Excerpts from:

The Rising Storm: What Breeders Need to Know about the Immune System

by C.A. Sharp

The immune system is governed by the Major Histocompatability Complex (MHC). This group of genes is referred to as a “complex” because they are all positioned close together on one chromosome. This positioning virtually guarantees that the genes will be inherited as a unit called a haplotype. The haplotype will be passed to offspring without the usual shuffling that occurs as genes are distributed into sperm or eggs. Every individual possesses two MHC haplotypes, one inherited from each parent.

The MHC enables the immune system to respond appropriately to the intrusion of infectious agents, like viruses or bacteria. It is not unique to dogs, but exists in all species of mammals. Genes within the MHC are unusual in that they are highly polymorphic, each having many—sometimes as many as 100—different alleles, or forms. There are so many alleles it is probable that most individuals in a randomly breeding population, such as wild species, will have unique combinations of MHC genes. It is this very lack of similarity that leads to graft-vs.-host disease in transplant patients and why full siblings make the best transplant donors.

MHC genes also have the highest mutation rate of genes for any germ-line cell. Germ line cells are those that ultimately produce sperm or eggs. 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. Such extreme polymorphism is unusual. 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 do we see all this complexity with the MHC? It is Nature’s answer to the problem of infectious disease. The immune system must be prepared to tackle many different infectious agents. A mere handful of alleles would not allow the necessary flexibility to face down an ever-evolving array of pathogens. In most cases, each haplotype a dog has will differ from the other, thus increasing its odds of having something in its immune arsenal that will work against whatever nasty bug it may encounter. 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. While each individual has only two 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) pairs 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.

Survivors of epidemics have the “right” combination of MHC alleles to combat that particular infectious disease. The same plague may occur again and again, but as time goes by it becomes less virulent because those with inadequate MHCs will have died and been removed from the breeding population. The high 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. All naturally reproducing species will avoid or significantly limit inbreeding. (For the purposes of this article, the term inbreeding includes what dog breeders refer to as linebreeding.) 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. In an inbred individual, the chance that both parents have passed on identical genes within the MHC increases. This situation diminishes the body’s capability to mount an effective immune response. Such dogs are more prone to infections and are more likely to suffer autoimmune disease or allergies.

The Genetic Problem
The over-all canine gene pool probably contains as much MHC diversity as it ever did. 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.

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. The cheetah provides an example from nature. This wild cat species went through an extreme genetic bottleneck sometime in the last ice age. All modern cheetahs are descended from a very few individuals, possibly from a single pregnant female. Thanks to Nature’s harsh culling practices—far more stringent than those applied by any dog breeder—the cheetah has survived, but even so it is extremely susceptible to some kinds of disease.

But purebred dog breeds 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 population may not be able to respond effectively to the next canine plague that comes along. Nor may they be able to effectively utilize vaccines. Rottweilers, for example, responded poorly to early parvo vaccines. This often left them vulnerable to the disease if they encountered it. 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, the parvo vaccines did not work because the body couldn’t react to it and thereby protect itself from the disease. Fortunately, the newest generation of vaccines seems to be much more effective in this breed.

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 which do not lend themselves to quantification (behavior, temperament, performance drives, etc.)

The practice of inbreeding to improve breed traits has inadvertently led 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, combined with the extensive use of popular sires, MHC diversity may be lowered to critical levels.

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 autoimmune disease can be seriously affected.

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.
 

What to do?
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”—one doesn’t see a purebred Aussie that looks like a Chinese Crested or trails with the obsession of a Bloodhound. Aussies look and act like Aussies, however much we quibble over the fine points. Given that, breeders must give the prevention of immune-mediated disease a much higher priority, maintaining MHC heterozygosity through reduced inbreeding and not using individuals with chronically impaired immune systems

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 of producing dogs with immune-mediated disease.

First, no dog affected with chronic autoimmune disease or serious allergies should be bred. If an animal is being maintained successfully on medication, the breeder should not delude himself that it is “cured” and the disease is not a problem. The sickly and poor keepers should also be removed from breeding programs. At all costs, avoid the over-use of any individual dog, no matter how fine a specimen it might be.

When making breeding decisions, the breeder should avoid crosses that increase the COI above that of the parents and, wherever possible, seek to reduce it. Breeders should be aware of their dogs’ COIs. To detect inbreeding that is not apparent in the common three to five generation written pedigrees, the COI should be calculated over several more generations. How many generations depends on the genetic history of the breed, but for most, including Aussies, ten will be adequate. If the COI is high (12.5% or more), mates should be selected which will give a COI in the puppies that is lower than that of the parent with the family history of immune-mediated disease. No matter what the COI, any dog from a family with these diseases should be bred to mates whose families do not.

Neither parents, siblings nor 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 disease. Breeding pairs should be selected that produce puppies with a lower COI than that of the parent from the autoimmune affected family. This will 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 an individual dog has produced multiple cases of autoimmune disease or allergies, especially in different and relatively unrelated mates, serious consideration should be given to withholding it from further breeding. Crosses that produce autoimmune disease or allergies should never be repeated.

If there is significant risk that a particular dog may develop autoimmune disease or allergy, as is the case with the siblings or offspring of one already affected, it would be wise to hold off breeding that dog until it is 3 or 4 years old to be reasonably assured it will not develop disease.

As with any inherited problem, breeders would do well to record as much information as possible on the allergy and autoimmune disease status of numerous relatives of the dogs they intend to use for breeding. This includes “his sisters and his cousins and his aunts”—those dogs not directly on the pedigree. The more affected family members a dog has, the more likely it is to develop allergies or produce young who will. If screening tests are available for a disease that is frequently encountered, such as thyroiditis they should be used, as should screening tests for diseases that have occurred in a dog’s family.

It is up to us
The storm is upon us and will not soon dissipate. Due to the complex nature of immune-mediated disease, its total eradication is unlikely the foreseeable future. Potential impact on breed health is great. Even though we lack the ability to eliminate this kind of disease, damage control must be instituted. We can shelter our dogs from this rising storm if we commit to working within our own breeding programs and in cooperation with fellow breeders to make that reduction a priority. While no breeder can guarantee he will not produce a dog affected with immune-mediated disease, with good record keeping, diligence and foresight the risk of producing these costly, potentially devastating, and sometimes-fatal diseases can be significantly reduced.