glycoprotein, has been described as "hypoxia-like". [24] Thanks to these pattern III models some specific experimental treatments have appeared [25]

The model for primary progressive MS is the Theiler's virus model. This model presents features not available in others, like microglial activation. [26]

Alternatives

Recently it has been found that CSF from MS patients can carry the disease to rodents, opening the door to an alternative model. [27]

Meningoencephalitis of unknown origin (MUO) in dogs shares some similarities [28]

Related Research Articles

<span class="mw-page-title-main">Acute disseminated encephalomyelitis</span> Autoimmune disease

Acute disseminated encephalomyelitis (ADEM), or acute demyelinating encephalomyelitis, is a rare autoimmune disease marked by a sudden, widespread attack of inflammation in the brain and spinal cord. As well as causing the brain and spinal cord to become inflamed, ADEM also attacks the nerves of the central nervous system and damages their myelin insulation, which, as a result, destroys the white matter. The cause is often a trigger such as from viral infection or vaccinations.

<span class="mw-page-title-main">Myelin</span> Fatty substance that surrounds nerve cell axons to insulate them and increase transmission speed

Myelin is a lipid-rich material that surrounds nerve cell axons to insulate them and increase the rate at which electrical impulses pass along the axon. The myelinated axon can be likened to an electrical wire with insulating material (myelin) around it. However, unlike the plastic covering on an electrical wire, myelin does not form a single long sheath over the entire length of the axon. Rather, myelin ensheaths the axon segmentally: in general, each axon is encased in multiple long sheaths with short gaps between, called nodes of Ranvier. At the nodes of Ranvier, which are approximately one thousandth of a mm in length, the axon's membrane is bare of myelin.

<span class="mw-page-title-main">Multiple sclerosis</span> Disease that damages the myelin sheaths around nerves

Multiplesclerosis (MS) is an autoimmune disease in which the insulating covers of nerve cells in the brain and spinal cord are damaged. This damage disrupts the ability of parts of the nervous system to transmit signals, resulting in a range of signs and symptoms, including physical, mental, and sometimes psychiatric problems. Specific symptoms can include double vision, vision loss, eye pain, muscle weakness, and loss of sensation or coordination. MS takes several forms, with new symptoms either occurring in isolated attacks or building up over time. In the relapsing forms of MS, between attacks, symptoms may disappear completely, although some permanent neurological problems often remain, especially as the disease advances. In the progressive forms of MS, bodily function slowly deteriorates and disability worsens once symptoms manifest and will steadily continue to do so if the disease is left untreated.

Myelitis is inflammation of the spinal cord which can disrupt the normal responses from the brain to the rest of the body, and from the rest of the body to the brain. Inflammation in the spinal cord can cause the myelin and axon to be damaged resulting in symptoms such as paralysis and sensory loss. Myelitis is classified to several categories depending on the area or the cause of the lesion; however, any inflammatory attack on the spinal cord is often referred to as transverse myelitis.

<span class="mw-page-title-main">Demyelinating disease</span> Any neurological disease in which the myelin sheath of neurons is damaged

A demyelinating disease refers to any disease affecting the nervous system where the myelin sheath surrounding neurons is damaged. This damage disrupts the transmission of signals through the affected nerves, resulting in a decrease in their conduction ability. Consequently, this reduction in conduction can lead to deficiencies in sensation, movement, cognition, or other functions depending on the nerves affected.

Neuromyelitis optica spectrum disorders (NMOSD), including neuromyelitis optica (NMO), are autoimmune diseases characterized by acute inflammation of the optic nerve and the spinal cord (myelitis). Episodes of ON and myelitis can be simultaneous or successive. A relapsing disease course is common, especially in untreated patients. In more than 80% of cases, NMO is caused by immunoglobulin G autoantibodies to aquaporin 4 (anti-AQP4), the most abundant water channel protein in the central nervous system. A subset of anti-AQP4-negative cases is associated with antibodies against myelin oligodendrocyte glycoprotein (anti-MOG). Rarely, NMO may occur in the context of other autoimmune diseases or infectious diseases. In some cases, the etiology remains unknown.

<span class="mw-page-title-main">Myelin oligodendrocyte glycoprotein</span>

Myelin oligodendrocyte glycoprotein (MOG) is a glycoprotein believed to be important in the myelination of nerves in the central nervous system (CNS). In humans this protein is encoded by the MOG gene. It is speculated to serve as a necessary "adhesion molecule" to provide structural integrity to the myelin sheath and is known to develop late on the oligodendrocyte.

<span class="mw-page-title-main">Pathophysiology of multiple sclerosis</span>

Multiple sclerosis is an inflammatory demyelinating disease of the CNS in which activated immune cells invade the central nervous system and cause inflammation, neurodegeneration, and tissue damage. The underlying cause is currently unknown. Current research in neuropathology, neuroimmunology, neurobiology, and neuroimaging, together with clinical neurology, provide support for the notion that MS is not a single disease but rather a spectrum.

<span class="mw-page-title-main">Lesional demyelinations of the central nervous system</span>

Multiple sclerosis and other demyelinating diseases of the central nervous system (CNS) produce lesions and glial scars or scleroses. They present different shapes and histological findings according to the underlying condition that produces them.

Remyelination is the process of propagating oligodendrocyte precursor cells to form oligodendrocytes to create new myelin sheaths on demyelinated axons in the CNS. This is a process naturally regulated in the body and tends to be very efficient in a healthy CNS. The process creates a thinner myelin sheath than normal, but it helps to protect the axon from further damage, from overall degeneration, and proves to increase conductance once again. The processes underlying remyelination are under investigation in the hope of finding treatments for demyelinating diseases, such as multiple sclerosis.

Inflammatory demyelinating diseases (IDDs), sometimes called Idiopathic (IIDDs) due to the unknown etiology of some of them, are a heterogenous group of demyelinating diseases - conditions that cause damage to myelin, the protective sheath of nerve fibers - that occur against the background of an acute or chronic inflammatory process. IDDs share characteristics with and are often grouped together under Multiple Sclerosis. They are sometimes considered different diseases from Multiple Sclerosis, but considered by others to form a spectrum differing only in terms of chronicity, severity, and clinical course.

<span class="mw-page-title-main">Balo concentric sclerosis</span> Medical condition

Baló's concentric sclerosis is a disease in which the white matter of the brain appears damaged in concentric layers, leaving the axis cylinder intact. It was described by József Mátyás Baló who initially named it "leuko-encephalitis periaxialis concentrica" from the previous definition, and it is currently considered one of the borderline forms of multiple sclerosis.

Research in multiple sclerosis may find new pathways to interact with the disease, improve function, curtail attacks, or limit the progression of the underlying disease. Many treatments already in clinical trials involve drugs that are used in other diseases or medications that have not been designed specifically for multiple sclerosis. There are also trials involving the combination of drugs that are already in use for multiple sclerosis. Finally, there are also many basic investigations that try to understand better the disease and in the future may help to find new treatments.

<span class="mw-page-title-main">Tumefactive multiple sclerosis</span> Medical condition

Tumefactive multiple sclerosis is a condition in which the central nervous system of a person has multiple demyelinating lesions with atypical characteristics for those of standard multiple sclerosis (MS). It is called tumefactive as the lesions are "tumor-like" and they mimic tumors clinically, radiologically and sometimes pathologically.

<span class="mw-page-title-main">CNS demyelinating autoimmune diseases</span> Medical condition

CNS demyelinating autoimmune diseases are autoimmune diseases which primarily affect the central nervous system.

Theiler's murine encephalomyelitis virus (TMEV) is a single-stranded RNA murine cardiovirus from the family Picornaviridae. It has been used as a mouse model for studying virally induced paralysis, as well as encephalomyelitis comparable to multiple sclerosis. Depending on the mouse and viral strain, viral pathogenesis can range from negligible, to chronic or acute encephalomyelitis.

<span class="mw-page-title-main">Pathology of multiple sclerosis</span> Pathologic overview

Multiple sclerosis (MS) can be pathologically defined as the presence of distributed glial scars (scleroses) in the central nervous system that must show dissemination in time (DIT) and in space (DIS) to be considered MS lesions.

MOG antibody disease (MOGAD) or MOG antibody-associated encephalomyelitis (MOG-EM) is an inflammatory demyelinating disease of the central nervous system. Serum anti-myelin oligodendrocyte glycoprotein antibodies are present in up to half of patients with an acquired demyelinating syndrome and have been described in association with a range of phenotypic presentations, including acute disseminated encephalomyelitis, optic neuritis, transverse myelitis, and neuromyelitis optica.

Several biomarkers for diagnosis of multiple sclerosis, disease evolution and response to medication are under research. While most of them are still under research, there are some of them already well stablished:

Anne Cross is an American neurologist and neuroimmunologist and the Section Head of Neuroimmunology at Washington University School of Medicine in St. Louis, Missouri. Cross holds the Manny and Rosalyn Rosenthal–Dr. John L. Trotter Endowed Chair in Neuroimmunology at WUSTL School of Medicine and co-directs the John L Trotter Multiple Sclerosis Clinic at Barnes-Jewish Hospital. Cross is a leader in the field of neuroimmunology and was the first to discover the role of B cells in the pathogenesis of multiple sclerosis in animals and then in humans. Cross now develops novel imaging techniques to observe inflammation and demyelination in the central nervous systems of MS patients for diagnosis and disease management.

References

  1. ↑ Rivers TM, Spunt DH, Berry GP (1933). "Observations on Attempts to Produce Acute Disseminated Encephalomyelitis in Monkeys". Journal of Experimental Medicine. 58 (1): 39–53. CiteSeerX   10.1.1.274.2997 . doi:10.1084/jem.58.1.39. PMC   2132279 . PMID   19870180.
  2. ↑ Rivers TM, Schwentker FF (1935). "Encephalomyelitis accompanied by myelin destruction experimentally produced in monkeys". Journal of Experimental Medicine. 61 (5): 689–701. doi:10.1084/jem.61.5.689. PMC   2133246 . PMID   19870385.
  3. ↑ Sriram S, Steiner I (2005). "Experimental Allergic Encephalomyelitis: A misleading model of Multiple Sclerosis". Annals of Neurology. 58 (6): 939–945. doi: 10.1002/ana.20743 . PMID   16315280. S2CID   12141651.
  4. ↑ MANNIE, M., R. H. SWANBORG and J. A. STEPANIAK, 2009,"Experimental autoimmune encephalomyelitis in the rat." Curr Protoc Immunol, Chapter 15: Unit 15 12
  5. ↑ MILLER, S. D., and W. J. KARPUS, 2007. "Experimental autoimmune encephalomyelitis in the mouse." Curr Protoc Immunol, Chapter 15: Unit 15 11
  6. ↑ Ellwardt, Erik; Zipp, Frauke (2014). "Molecular mechanisms linking neuroinflammation and neurodegeneration in MS". Experimental Neurology. 262: 8–17. doi:10.1016/j.expneurol.2014.02.006. PMID   24530639. S2CID   34157793.
  7. ↑ Sefia Eseberuo, Pryce Gareth, Meier Ute-Christiane, Giovannoni Gavin, Baker David (2017). "Depletion of CD20 B cells fails to inhibit relapsing mouse experimental autoimmune encephalomyelitis". Multiple Sclerosis and Related Disorders. 14: 46–50. doi:10.1016/j.msard.2017.03.013. PMID   28619431.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  8. ↑ Hans Lassmann, Jack van Horssen, "Oxidative stress and its impact on neurons and glia in multiple sclerosis lesions", Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease, Volume 1862, Issue 3, March 2016, Pages 506-510, https://doi.org/10.1016/j.bbadis.2015.09.018
  9. ↑ Tobias Zrzavy Simon Hametner Isabella Wimmer Oleg Butovsky Howard L. Weiner Hans Lassmann, Loss of 'homeostatic’ microglia and patterns of their activation in active multiple sclerosis, Brain, Volume 140, Issue 7, 1 July 2017, Pages 1900–1913, https://doi.org/10.1093/brain/awx113
  10. ↑ Reza Rahmanzadeh, Wolfgang Brück, Alireza Minagar, Mohammad Ali Sahraian, Multiple sclerosis pathogenesis: missing pieces of an old puzzle, 2018-06-08, DOI: https://doi.org/10.1515/revneuro-2018-0002,
  11. ↑ Zipp Frauke; Ellwardt Erik; Pramanik Guatam; Mittmann Thomas; Stroh Albrecht (2016). "Cortical Hyperactivity beyond the Immune Attack: Starting Point of Neurodegeneration". Neurology. 86 (16 Supplement): S2.002.
  12. ↑ Marti Fernandez I; et al. (2019). "The Glycosylation Site of Myelin Oligodendrocyte Glycoprotein Affects Autoantibody Recognition in a Large Proportion of Patients". Front Immunol. 10: 1189. doi: 10.3389/fimmu.2019.01189 . PMC   6579858 . PMID   31244828.
  13. ↑ Korn, Thomas; Bettelli, Estelle; Oukka, Mohamed; Kuchroo, Vijay K. (2009). "IL-17 and Th17 Cells". Annual Review of Immunology . Annual Reviews. 27 (1): 485–517. doi:10.1146/annurev.immunol.021908.132710. ISSN   0732-0582. PMID   19132915. (VK ORCID: 0000-0001-7177-2110 GS: h6h5FdoAAAAJ).
  14. ↑ Lassman Hans (Feb 2010). "Acute disseminated encephalomyelitis and multiple sclerosis". Brain. 133 (2): 317–319. doi: 10.1093/brain/awp342 . PMID   20129937.
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  16. 1 2 Höftberger R, Leisser M, Bauer J, Lassmann H (Dec 2015). "Autoimmune encephalitis in humans: how closely does it reflect multiple sclerosis?". Acta Neuropathol Commun. 3 (1): 80. doi: 10.1186/s40478-015-0260-9 . PMC   4670499 . PMID   26637427.
  17. ↑ Young NP, Weinshenker BG, Parisi JE, Scheithauer B, Giannini C, Roemer SF, Thomsen KM, Mandrekar JN, Erickson BJ, Lucchinetti CF (2010). "Perivenous demyelination: association with clinically defined acute disseminated encephalomyelitis and comparison with pathologically confirmed multiple sclerosis". Brain. 133 (2): 333–348. doi:10.1093/brain/awp321. PMC   2822631 . PMID   20129932.
  18. ↑ Lassmann H (2010). "Acute disseminated encephalomyelitis and multiple sclerosis". Brain. 133 (2): 317–9. doi: 10.1093/brain/awp342 . PMID   20129937.
  19. ↑ Sinah Engel et al., PPMS onset upon adalimumab treatment extends the spectrum of anti-TNF-α therapy-associated demyelinating disorders, January 2, 2020
  20. ↑ Rana Alnasser Alsukhni, Ziena Jriekh and Yasmin Aboras, 2016. "Adalimumab Induced or Provoked MS in Patient with Autoimmune Uveitis: A Case Report and Review of the Literature." Case Reports in Medicine, Volume 2016 (2016), Article ID 1423131, doi https://dx.doi.org/10.1155/2016/1423131
  21. ↑ Marzia Anita Lucia Romeo et al, Multiple sclerosis associated with pembrolizumab in a patient with non-small cell lung cancer, Journal of Neurology, pp 1–4, 04 October 2019
  22. ↑ Alicja Kalinowska-Lyszczarz, Mahboobeh Fereidan-Esfahani, Yong Guo, Pathological findings in central nervous system demyelination associated with infliximab, https://doi.org/10.1177/1352458519894710
  23. ↑ D. Anthony et al. "Anti-CD20 Therapy Down-Regulates Lesion Formation And Microglial Activation In Pattern I And Pattern II Rat Models Of Multiple Sclerosis." Neurology, April 2014.
  24. ↑ Desai RA, Davies AL, Tachrount M, Kasti M, Laulund F, Golay X, Smith KJ (2016). "Cause and prevention of demyelination in a model multiple sclerosis lesion". Annals of Neurology. 79 (4): 591–604. doi:10.1002/ana.24607. PMC   4949637 . PMID   26814844.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  25. ↑ Desai, RA; Davies, AL; Tachrount, M; Golay, X; Smith, KJ; (2015) Normobaric hyperoxia protects against demyelination in an experimental model of pattern III multiple sclerosis lesions. In: (Proceedings) 116th Meeting of the British-Neuropathological-Society. (pp. p. 28). WILEY-BLACKWELL
  26. ↑ Mack CL, Vanderlugt-Castaneda CL, Neville KL, Miller SD (2003). "Microglia are activated to become competent antigen presenting and effector cells in the inflammatory environment of the Theiler's virus model of multiple sclerosis". Journal of Neuroimmunology. 144 (1–2): 68–79. doi:10.1016/j.jneuroim.2003.08.032. PMID   14597100. S2CID   24384220.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  27. ↑ Cristofanilli M, Rosenthal H, Cymring B, Gratch D, Pagano B, Xie B, Sadiq SA (2014). "Progressive multiple sclerosis cerebrospinal fluid induces inflammatory demyelination, axonal loss, and astrogliosis in mice". Exp Neurol. 261: 620–32. doi:10.1016/j.expneurol.2014.07.020. PMID   25111532. S2CID   21263405.
  28. ↑ Prümmer, Julia K.; Stein, Veronika M.; Marti, Eliane; Lutterotti, Andreas; Jelcic, Ilijas; Schüpbach-Regula, Gertraud; Buch, Thorsten; Maiolini, Arianna (25 January 2023). "Assessment of oligoclonal bands in cerebrospinal fluid and serum of dogs with meningoencephalitis of unknown origin". PLOS ONE. 18 (1): e0280864. doi: 10.1371/journal.pone.0280864 . PMC   9876372 . PMID   36696385.
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