The Major Histocompatibility Complex
by C. A. Sharp
Rev. May 2013
“The MHC is an integral part of the immune response. Loss of MHC allele heterozygosity and/or inadvertent selection for disease-associated alleles due to standard breeding practices may be involved in this increasing incidence of immune-mediated disease.” – Niels Pederson PhD
Reports of immune-mediated disease in Australian Shepherds, as well as other purebred dogs, are on the rise. In magazines and journals, Internet discussion lists and gatherings devoted to canine immune mediated disease, vaccine resistance and allergies are regular topics. Immune-mediated diseases result from excessive action by the immune system, targeting things that are not threats – like pollen or the body’s own tissue. But are dogs, especially purebreds, really experiencing a plague? If so, why? And most important from a dog breeder’s viewpoint, is it hereditary?
Mix-breed dogs and other species, including humans, have also experienced apparent increases in immune-mediated disease. That being the case, it is necessary to consider possible non-hereditary causes that all these groups may share and, setting those aside, determine what additional factors might affect purebred dogs.
One factor is the awareness and knowledge of immunity issues by both the scientific community and the general public in the wake of the AIDs crisis. We know a lot more today about how the immune system works and how it fails than we did only a couple decades ago due to AIDs research.
Another factor is our modern emphasis on cleanliness. This arose for excellent reason: We learned that it was the best way to prevent infectious diseases and the benefits to that have been manifold. However, it also means that young immune systems, whether in children or puppies, experience fewer exposures to minor threats and have less opportunity to learn how to function properly. The ultimate result of this has been an increase in immune mediated diseases. Even so, it is important to remember that these diseases also have genetic underpinnings.
Diagnosis has improved: The presenting signs of some immune mediated diseases, like autoimmune thyroiditis or lupus, may also be seen in individuals suffering from a variety of other conditions. In the past, cases probably went without proper diagnosis where today improved knowledge, diagnostic tools and techniques enable vets to mace more accurate diagnoses.
Present day dog owners are more likely than was once the case to take an ailing pet to the vet for conditions that do not present an obvious or immediate threat to life or soundness. The increase in numbers of dogs being seen by vets has probably added to the numbers of disease reports.
Environment is also a major factor in immune mediated disease. We live today in a world awash in chemicals and combinations of chemicals our great-grandfathers never encountered. Some of these have been shown to affect various bodily functions, including that of the immune system. Our technological culture has made changes in our environment that would never occur in nature and we are only beginning to figure out what is going on.
Vaccines are a part of this technological effect. They are valuable medical tools that have saved countless lives, but improper use of them, via over-aggressive administration, can compromise immune function.
All of these factors are shared by dog breeds and other species. But purebred dogs carry an additional—hereditary–risk in the form of a group of genes called the Major Histocompatibility Complex (MHC).
The MHC is a group of genes positioned close to one another on one chromosome. It is called a “complex” because this positioning virtually guarantees that they will be inherited as a unit, called a haplotype. Therefore, each individual possesses two MHC haplotypes it can pass on to its offspring. The complex governs the functioning of the immune system, enabling it to respond appropriately to the intrusion of foreign objects, such as viruses or bacteria. It is not unique to dogs, but exists in all species of mammals. Many MHC genes (often referred to as DLA – dog leukocyte antigen – genes) are highly polymorphic; there are numerous, sometimes as many as a hundred,-different alleles, or versions, of individual genes. There are so many alleles; it is probable that most individuals in a randomly breeding population will have unique combinations of MHC genes. It is this very lack of similarity that leads to graft-vs.-host disease in transplant patients. Thus, close relatives of transplant patient, who are more likely to be similar in MHC, are the first organ donor candidates to be considered.
MHC genes also have the highest mutation rate of genes for any germ-line cell. In other genes mutations usually confer little benefit to the individual and may cause considerable difficulty. MHC genes mutate readily because their diversity is important to species survival.
Since any one individual can have only two alleles for any gene, this multiplicity of alleles and tendency to mutate seems excessive. But Nature does not go to excess without a reason. While an individual has only two MHC haplotypes, the overall population of its species will have many. Therefore, when a new plague organism comes along, as they inevitably do, the species will survive even though some or even many individuals may be lost. As an example, HIV-positive individuals that have considerable MHC heterozygosity—meaning they have different, rather than similar (homozygous) forms of MHC genes—are more likely to survive to 10 years without succumbing to AIDs. On the other hand, those who are homozygous for certain MHC genes are certain to die within the same period.
Plague or epidemic survivors have the “right” combination of MHC alleles to combat that particular infectious disease. The plague may occur again, but as time goes by it becomes less and less virulent because the individuals with inadequate MHCs will have died and been removed from the breeding population. The MHC mutation rate guarantees that there will be plenty of ammunition for any new plagues that occur.
MHC complexity is an excellent example of the importance of biological diversity—not only among species but also within them. In order to preserve diversity all species will avoid or significantly limit inbreeding if left to themselves to make mating choices. (For the purposes of this article, the term inbreeding includes what dog breeders refer to as line-breeding.) Studies in mice have shown that females, given a choice, show significant preference for mates with dissimilar MHCs, thereby conferring offspring sired by those males with more flexible immune systems. Even in humans a study has indicated females have some degree of preference for males with different MHCs, though no one argues that there are a plethora of other considerations that strongly influence a woman’s mate choice. No studies have been done on dogs to date, but anecdotal reports of bitches that refuse to mate with closely-related dogs are not unusual.
As with any genes, a bad combination of MHC genes can predispose an individual for disease. All of the more than three dozen recognized autoimmune diseases are influenced by certain of the MHC genes. In auto-immune disease, the immune system loses its ability to distinguish self from non-self and attacks the body’s own tissues.
Autoimmune disease is multi-factorial, meaning several things must happen for an individual to develop disease. First, the dog must be genetically pre-disposed via the makeup of its MHC. To develop disease, the genetically predisposed dog must experience an environmental “trigger.” A dog which never experiences a trigger will never develop disease even though it has the necessary genes. The trigger can be any or a combination of things, including toxic exposure, physical or mental stress, viruses, and even fluctuating sex hormones. This need for a trigger before disease occurs is why these diseases have long been recognized as familial but no specific mode of inheritance could be determined.
The author’s family is an example of this familial effect. The author suffers from an auto-immune eye disease that has significantly reduced her vision, her sister, her brother’s daughter, and her other sister’s daughter all have autoimmune diseases, indicating that the author’s parents had an unfortunate combination of MHC haplotypes to pass on to their offspring.
The over-all canine gene pool probably contains as much MHC diversity as is found in naturally mating (i.e. wild) species. However, the division of that gene pool into mutually exclusive sub-sets, or breeds, has guaranteed that any one breed cannot have the full range of MHC alleles present in the species. This limiting factor is further exacerbated by standard breeding practices such as inbreeding and the use of popular sires.
For more than a century, inbreeding has been the norm in domestic dogs. The technique is used, quite effectively, to “fix” traits deemed desirable. This works very well with traits that can readily be observed and measured, such as shape, size and color. It also works, though less well, with complex traits that do not lend themselves to quantification (temperament, performance drives, etc.)
The practice of inbreeding to improve breed traits has inadvertently lead to a reduction of MHC diversity within the various breeds. When added to genetic bottlenecks due to wars, loss of popularity and other drastic population-reducing events, and combined with the extensive use of popular sires, MHC diversity may be lowered to critical levels. For instance, Rottweilers are resistant to parvovirus vaccine. This may be because their MHC is incapable of recognizing parvovirus antigens (anti-body gen-erating– foreign proteins or parts thereof.) Before the immune system can mount a response to an antigen, the antigen must be first broken into pieces inside the cell and transported to special cell surface receptors. These antigen-binding molecules are called histocompatibility molecules In Rotts, early parvo vaccines did not work because their immune systems couldn’t react to it and thereby protect itself from the disease. (Fortunately for Rotts, newer vaccines do work for them.)
Popular sire use is especially pernicious because each such sire can have only two MHC haplotypes–nowhere near the hundreds that exist in the canine genome. Therefore, when a significant portion of a breed descends from one individual, those dogs’ resistance to infectious disease or susceptibility to auto-immune disease can be seriously impacted.
A correlation has been drawn between the coefficient of inbreeding (COI) and MHC heterozygosity. The COI is a measure of how inbred an individual is. Individuals with low COIs (less inbred) are more likely to have two different MHC haplotypes.
Indications of MHC homozygosity are not always as obvious as an Aussie’s susceptibility to allergies and autoimmune diseases or a Rott’s inability to react to early parvo vaccines. Sometimes the effects are quite subtle. The dog may be a “poor keeper” which fails to put on condition with quality feed. Or it may be sickly, never coming down with anything really serious but catching one minor infection after another, or it may be unable to shake an infection in spite of diligent treatment.
Unfortunately, there is no way for a dog breeder to determine what MHC haplotypes his breeding stock have. However, there are several steps a he can take to limit the risk. First, dogs affected with chronic autoimmune disease or severe allergies should not be bred. The sickly and poor keepers should also be removed from breeding programs. When making mate selections, the breeder should avoid crosses that increase the COI above that of the parents and, wherever possible, seek to reduce it. And at all costs, avoid the over-use of any individual dog, no matter how fine a specimen it might be.
While homozygosity of some genes is desirable, particularly those for breed traits like physical type or character, it clearly is not where the MHC is concerned. Most important breed traits are already “fixed.” Given that, breeders must make preventing immune-mediated disease a much higher priority, maintaining MHC heterozygosity through reduced inbreeding and not using individuals with chronically impaired immune systems.