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GENETICS AND BREEDING STRATEGIES: Essays for the Dog Breeder

copyright © 2009 by Dr Susan Thorpe-Vargus

Chapter 6: CANCER, IMMUNE PROBLEMS AND VACCINATIONS

According to the AKC figures, the incidence of cancer in the purebred dog is epidemic. Why is this so? Due to advances in veterinary healthcare, many dogs are living to an age where cancer is more likely to appear. We are also living in a polluted environment. Our canine companions are at an even higher risk for exposure to environmental toxins. Not only do some of us load our dogs up with flea and tick collars and dips, but their grooming habits make it much more likely they will ingest pesticides and other chemical carcinogens. One ubiquitous carcinogen is found in the outgassing of asphalt on hot days. It is also seen in meat that has been charcoal broiled. The chemical name for this substance is benzo [o] pyrene, and dogs simply crossing the street can get it on their paws and later lick it off. This chemical does its dirty work by causing missense mutations, a type of mutation that causes the replacement of a different amino acid in a protein and that can result in cancer.

At a recent conference, hosted in part by the AKC, it was revealed that cancer is the leading cause of death in dogs, after euthanasia. Lymphomas are the most common cancer found in canines, comprising about 20% of all malignancies. In humans, this type of cancer has been associated with chromosomal anomalies, it is most likely that this will prove to be true for dogs as well. What must be emphasized is that all cancers have a genetic component. We know that there are familial and breed related cancers and that only emphasizes the genetic aspects of the disease. Identification of affected families within the canine population may lead to the discovery of cancer susceptibility genes. It is no surprise to learn that those breeds with very small foundation numbers and those breeds with an overabundance of popular sires are those most valuable for this study.

THE GENETICS OF CANCER

Two classes of genes are suspected of being involved in the occurrence of cancer when they are mutated: Tumor-suppressing genes and proto-oncogenes, genes that function to encourage and promote normal growth and division of cells. The progression of tumor growth correlates with mutations that activate oncogenes (mutated proto-oncogenes) and render tumor-suppressor genes inactive. These mutations somehow “uncouple” the same mechanisms that allow normal cell division. What is so frustrating for both researchers and clinicians alike is that different combinations of mutations are found in different types of cancer and even in cancers of supposedly the same type in different patients. This reflects the random nature of these mutations.

Cancers caused by these loss-of-function mutations are more likely to be inherited. Parents that pass on a mutation in one copy of the gene produce offspring with a predisposition for cancer in that the disease requires only one mutation in the remaining “good” copy of the gene to be expressed.

Another familial type of cancer predisposition would be those that involve DNA repair. The body has mechanisms in place to detect errors in duplicated DNA. If mutations occur in the genes that code for the proteins responsible for this repair process, bad copies of the cellular DNA will accumulate. The initiation of cancer requires multiple events, which is perhaps one of the reasons cancer is seen more often as we age. The first mutation that is not repaired is thus inherited by any subsequent daughter cells. Cells thus affected do not undergo apoptosis--cellular suicide--and are rendered immortal. (both definitions are fine) Even though immortalization is not the same as carcinogenisis, which is the generation of cancer from normal cells, most transformed cell lines do not die after their normal number of cell divisions. This is a requirement for the further development of malignancies.

There appear to be several stages in the development of tumors. First, there is an initiation phase, in which an optimum or threshold level of mutations occurs and “tips the scales” toward tumor genesis. Once the cell has been transformed, there is a latent stage, in which mutations that have a selection advantage start to proliferate. During the clinical phase, the tumor becomes large enough to induce symptoms. These symptoms are caused by tissue destruction, or the production of soluble factors that can be detected in the blood or the tumor can depress vital functions and act as a space-occupying lesion in a confined anatomical space.

GENETIC MISTAKES INITIATE CANCER

Since apoptosis is also under genetic control, it is not surprising that many of the proto-oncogenes and tumor-suppressor genes altered during apoptosis are those genes involved with cell death. Many proto-oncogenes code for proteins involved in mechanisms that regulate the social behavior of cells. Signals from those cells in the immediate environment induce their neighbors to divide, differentiate and even undergo apoptosis. It also appears that both types of genes are involved with or expressed during the control points of the cell cycle. Human cancer studies show that mutations in the tumor suppressor gene called p53 account for many tumors. One of the functions of this gene is that it normally prevents cells with damaged DNA from proceeding through the cell cycle. The presence of the protein product encoded by p53 induces the expression of the waf-1 gene. The waf-1 gene produces a protein that normally inhibits the activity of several similar cellular proteins called kinases (enzymes that catalyze the conversion of proenzymes to active enzymes) that are involved in stopping cell cycle progression. A mutation in either the p53 or waf-1 gene sometimes can cause the loss of that “emergency brake” function and allow uncontrolled growth. One recent study has linked a case of benign canine melanoma to loss of this function. However, loss of apoptosis isn’t the only culprit that causes cancer.

Many types of genetic mishaps can occur and can lead to disease. The basic types of genetic accidents include point mutations, deletions and chromosomal translocations mentioned earlier. The insertion of mobile genetic elements such as transposons--segments of DNA that are capable of moving to a new position within the same or another chromosome--or retroviral DNA-- retroviruses are potent disease agents with the capability of incorporating their DNA into the host cell’s DNA--into the cell’s genetic material are two other types of mutations.

Malignant transformations occur for a variety of reasons. Oncogenes, exposure to chemical carcinogens and ionizing radiation such as X-rays all play a role in inducing neoplasias. We even can “catch” cancer. In a number of species, although not yet demonstrated in dogs, retroviruses have been proved to be the cause of a variety of different diseases, including cancer.

A virus does not have the ability to reproduce itself but instead hijacks the host cell’s reproductive capability by inserting its own DNA into the genome of the cell it has infected. It then forces that cell to produce the proteins it needs. This can cause something called an insertional mutation. Depending on where it inserts its viral DNA, the mutation can wreak havoc in a variety of ways. The result of these genetic accidents can alter the gene sequence so that it produces a protein with abnormal activity or even no activity at all.

FREE RADICALS CAN ATTACK DNA

Outside influences also can lead to mutations and changes in cellular genetics. Because we breathe an atmosphere that contains oxygen and we digest food, our bodies are constantly producing free radicals--highly reactive oxygen molecules that occur naturally in the body because of metabolic processes. Environmental factors such as air pollution, radiation, pesticides, herbicides, many drugs and cigarette smoke react within the body to cause free radical production. These molecules can damage DNA, affect the structure and function of cell membranes and damage certain regions of proteins that have enzymatic functions. Older humans and animals are more at risk due in part to increased levels of free radicals as well as an impaired ability of the immune system to eliminate altered cells. Very inbred dogs also have weakened immune function. http://cc.ysu.edu/~helorime/inbrimmune.html

AUTOIMMUNITY & VACCINATIONS

Autoimmune disease is genetic but like many other polygenic diseases, there is an environmental component. In the case of thyroiditis and diabetes, there is an established link to environmental triggers. Why are we seeing a rise in such diseases in the purebred dog? One could suggest it might be poor and outmoded breeding practices, i.e, inbreeding referred to as line breeding by many dog breeders. The portion of the genome that codes for the genes that help us recognize “self” is called the MHC--the Major Histocompatability Complex. These genes are located very close to each other and therefore it is very rare for recombination to occur. This in effect means that the genes from each parent are inherited intact as haplotypes. If the parents are closely related, then the possibility exists that they share the same genes at that site, i.e., they are homozygous by decent. This essentially cuts the functionality of the immune response in half- not a good thing. Normally, autoimmune diseases can be separated into diseases that are “organ-specific” and “systemic” categories. For instance, an organ specific example would be Graves’ disease that is characterized by the production of antibodies to the thyroid-stimulating hormone (TSH) receptor in the thyroid gland. In the case of Hashimoto’s, thyroiditis antibodies are formed against thyroid peroxidase; and in type I diabetes (the type most often seen in dogs) by anti-insulin antibodies. An example of a systemic autoimmune disease would be SLE (systemic lupus erythematosus). It also appears that some individuals are more at risk than others of developing particular diseases. As mentioned before, susceptibility to autoimmune disease is controlled by environmental and genetic factors, especially MHC genes. Results from both twin and family studies show an important role for both inherited and environmental factors in the induction of autoimmune disease. In addition to this evidence from humans, certain inbred mouse strains have an almost uniform susceptibility to particular spontaneous or experimentally induced autoimmune diseases, whereas other strains do not. These findings have led to an extensive search for genes that determine susceptibility to autoimmune disease.

One way of determining this in humans is to study the families of affected patients; it has been shown that two siblings affected with the same autoimmune disease are far more likely than expected to share the same MHC haplotypes. The more closely related two individuals are, the more likely that they share the same haplotype. The association of MHC genotype with autoimmune disease is not surprising, because autoimmune responses involve T cells, and the ability of T cells to respond to a particular antigen depends on MHC genotype. It appears that susceptibility to an autoimmune disease is determined by differences in the ability of variations of the MHC haplotypes to present various proteins that mimic ”self” to those T cells that react to them. Inbred animals have fewer allelic variants. An alternative hypothesis for the association between MHC genotype and susceptibility to autoimmune diseases emphasizes the role of MHC alleles in controlling the variety of T-cell receptors. This lack of diversity means that developing and immature immune cells that are specific for particular self-antigens are not selected against and so are allowed to reproduce themselves.

However, MHC genotype alone does not determine genetic susceptibility to disease. Identical twins, sharing all of their genes, are far more likely to develop the same autoimmune disease than MHC-identical siblings, demonstrating that genetic factors, other than the MHC also affects whether an individual develops disease. One of these genetic factors would be B or T cell immunodeficiencies. Symptoms of this condition include eczema, dermatitis, heart disease, inhalant and food allergies and neurological disease. These conditions are often seen in the purebred dog.

This however begs the question as to why we are seeing a rise in autoimmunity associated with vaccinations. J Autoimmun. 2000 Feb;14(1):1-10.   Vaccination and autoimmunity-'vaccinosis': a dangerous liaison?Shoenfeld Y, Aron-Maor A. The whole duration of immunity and the timing and necessity for various vaccinations are being questioned. Many veterinary training schools are changing their recommended vaccination protocols. The practice of annual vaccinations lacks scientific validity or verification. There is no immunological requirement for annual vaccinations. The practice of annual vaccinations should be considered of questionable efficacy. Instead, clinicians, in the absence of legal requirements, should educate their clients that an annual physical examination is the better option.

ALTERNATIVES TO VACCINATIONS

Monitoring Serum Antibody Titers As mentioned before, one of the “unknowns” with animal vaccinations is the duration of immunity. What this means is that the pharmaceutical companies have not determined how long a vaccination will protect against infection. One way to find out if an animal is still protected is to measure the amount or level of antibodies to a particular antigen is still present in the blood serum. This is called titering. Once an animal has been exposed to a particular disease pathogen the body makes antibodies against that organism. After they have done their “job”, some of those antibodies change and become dormant so that the next time the animal is exposed to that same pathogen there is a stockpile of clones that can jump in and fight off that same infection. It is these antibodies that are being measured when an animal is titered. One point to consider is that titer levels do not really reflect the ability of an animal to fight of an infection, but rather how recently they have been “challenged” or exposed to that infectious agent. What this means is that the dog that stays at home and is never around other dogs is more at risk than those that have an active social life.

New Vaccination Protocols

1. Colorado State University
2. University of California, Davis
3. University of Florida
4. Washington State University

Recent research may have uncovered the link between vaccinations and autoimmunity. Most autoimmune disorders appear to be triggered by some type of toxic assault or a viral or bacterial exposure. Why is this important? Preliminary studies have shown that something called molecular or antigenic mimicry may be involved. This intriguing model argues that the body is reacting to small protein-like fragments of the pathogen that are homologous to normal cellular components. If true, this would be a form of antigen or molecular mimicry in which antibodies formed against one molecule react with another similar looking molecule. Another factor to consider is illustrated in a recent study that showed that contaminants (specifically bovine thyroglobulin in rabies vaccine) that remain from growth of the cells in culture during vaccine production cause the dog to make antibodies against these contaminants. Since the bovine thyroglobulin molecule is very similar to the dog's own thyroglobulin, the antibodies produced against the bovine thyroglobulin cross-react with the dog’s thyroglobulin. This could explain why so many dogs have thyroiditis characterized by high levels of antithryoglobulin antibody in their serum. This may in turn, explain why we currently have an epidemic of hypothyroidism in dogs in the United States.

Vaccination Take Home Message

Vaccination should only be given at age appropriate times – the most common reason for vaccine failure is maternal antibody interactions.

1. Never vaccinate a dog that is ill or malnourished (the second most common reason for vaccine failure is nutritional deficits).
2. Only vaccinate for the:
1. “core” diseases like distemper and parvo,
2. those diseases appropriate for your dog’s environment and
3. those mandated by law.
3. Follow the new guidelines for frequency of vaccinations and suggested combinations of vaccines.

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