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Encephalitogens

An encephalitogen is an agent that is capable of producing encephalitis. Encephalitis is caused by infections or allergic reactions. Cytokines, released by the host to fight pathologic agents, act as encephalitogens. The clinical presentation can be similar in central and peripheral events because cytokines act outside the brain on peripheral nerves using common mechanisms. The purpose of this discussion is to review some human research that can be applied to encephalitogens that we investigate and suggest how you can participate in our research.

Inflammation, when treated, can resolve or it can become chronic.  Chronic inflammation destroys tissue and can eventually remove insulating myelin protein from nerves.  Tissue damage isn’t necessarily permanent.  The body repairs the damaged protein along with or after the inflammatory cycle.  However, left long enough, the body will permanently bandage the area by laying down calcium.  Once calcium is deposited, the damage is permanent.

An antemortem biopsy sample from horses with disease can help us in several ways.  Skeletal muscle innervated by nerves arising from the cauda equina can show abnormalities that may help us further define polyneuritis equi. The types of cells present in disease can be characterized by special stains and molecular analysis. The long term goal of these types of analysis is to provide veterinarians with effective treatment protocols. Veterinarians can send a biopsy sample to us for a free analysis. We will analyze the tissues, archive the tissue samples, and publish the results. Please find the biopsy submission form on the testing page or follow this link: http://pathogenes.com/w/epm-testing/

New research shows the beneficial effects of non-toxic, non-steroidal treatments that could potentially improve neuroinflammation, protect from demyelination and axonal loss in people with multiple sclerosis (MS). We wonder if that is also true for horses with polyneuritis.  The advantage MS-researchers have in studying this complicated disease is a good animal model.  MS is hard to understand because small parts of protein molecules can trigger a cascade of common reactions and that makes it difficult to parse out cause and effect.

A disease that looks just like MS can be induced in laboratory animals: guinea pigs, mice and rats.  In some guinea pig and rat models, steroids make the signs worse.  Yet other studies report a decrease in pro-inflammatory cytokines suggesting a beneficial effect.

Once disease is induced in the mouse model, steroids reversed the pathology associated with the MS-like condition. Following oral steroid administration, mice lost the disease-associated clinical signs and regained normal motility.  In the mouse model, mice become ataxic with induced disease.  The mice relapsed following withdrawal of steroids, usually in less than two weeks. Polyneuritis equi is similar in pathology to MS in people (or another neurologic disease, Guillian Barre syndrome).

Horses with polyneuritis equi can show spontaneous remission early in the disease process.  [The MS mouse model is one in which spontaneous remission is not seen, leading to the conclusion remission in the signs was due to the steroid treatment.]  While steroids resolve disease signs, it is not long-term and the autoimmune process associated with the model disease is re-initiated with steroid withdrawal. An interesting finding is that the efficacy of the dose used in the studies was similar over a range of doses, although occasionally a mouse treated with the lowest dose did not respond to steroids.  The outcome of treatment of polyneuritis equi is generally poor and there are no published treatment protocols.

Scientists looked at the type of cells that responded to steroid treatment in the animals with induced MS.  A specific type of inflammation (infiltrate) was noted and it was accompanied by demyelination.  Following withdrawal of the steroid, there was a sharp rebound in the infiltrate that was initially observed. The researchers were left questioning the types of cells that were suppressed and what type of cells rebounded to cause the relapse. They focused on developing strategies for treating autoimmune disease by eliminating inflammatory cells produced in the initial response.  Their impression is that there are  pathogenic clones of cells responding from the host’s immune system and possibly target organs.  They also focus on inducing life-long antigen-specific immunological tolerance to prevent development or activation of new pathogenic clones, in other words, a vaccination. They concluded that steroids may provide a beneficial immunosuppressive effect.

So why are steroids not effective in horses with polyneuritis equi? In MS ,steroids are not curative because withdrawing steroids initiate clinical and pathological disease relapses that are accompanied by a return of the infiltrate reactive to the initial encephalitogen.  When they looked at all the data, they felt new autoantigen-specific clones (of cells) were prominent in the relapse, the term for this is epitope spread. The body was making new responses to the tissues.

If polyneuritis equi is stimulated by an organism, say Sarcocystis, then it becomes important to know if there is chronic exposure or if a one time infection caused disease.  These horses would react differently to treatment than for the antigen-associated autoimmunity.

Mouse-modelers also asked, What causes the clinical signs associated with the model? Is it the inflammation or the resultant pathology to the axons and myelin? Their data supported the concept that inflammatory cells, and the products they secrete, may be responsible for initiating and promoting the signs induced by the model. It is the immune response that caused disease. The mice completely recovered in the presence of existing lesions if that pathologic clone was absent. They suggest this is a direct influence of the lymphocytes, or their products, on the clinical signs of the disease.

Mice treated with steroids had less severe demyelination than untreated mice that already had disease or in mice with a relapse. There was less demyelination during remission suggesting that remyelination may have occurred in treated mice. The phenomenon of nerve regeneration or remyelination in a horse with polyneuritis equi was detected by histopathology and at the time, it was posed that enhanced regeneration could be possible if the inflammatory response was controlled early in the disease.

What does this mean to you and your horse?  Proteins that make up myelin are targets for immune responses in some diseases. The one we work with is MP2, myelin protein 2.  The pathogenicity of myelin proteins in human disease is envisioned because, in mice and rats and guinea pigs and horses, these proteins elicit an autoimmune response that leads to a disease that includes some degree of paralysis and motor impairment. The initial episode may become debilitating but most animals recover and are free of disease.  With time animals develop relapsing disease.

The widely held belief is that the basis for relapsing disease is a response to encephalitogens that are different that those there triggered the initial response, epitope spread, and was not detected in all studies. Researchers used mice to show that relapse was related only to the cells with the same specificity as the initial encephalitogen. They concluded with some encephalitogens epitopes don’t spread. Said another way, relapsing disease is due to the encephalitogen used to initiate the primary disease. Moreover, they could vaccinate and prevent relapses in mice. Because other researchers did demonstrate pathogenic epitope spread following encephalitogen-induced disease it is possible that outcome is dependent on the encephalitogen used to induce the primary disease episode.

The study to show this in horses is prohibitively expensive and there is no model to reliably create relapsing polyneuritis equi. Horses have different relapse rates, some months and some years. We can get meaningful data from natural cases.  If we analyzed biopsy samples from horses diagnosed with polyneuritis equi on a molecular level we could gather information on the types of lymphocytes present, the healing process, and document treatment protocols.  The biopsy can be done standing under local block by a field veterinarian.  Samples can be placed in the same fixative that is used for uterine biopsies.  Call to find out how you can help and if your horse would benefit from this study.