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IMMUNE SYSTEMImmune-mediated diseases
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A House Divided
by C.A. Sharp
Every living thing, whether dogs, human or microbe, will sooner or later experience ill health. The cause may be a virus or bacterium, an injury or even old age, but that your dog's own body might attack itself and cause serious illness seems bizarre. This is the case with autoimmune disease.
The immune system is designed to search out and destroy microscopic invaders. Its specialized cells circulate through the bloodstream, hunting down, disabling and consuming viruses and bacteria, which they recognize by their foreign proteins. These cells are programmed to recognize the body's proteins as well as those of the various organisms that lead their quiet and often beneficial lives on or within our dogs. But, sometimes something goes wrong, resulting in immune cells that target one or more of their own body's tissues, or attack benign residents. The author has personally experienced this; her eyes have suffered significant damage wrought by her own immune cells.
Autoimmune diseases, most notably thyroiditis, are being reported in dogs with increasing frequency. The increase is in part due to better veterinary knowledge of this type of disease and improved diagnostic techniques. Environmental conditions (toxic exposure, diet, stress, etc.) can induce autoimmune disease. A dog's genetic make-up plays a role. It is vital that breeders inform themselves about the treatment and inheritance factors of autoimmune disease.
Autoimmune disease does not just happen; it requires a "trigger," an event that starts the disease process. The cause will be some sort of stress factor-another disease, an injury, exhaustion, exposure, emotional distress, toxic exposures, or even something so subtle you may never know exactly what precipitated the disease. Sometimes the result will be temporary and the autoimmune reaction will cease as the body recovers, never to return.
An example of this would be localized demodectic mange. The demodex mites live in the hair follicles of most, if not all dogs. In normal circumstances, they are benign residents, bringing no apparent benefit but not causing any harm, either. Sometimes a puppy will have a reaction to the presence of these mites, resulting in localized demodectic mange. A small, coin-sized bald spot will develop, usually on the dog's face or forelegs. Most vets will prescribe a miticide, but treated or not it will eventually go away on its own. (There is another, virulent form of this disease discussed below). The disease is brought on by temporary compromise of a young immune system still learning how to function. The crisis past, the disease goes away.
Of greater concern, especially to a dog breeder, are the chronic, genetically influenced, forms of autoimmune disease-the ones that, once started, will be a health concern for the balance of the dog's life.
While the affected dogs may be relatively free of symptoms when the disease is not active, there will be continuing flare-ups even with treatment. While some diseases are readily identified, others can be difficult to diagnose as they mimic other conditions. Diagnostic tests are available for some, but not all. These diseases cannot be cured and require life-long treatment for the affected dog. Sometimes they are fatal.
Steroids are a common treatment for many autoimmune disorders. These are medications that can have serious side effects if taken in large enough doses or administered constantly over an extended period of time. Non-steroid medication may not be available for some diseases. There may come a point where the disease ceases to respond to one or all medications. While autoimmune diseases can be serious enough to result in the dog's death, most dogs can be maintained in reasonable comfort with proper medication.
These diseases usually do not appear until the dog is a young adult. Sometimes they will arise later. It is possible affected dogs may be bred prior to the disease becoming known.
THE MAJOR PLAYERS
Thyroiditis is the most frequently reported autoimmune disease in dogs, both purebred and mongrel. The slow, and eventually total, destruction of the thyroid gland can cause a wide variety of signs in the affected dog, with the most common being hair loss with thickened oily skin, obesity and lethargy. Less frequently, affected dogs may develop other problems, including reproductive failure, seizures and corneal dystrophy. Sometimes these dogs will not display any of the more "classic" signs of hypothyroid disease. All of these signs might also be caused by other diseases; therefore a thorough veterinary exam is indicated so proper treatment can be given.
Blood panels can be done to diagnose this disease, as well as identify probably carriers of the disease, but the tests are not black and white and may need to be repeated at intervals.
Lupus comes in two forms. The least serious is discoid lupus, a skin disease causing hair loss and crusty, irritated areas of skin, usually on the face and head. Discoid lupus can advance to the more serious lupus erythematosus, a systemic disease. Dogs with systemic lupus suffer a variety of problems. Other autoimmune diseases, including hemolytic anemia and thrombocytopenia can be secondary to lupus. Serious cases can be fatal.
Generalized Demodectic Mange. Sometimes a dog's immune system will be incapable of accepting the presence of demodex mites and will repeatedly react, with affected areas spreading across the body. Untreated, the entire skin surface can become involved with severe secondary bacterial infections, a miserable, potentially fatal state. Diagnosis is made on the appearance of the lesions and case history. There are no screening tests.
Myasthenia Gravis. In this disease the immune system targets the motor end plates-the connection between the nerves and the voluntary muscles. Affected dogs tire easily and may stumble for no apparent reason. They often also have megaesophagus. Vigorous exercise may bring on collapse and severe attacks may mimic toxic exposure. The disease can be acquired, but is more likely to be inherited. There is no screening test.
Other, less frequently seen, autoimmune diseases include pemphigus, uveodermatologic (Vogt-Koyanagi-Harada) syndrome, Addison's Disease, idiopathic thrombocytopenic purpura, diabetes mellitus, glomerulonephritis and Graves' Disease.
Modes of inheritance for these diseases are not fully known and are likely to be complex, with multiple genes involved. The immune system is governed by a group of genes called the Major Histocompatability Complex (MHC). These genes are a "complex" because they are all located close together on a single chromosome. They are, therefore, likely to be inherited as a group, without the usual genetic shuffling that occurs as a dog's genes are distributed into sperm or eggs. Genes within the MHC are unusual in that they are highly polymorphic, each having many-sometimes as many as 100-different alleles, or forms. They also have a much higher mutation rate than normally seen.
Such extreme polymorphism is unusual in genes. Biological systems tend to be conservative, keeping energy and resource needs to a minimum. The simpler a system, the less prone it is to breakdown. So why all this complexity with the MHC?
The immune system must be prepared to tackle many different infectious agents. A mere handful of alleles would not allow the flexibility to face down an ever-evolving array of pathogens. Every individual inherits two copies of the MHC, called haplotypes. In most cases, each haplotype will differ from the other, thus increasing the dog'' odds of having something in its immune arsenal that will work against whatever nasty bug it may encounter. In an inbred individual, the chance that both parents have passed on identical genes within the MHC increases. This situation effectively diminishes the capability to mount an effective immune response.
Nutritional issues can also affect the efficiency of the immune system. Deficiencies in Vitamin E or selenium, a trace mineral, can result in a deficit of immune competent cells. These substances aid the body mechanisms that counteract damaging free radicals that arise from normal metabolic functions such as breathing. As your dog ages, its immune system becomes less efficient in handling free radicals. Proper levels of Vitamin E and selenium in the diet can help the immune system function, especially in dogs that are sick or old.
Most commercial dog feeds and the commonly used raw diets have sufficient selenium but may be lacking in Vitamin E, so supplementation may be advised. Some areas have selenium-deficient soils (the Columbia River Gorge in Oregon and Washington is one example). If crops which form the basis of the diet you are feeding come from such an area, careful supplementing may be necessary (excess selenium can be unhealthy, so follow professional advice and label directions carefully).
But, whatever the nutritional situation, the MHC must be genetically diverse or it cannot do its job. Without diversity within the MHC, the dog will catch a disease. If the disease is bad enough, the dog may die. If there were only a few possible MHC haplotypes in a breed or species, the risk of an entire population being wiped out by a virulent plague would be very high. Nature has answered this challenge with polymorphism. A plague may kill those individuals who don't have the correct combination of MHC alleles to fight the disease. It may even kill a major part of a population, as happened with bubonic plague among humans in centuries past, but there will certainly be some individuals who survive to carry on the species.
But purebred dog breeds are not natural species. They have been artificially selected to meet human needs. In recent decades that selection, especially in show breeds or lines, has included significant inbreeding. The regular use of popular sires over several generations can play havoc with MHC diversity. Since any individual can only have two MHC haplotypes, if a significant portion of a breed descends from a relative few individual dogs the present population may not be able to respond effectively to the next canine plague that comes along. Nor may they be able to utilize vaccines effectively. Rottweilers, for example, responded poorly to parvo vaccines, which often left them vulnerable to the disease if they encountered it, although the newest generation of vaccines seem to be much more effective.
Genes that cause autoimmune diseases are not necessarily single distinct entities. There is a tendency for multiple diseases to occur in the same family. The author's own family provides an example of this. As mentioned earlier, she has an autoimmune eye disease. One of her two sisters has lupus. Her brother's daughter has rheumatoid arthritis, another autoimmune disease. Her other sister's daughter has inflammatory bowel disease. There is apparently a significant weakness in the MHC haplotypes their parents were able to pass on and which some of them in turn passed to their offspring. The same thing can happen in dogs and the more inbred the dogs are, the more widespread the incidence of autoimmune disease will be in the line or breed.
A PLAN OF ACTION
No dog affected with chronic autoimmune disease should be bred. If an animal is being maintained successfully on medication, the breeder should not delude herself that it is "cured" and the disease is not a problem. If an individual dog has produced multiple cases of autoimmune disease, especially in different and relatively unrelated mates, serious consideration should be given to withholding it from further breeding. Crosses that produce autoimmune disease should not be repeated. Neither the parents, nor siblings or offspring of affected individuals should be bred back on the affected pedigree. Members of affected families used for breeding should be paired with mates from families free of autoimmune disease. Breeding pairs should be selected that produce puppies with a lower Coefficient of Inbreeding (COI) than that of the parent from the autoimmune affected family in order to increase the probability of diversity in the MHC. The closer the relationship between an individual and its affected family member, the more care should be taken in mate selection as regards this kind of disease. If there is significant potential for a particular dog developing autoimmune disease (as with the siblings or offspring of one already affected), it would be wise to hold off breeding those individuals until they are three or four years old to be reasonably assured that they will not develop disease.
On a more general level, over-use of particular individuals in a breeding program should be avoided as this can reduce the number of MHC haplotypes in the breeder's or the breed's gene pool. Making lower COIs a selection factor can also aid in maintaining MHC diversity. For most breeds this should be calculated over 8-10 generations. Five or fewer is insufficient to give an accurate picture of the level of inbreeding for most breeds. Ideally, one would want COIs to be 5% or lower, but in some breeds and lines this may not be possible, so any percentage lower than that of the problem parent should be considered a plus for that particular cross.
If screening tests are available for an autoimmune disease that is frequently encountered in your breed, they should be used, especially if that disease has occurred in your dog's family.
No breeder can guarantee that he will never produce a dog that develops autoimmune disease, but with knowledge, good record keeping, diligence and foresight the risk of producing these potentially devastating and sometimes fatal diseases can be significantly reduced.