AUTO-IMMUNE
DISEASE IN THE DOG SEMINAR
The seminar held on 22nd October
2000 was sponsored by The Carol Peters’ Memorial Fund and supported by
Southern Beardie Aid and all the UK Bearded Collie clubs. Nearly
200 people attended, representing 36 different breeds. The speakers
were Sara Gould, BvetMED.CertSAM.MRCVS of The Queen’s Veterinary School Hospital,
Cambridge, Dr Richard Dixon, a Veterinary Clinical Pathologist and Dr Jeff
Sampson, Canine Genetics Co-ordinator at The Kennel Club.
SARA GOULD gave a brief overview of the complex immune system of
the dog, outlining the role that cells, hormones, inflammatory mediators
and various other mechanisms play in the correct functioning of the immune
system. A healthy immune system will help the body to fight off disease
and infection, whereas a poor immune system will leave the body vulnerable
to all manner of infections. She then went on to explain that:
The Immune System and Why it Goes Wrong
The immune system’s function is to protect the body from substances such
as antigens. An antigen can be a virus, bacteria, chemicals or neoplastic
cells and is usually foreign to the body. In a healthy immune system,
the B and T cells recognise antigens as alien and mount an immune response.
Antibodies are a special form of B cell. T and B cells maintain
a memory, so if the body is challenged again by the same virus the immune
system can mount a better response. This is the whole basis of vaccination.
There are cells in the T and B cell line that could cause self-antigens to
be formed, but these are usually deleted in early life. However, some
do remain and can become activated later in life, which causes auto-immune
disease, although it is not certain what mechanisms are involved.
In a dog with an auto-immune disease, the immune system fails to discriminate
between foreign antigens and the body’s own healthy cells. The body’s own
proteins, which are found in every body tissue and living cell, may act
as self-antigens, which make them appear foreign, consequently antibodies
are generated which bind themselves to the self-antigens and are removed
from the system, resulting in the immune system destroying its own body.
Hereditary Factors
Auto-immune disease is not common although some breeds of dogs have a
much higher incidence than one would expect within the general dog population.
It seems that certain family lines are more prone to be affected by auto-immune
disease.
The dog’s immune system may be abnormal in a number of ways, which can
result in a variety of auto-immune diseases.
Studies have revealed that the bearded collies in America have 3-4 more
times higher incidence of Addison’s disease than across the general dog population.
This has been observed from the data obtained from surveying the breed.
The scientists and vets are not sure how a genetic pre-disposition subsequently
develops into an auto-immune disease and how this translates into a particular
breed of dog developing the disease. Studying auto-immune disease
in humans has shown that a lack of variation in the major histocompatibility
genes (MHC) makes a person more vulnerable to developing auto-immune disease.
Trigger Factors
It is likely that a number of complex events occur for an animal to develop
an auto-immune disease. A dog may have a genetic susceptibility
but they may then have to come across a number of events or challenges
that progress to an auto-immune disease. Other factors that trigger
auto-immune disease may include age, sex and environmental influences.
Most auto-immune diseases occur in young to middle age and the disease
may be ongoing for several months or even years before clinical signs show.
Also, auto-immune diseases are more prevalent in females.
Research at Cambridge has shown that nearly half the cases of auto-immune
haemolytic anaemia (AIHA) occur in the summer months. Although
this suggests that some environmental influences play a part in auto-immune
diseases, it is not yet clear exactly how or why.
A study of 12 dogs with AIHA was undertaken at Cambridge. 3 out
of the 12 were vaccinated within one month of presenting signs of the disease
and some hadn’t been vaccinated for more than one year, so in some individuals
the onset of this disease may be related to vaccines but in others there
is no vaccine link. A vaccine may be implicated if the animal shows clinical
signs within one month of the vaccination. It is very difficult to prove
conclusively a link between vaccinations and disease, when exposing a dog,
or human, to a virus that they could have come across in the environment
anyway, could trigger a disease.
It is thought that AI disease is increasing, although the problem may
have been there for sometime but with modern, scientific methods veterinarians
are now able to diagnose these diseases more frequently.
Addison’s Disease
Breeds that appear to be predisposed to Addison’s disease are standard
poodles, bearded collies, pointers, and weimaraners, there are probably
others but no statistical evidence is available at the moment. It is frequently
associated with other auto-immune diseases such as hypothyroidism or diabetes.
Addison’s disease is thought to be caused by a gradual, immune mediated
destruction of the adrenal glands. Currently, the veterinary profession lacks
the ability to diagnose Addison’s disease before the adrenal glands are
all but destroyed.
Clinical Signs and Diagnosis
Clinical signs of Addison’s disease are weakness, lethargy, diarrhoea,
vomiting, increased thirst, decrease in appetite and muscle tremor.
These symptoms can wax and wane and sometimes the dog can appear quite
well. Some dogs may exhibit signs of shock or collapse, which is known
as an Addisonian crisis, which is life-threatening.
Blood tests may show elevations in potassium and decrease in sodium and
chloride. About 10% of Addisonian cases do not show these abnormalities.
Renal dysfunction is often developed as a result of dehydration, and
the elevation of potassium causes heart rhythm problems and a very slow
heart beat. Often rapid fluid therapy will re-hydrate the dog and
correct the life threatening problems.
A diagnosis can be reached by assessing the dog’s adrenal response to
a stimulating hormone called ACTH but this can only be achieved after 80%
of the adrenal gland has been destroyed.
Treatment and Prognosis
The treatment is to supplement the hormones that would normally be produced
by the adrenal gland, Florinef (mineralocorticoid) and Prednisolone
(glucocortcoid). Once the treatment has begun, a very rapid recovery
is often seen. The medication has to be given on a daily basis for
the rest of the dog’s life. The prognosis and quality of life
is very good.
Auto-immune Haemolytic Anaemia (AIHA)
Auto-immune haemolytic anaemia is caused by antibodies binding to self-antigens
on the red blood cells, which the body recognises as foreign. This
results in the immune system attacking the red cells, and instead of lasting
90-120 days they are destroyed in a matter of hours. This process
can occur within the circulation of the blood or outside, eg. in the bone
marrow. Breeds that are known to be pre-disposed are cocker and springer
spaniels, OES, Irish setters and bearded collies.
Clinical Signs & Diagnosis
Clinical signs of AIHA are usually weakness and lethargy, but if the
anaemia is coming on gradually the animal may just slow down and not show
obvious signs. The rapid onset of this disease may cause collapse
and sometimes an abnormal appetite, which may show in the dog eating concrete,
stones or soil. Discoloured, (bright orange) urine/faeces is also
common.
Diagnosis is made by clinical examination. Severe anaemia (pale gums)
is usually present, and occasionally jaundice. The Coombs test can
only detect abnormal antibodies on the red cells in the blood. If the red
cell destruction is in the bone marrow, a bone marrow biopsy is necessary
for a correct diagnosis. Of 26 cases of AIHA that were seen at Cambridge
Veterinary School, 18 dogs required blood transfusions. There is a
shortage of donor dogs available to the vets.
Treatment and Prognosis
High doses of immunosuppressive drugs such as Prednisolone or Azathioprin
are used to slow down the rate of red cell destruction.
70% of the dogs treated at Cambridge survive. Dogs that survive
their initial crisis usually do well and most seem to be able to come off
all medication. Some dogs are unable to be ‘weaned off’ of the
treatment, so medication is gradually reduced to the lowest maintenance
dose possible. Unfortunately, about 10% of dogs relapse. Female should
be spayed to prevent a relapse. If it is thought that a vaccine is
implicated, then the recommendation would be that the dog is not vaccinated
again, or perhaps only partially vaccinated.
Immune Mediated Thrombocytopenia (IMTP)
Immune Mediated Thrombocytopenia (IMTP) is very similar to AIHA.
IMTP is when the immune system attacks the blood platelets. Clinical
signs will only show when the platelets have become sufficiently low to
cause bleeding. IMTP can occur in conjunction with AIHA and this is
called Evans syndrome.
Clinical Signs and Diagnosis
Clinical signs are bruising or bleeding, especially from the digestive
tract, which will show dark or black faeces, discoloured urine. The
dog may present anaemia, haemorrhage or collapse. Blood transfusions are
given if the dog is very anaemic. This does not increase the platelet count
but it does buy the dog some time to enable the treatment to work.
Treatment and Prognosis
The same immunosuppressive drugs are used to treat IMTP. The platelet
count needs to be monitored. Most dogs can be weaned off of treatment.
Again, spaying is recommended for females, and if it is thought that a
vaccine was implicated, then it would also be advisable not to vaccinate
again.
The prognosis of IMTP is the same as AIHA, although dogs with Evans syndrome
do have a much poorer prognosis.
Systemic Lupus Erythematosus (SLE)
Systemic lupus erythematosus (SLE) is a rare disease that is often over-diagnosed.
It is a multi-system auto-immune disease. It can involve white and
red cells, the heart muscle or the kidneys.
Clinical Signs and Diagnosis
Depending on what cells are being attacked by the immune system, the
clinical signs are skin lesions, joint problems, anaemia, thrombocytopenia,
or low white cell count.
The symptoms vary from one individual to another. Diagnosis depends on
meeting criteria for certain auto anti-nuclear antibodies within the blood,
and skin biopsies.
Treatment and Prognosis
Immunosuppresive drugs such as prednisolone, azathioprine and cyclophosphamide
are used.
The prognosis is usually poor, despite aggressive steroid therapy, most
dogs die within one year.
Immune Mediated Polyarthritis
Immune mediated polyarthritis is different to developing degenerative
arthritis from wear and tear. This is divided into two categories,
eg. erosive (Rhumatoid arthritis) and non-erosive.
Erosive means that it destroys the joints and bones and causes severe
deformation of the digits. Non-erosive polyarthritis can occur with
SLE complex, poly-myosytis (auto-immune disease of the muscles), sterile
meningitis. The cause is unknown but it is thought that an environmental
trigger is more likely to be responsible.
Clinical Signs and Diagnosis
The signs are lameness or joint swelling. High fever is often present.
In the erosive form, an x-ray of the joint will show changes in the cartilage
and bone. Swelling will be present. In the non-erosive form,
there may not be visible changes but there will be fluid around the joint.
If there are neutrophils in the fluid, this is a sign of an auto-immune
disease.
Treatment and Prognosis
Prednisolone, is usually prescribed for polyarthritis. Rheumatoid arthritis
is more severe and often, a combination of drugs are used, including gold
salts.
The prognosis for polyarthritis is usually good. Dogs can usually
be weaned off of treatment altogether. Occasionally, a relapse will
occur.
Rheumatoid arthritis carries a less favourable prognosis, as nothing
can be done to repair the damage that has already occurred. The progression
of damage to the joints may be able to be controlled but the animal will
still suffer with pain.
Auto-immune Skin Disease
Auto-immune skin disease is probably a lot more common than is thought.
Diseases such as pemphigus and bullous pemphigoid, discoid lupus erythematosus
(DLE) occur as a result of the formation of autoantibodies against the
epidermal.
Clinical Signs and Diagnosis
The type of skin lesions vary, but they are usually severe and cause
the animal some discomfort. Ulcerations, erosions, crusting, lesions,
nail bed infection and the skin around the mouth and vulva can be affected,
and may indicate an auto-immune skin disease.
Auto-immune skin disease is diagnosed by skin biopsies demonstrating
histopathological features.
Treatment & Prognosis
Immunosuppressive drugs such as prednisolone are given and prolonged
use of antibiotics is sometimes necessary. Vitamin E may also be prescribed.
Some dogs respond better than others. Dogs with SLE may not respond as
well as dogs with pemphagoid.
The Future – How We Can Help
The specialists do not know enough about these diseases, as the affected
dogs that they see are invariably, in a late stage of the disease.
If it were possible to see these animals before they develop clinical signs
then the vets may be able to detect them earlier.
.
The Bearded Collie Foundation for Health, in America, is currently looking
into the genes responsible for Addison’s disease. They have discovered
that it is a polygenic disease with a single dominant gene. They are certainly
very close to identifying the dominant gene and hope to have a gene marker
test within 18 months.
A greater understanding is necessary if progress is to be made
in preventing and successfully treating AI disease.
Thyroid Disease and Hypothyroidism in the Dog
DR RICHARD DIXON - Recently awarded a PhD for his research into canine
hypothyroidism.
The Importance of the Thyroid Glands
The thyroid gland is a bean like structure located in the neck of
most mammals. It is usually just behind the larynx. The purpose of
the thyroid is to produce thyroid hormones. The most important one
is thyroxin – otherwise know as T4. The other main hormone is
triiodothyronine abbreviated to T3. The hormone T4, from a diagnostic
point of view, is the most important one.
The thyroid gland produces the hormones which enter the blood, and circulate
throughout all the body tissues. They essentially permeate all body
cells; eg. muscles, skin and the heart, and play a very important roll
in controlling the metabolism. They help maintain body temperature, a healthy
skin, and assist the immune system to fight off infections. They
help the brain to function and maintain alertness, awareness, and energy,
and are essential for life.
What is Thyroid Disease?
Thyroid disease is very common in dogs. There is no age at which thyroiditis
in the dog cannot occur, but it is more commonly seen before 7 years.
Hypothyroidism in the dog is when the thyroid gland slowly disintegrates.
The ability of the thyroid to produce the thyroid hormones progressively
diminishes. When there are not sufficient hormones to keep the animal going,
clinical signs appear.
Disease of the thyroid gland itself is not hypothyroidism. Hypothyroidism
is clinical signs that show when the dog does not produce enough of the
thyroid hormone. Thyroid disintegration can take months, even years,
from the start of the disease process before hypothyroidism becomes apparent.
75% of the thyroid tissue is destroyed before clinical signs occur.
The Clinical Signs
Dermatological signs and hair/coat changes are common signs of hypothyroidism,
also hair loss down the flanks or on the tail. Dandruff is an indication,
also weight gain and lethargy. Affected dogs are prone to skin infections,
intolerant to exercise, and to many owners it looks as if the dog has aged
prematurely. Many have a sad or tragic look on their face.
Neurological, cardiovascular and reproductive abnormalities also occur.
Breeds predisposed to hypothyroidism are spaniels, retrievers, dobermanns,
collies, shelties and boxers, and many others.
Diagnostic Tests
Diagnosing hypothyroidism can be quite difficult. There are a variety
of tests available but none are totally conclusive.
Treatment and Prognosis
The dog has to be given the thyroid hormone (Soloxin) in tablet form,
on a daily basis. Treatment helps 99% of dogs.
The effect of Soloxin can be dramatic. The hair growth is rapid,
often returning to near normal in 7 weeks. The prognosis, once the
dog has started treatment, is excellent.
The Immune System and Thyroid Disease in Dogs
The most commonly recognised cause of hypothyroidism is immune mediated
destruction of the thyroid. When the thyroid is being destroyed in dogs with
lymphocytic thyroiditis, the thyroid becomes damaged and exposed to the
immune system in a way that it wouldn’t normally be. As a consequence, the
immune system fails to recognise the thyroid as a healthy part of the dog’s
own body and produces anti-bodies against the thyroid. These are the
thyroglobulin autoantibodies (TgAb). The presence of TgAb in the blood
is now an accurate way to confirm thyroiditis (before the dog shows signs
of hypothyroidism).
Hereditary and Trigger Factors
The cause of this infiltration of immune mediated cells is unknown. There
is probably a combination of both genetic influences and trigger factors,
which if the predisposed animal is exposed to, will develop thyroiditis.
Some of the trigger factors that may be implicated are: stress,
diet, pregnancy, infectious agents, other hormones, toxins and various components
of the immune system.
To find out what triggers activate this disease, more genetic data is
required. There is a need for dogs to be monitored from when they are perfectly
healthy, following their thyroid status over a period of years, so that the
dogs who ultimately become hypothyroid are fully documented.
Further Implications
Dogs that are predisposed to developing hypothyroidism are more likely
to develop other immune mediated diseases. There are polyglandular
syndromes in dogs whereby the immune mediated destruction, which is damaging
the thyroid tissue, can damage other tissues. The most common combination
found, at the Glasgow Veterinary School, was dogs that had destruction
of pancreatic tissue also became diabetic. In the USA, the most commonly
recognised combination is, dogs that have thyroiditis and Addison’s disease.
There are reports of dogs that have three or four different conditions,
which is difficult to confirm, and is very bad news for the individuals
concerned.
Screening for Thyroiditis
The purpose of a screening programme is to identify apparently healthy
dogs that have thyroiditis, but have not yet shown clinical signs of hypothyroidism.
The PAW screening process uses the thyroglobulin antibody method to confirm
dogs that have thyroiditis. Although it can be predicted that TgAb
positive dogs will become hypothyroid the disease process cannot be stopped.
With regard to thyroid disease alone, the TgAb test gives the breeder
the opportunity to remove affected dogs from the breeding pool, if they feel
it is appropriate.
The test is run in association with your vet and can be performed routinely,
either every couple of years or as a pre mating test, a few months before
you mate your dog. The dog, which you are planning to mate your dog
with, should also be tested.
The scheme is based at Glasgow Veterinary School and the results are
confidential between PAW and yourself. You will receive a certificate if
your dog is clear of thyroiditis.
Thyroiditis can develop at anytime. PAW recommends that a
one off blood sample that shows ‘clear’ is of value at that time, but there
are no guarantees that thyroiditis will not develop at a later date.
It is suggested, that dogs used for breeding should be tested every two
years. Even if your dog is not used for breeding, monitoring its thyroid
status is still important for that dog.
Thyroid Disease – The Future
The diagnosis of hypothyroidism is complicated, but is undoubtedly becoming
more clear. Diagnostic methods are now at a stage whereby the dogs that
are about to become hypothyroid can be monitored, but ultimately there is
a need to reduce the number of dogs that are genetically pre-disposed. The
aim is to reduce the incidence of hypothyroidism; to rapidly achieve an
accurate diagnosis when it does occur, and to accurately predict that a
particular mating would increase the likelihood of producing
hypothyroid offspring, so the breeder can make an informed decision on
whether a mating is appropriate. It can be predicted that over the
next ten years hypothyroidism will be reduced dramatically because of genetic
testing.
Inherited Disease in the Dog and its Control
DR. JEFF SAMPSON spoke about Inherited Disease in the Dog. Dr Sampson
is a Biochemist, and for a number of years has been trying, in collaboration
with colleagues all over the world, to understand more about the genes
of the dog and also, how the genes go wrong in inherited disease and how
best to use this information to produce tests for breeders to use. It is
hoped that the knowledge gained will give breeders a greater understanding
about the genes that their dogs have, and more particularly, what their
dogs are likely to pass on to future generations.
Genes and Chromosomes
There are 370 different conditions in the dog that are known to be inherited
or that inheritance plays a major role.
Genes are simply plans that we inherit from our parents that allow us
to express particular characteristics. We have 50-75,000 different
genes and have two copies of each of them. We share over 90% of our genes
with the dog and the majority are identical to ours. So we are genetically
very like our dogs.
These genes are collected on special structures present on each cell,
called chromosomes. The dog has 39 different sets of chromosomes.
If you could look down the length of a chromosome you would see a lot of
different genes arranged side by side.
Because there are two copies of each gene, there are two copies of each
chromosome. Sex determination is the same in the dog as it is in humans.
Two x chromosomes constitutes a bitch and one x and one y chromosome constitutes
a dog.
Dominant, Recessive and X linked Inheritance
When the plan of the gene changes it does not work properly and this
is called a mutation. A mutation can be dominant or recessive.
If a disease is the result of a dominant mutation then one copy of the gene
is normal and the other is mutant. Because it is a dominant mutation
it overrides the good copy of the gene. To be affected by a dominant
condition, only one dominant mutant gene needs to be inherited.
A recessive mutation is a little more sinister because two copies of
the recessive mutation are needed to produce an affected animal.
One recessive mutation and one normal gene copy means that the dog is clinically
clear and will never get the condition, but it will be a carrier.
These dogs appear perfectly healthy but they carry a mutation in a gene
that has the potential to pass on an inherited disease. If the dog
is unfortunately mated to another carrier then about one quarter of the
offspring will be affected with the disease. The vast majority of inherited
disease in the dog is of the recessive nature, and these are the ones that
are difficult to approach because the only way forward is to have some way
of identifying carriers.
The x linked diseases are due to genes that are present on the x chromosome.
This means that the mother (who is not affected because she has two x chromosomes)
can pass their recessive mutation gene onto their sons because they will
inherit the y chromosome from their father, so they do not have a normal
x linked gene to override the recessive mutant gene. About half of
their sons will be affected with this condition.
Polygenic Inheritance
There is a group of conditions called polygenic conditions. These
have more than one gene involved. An affected individual has to inherit
a number of different mutant genes for them to become affected. Hip dysplasia
is polygenic. Epilepsy and some auto-immune diseases may also be
polygenic.
The Importance of Reliable Data
There is very little reliable data about inherited disease in the dog.
Most of the evidence is anecdotal because a comprehensive health study
into specific breeds has never been undertaken. The Kennel Club has
been encouraging breed clubs to take responsibility for their breed. Breeders
are the ideal people to give the information that is needed to analyse these
diseases and to enable the veterinarians to know more about inherited health
problems.
The Kennel Club sent a questionnaire to all UK breed clubs to ascertain
if they had a committee or anyone who was responsible for health surveillance
in their breed. The survey showed that 80% of breed clubs do not monitor
their breed’s health.
The Responsibility of the Breeder/Breed Clubs
It is important that breeders take more responsibility for discovering
what is going on in their breed. If a wide health survey were undertaken,
some idea of what conditions affect the breed would emerge, and how prevalent
these conditions were. It is important that the breeders/breed clubs/councils,
are able to establish, and prioritise, which conditions are causing most
concern. This is the fundamental information needed in order for breeds
to go forward and address many of these inherited conditions.
Open Registries
There is a lot that the breeder can do to improve the health of future
puppies, open registries are one example. It is very difficult for
a breeder to admit to having bred a puppy with an inherited disease because
of the backlash that may be aimed at them. Perhaps by being open about inherited
diseases, it may become more accepted.
Open registries are incredibly valuable. They can give lists of
affected animals. Most of these dogs will be affected by recessive
genes, so by definition the parents of those animals are ‘carriers’.
To say that known carriers must not be bred from would be detrimental
to the breed. Open registries might be able to identify dogs clear of diseased
genes. The problem is that a carrier cannot be distinguished from
a clear simply by looking at it. ‘Carriers’ and ‘clears’ both appear
clinically clear. However, you may be able to identify the clears by pedigree
analysis. This is particularly useful for stud dogs which may generate
hundreds or even thousands of puppies by being mated to numerous bitches.
By analysing their progeny you can get a fairly good idea as to whether
the stud dog is likely to be a carrier or not. If a dog has mated
many bitches the chances are that one of the bitches would be a carrier.
If an affected puppy is produced then this would show him to be a carrier.
Therefore one can look retrospectively at pedigrees and get an indication
of clear dogs. This is not so easy with bitches as they do not have
so many puppies. With this information, if you have a carrier bitch
and you mated her with a clear dog then you would not produce affecteds.
It is not the ideal scenario but it may be a starting point to limiting the
disease. In the short term, a little bit of thought about breeding
with compatible lines will at least reduce the disease level.
At present, there are screening schemes for HD, OCD (elbows) eye problems
and thyroiditis. These will identify the dogs that are affected.
If you stop breeding from your affecteds, it has a very marked result,
and the overall incidence of the disease falls quite precipitously over
the generations.
The Silent Reservoir – Carriers
Unfortunately, withdrawing affected dogs has much less effect on the
most important population - the carriers. The carrier frequency does
reduce, but not as dramatically as the affecteds. Carriers have a
silent reservoir, and they pass their diseased gene onto half of their
off spring. These carriers are the continuing source of mutant genes within
a population. What is really needed is to identify carriers.
If a litter has one or more puppies that are affected with a disease
known to result from a single recessive mutation, then both parents are
carriers. It has already been stated that when two carriers mate
25% of the litter will be affected. Unfortunately this is only a probability
estimate. So there is a need for identifying the diseased genes.
Identifying Diseased Genes
There are two ways at present of identifying inherited disease in the
dog. The first approach relies on the fact that dogs and humans are genetically
very similar and many of the inherited diseases that affect humans affect
the dog. PRA is an inherited condition that is well known in
dogs. It affects a number of breeds and eventually causes affected
dogs to go blind. It is caused by a single, recessive mutation. Human
beings, and mice, have a similar condition and again it is caused by a single
recessive mutation causing clinically, very similar symptoms. It was
discovered that the degeneration of the retina in the mouse was caused by
the same mutation, in the same place in the gene that caused the corresponding
condition in the human. This was applied to PRA in Irish setters, and
again the same gene was found to be responsible. In conclusion, much benefit
can be gained from studies into the genes of other species.
The Canine Genome
Recently, a map of the canine genome has been discovered. The scientists
are now able to use markers to find their way around the chromosomes and
discover where the diseased genes are located. Pieces of DNA, that
are next to each other on a chromosome, tend to be inherited together.
Blood taken from family members of both affected and unaffected is analysed
to see if the same markers are inherited from the affected dogs, but are
not always there in the DNA from clinically normal dogs. The scientists
are looking for the markers that are always inherited together with the
diseased genes. That is called linkage – the marker is linked to the
diseased gene. Because the scientists now know where each of those
markers come from, they would be able to identify the markers that are linked
to a disease. So in a particular pedigree, those dogs that have this
disease will always have those particular markers, but they are not always
present in the dogs that are clinically clear. Linkage analysis actually
allows the scientist to home in on small chromosome regions. It is
known that there are 50-75 genes in that region, so the search has been narrowed
down considerably when you consider that there are 50-75,000 genes required
to make a dog. This particular analysis not only identifies the mutation,
but it can be the basis to a test for finding the diseased gene, because
wherever the diseased gene is the markers are always with it.
If a dog has two copies of these markers, it is likely to have two copies
of the diseased gene, then it is likely to be an affected. If it
only has one copy of each of the markers, then it will only have one copy
of the diseased gene and one normal copy, which will make it a carrier.
If there are no copies of these markers, then the dog is a clear.
These linkage tests are 99% accurate.
Once the diseased gene has been identified then a DNA test will give
100% accuracy.
If individuals are DNA tested before they are mated, breeders will know
the genetic makeup of their dog, and can avoid mating carriers to carriers.
Mating a carrier to a carrier on average 25% of the offspring will be
genetically clear, 25% clinically affected and 50% carriers.
The Future – DNA Technology
It is predicted that over the next 5 years scientists will know where
every human gene is, and exactly what they do. When a diseased gene for a
particular disease in humans is found, then it will be easy to find that
diseased gene in the dog.
DNA testing is not the be all and end all in breeding. The basic
principles of dog breeding will remain the same. You will decide
which dogs you want to put together to give you good quality puppies of
the right type and temperament. DNA technology is another level of
discrimination. All these tests are going to give added security
that will be able to tell that not only are you producing good specimens
of the breed but that they are also genetically healthy.
Working Together for the Good of the Breed
Once a new DNA test becomes available, and the breed want to develop
a control scheme, the KC and the breeders can discuss the best way to progress
towards eliminating this diseased gene without compromising the gene pool
significantly. To remove all carriers from the word go would be counterproductive.
All breeding stock would be DNA tested so that the breeder was aware of
their dog’s genetic status. If carriers are to be bred from, they should
be mated to a genetically clear dog. Don’t ever mate a carrier to
a carrier. Also progeny from a carrier/clear mating have to
be tested and registered with that result. If the clear puppy from
the litter was not of sufficiently good standard to breed on from, then
repeat matings would be allowed to enable them to keep a ‘clear’ puppy that
was potentially good for breeding.
Recently, the KC and the breeders of the Irish Setter decided that a
period of 5 years was needed to eradicate the inherited disease, CLAD,
by means of a DNA test. A date has been set for 5 years time and no
dog will be registered after that date if it is a carrier of CLAD.
Thereafter, all Irish Setters will have to be DNA tested clear or hereditarily
clear, eg. to have come from parents or grandparents that are clear.
The breed will benefit from the qualities of the carriers but at the same
time the CLAD gene will be slowly removed from the gene pool.
The future programme for healthy dogs, should be a true collaboration
between The Kennel Club, Science and the breed clubs/councils. Working
together allows new research to grow; which will progress to gene based tests
for breeders to use. This will eliminate the disease gene without compromising
the breed as a whole.
In the mean time we can start collecting breed information to identify
the affecteds and to know who their parents are, and use the information
to minimise their future offspring. All the carriers may not be detected,
but maybe fewer affecteds will be produced. When the new DNA tests
are available they can be introduced into the breeding programmes.
At the end of the day it will be our dogs that will benefit because we would
have eliminated the diseased genes.
Some of the Questions Answered by: Sara Gould (SG)
& Richard Dixon (RD)
Q Can vaccinations cause auto-immune disease?
A SG. The diseases that we vaccinate against are not common because
we vaccinate. In the human field, whenever people think that
a disease is not occurring and stop vaccinating, that is when the disease
becomes a problem. What we mustn’t do is to have a knee jerk reaction
and stop vaccinating because many more dogs will die of parvo, leptospirosis
or distemper than would ever die of immune mediated disease. There
are suggestions, however, that perhaps we are over vaccinating. There has
been recent publicity about the human MMR vaccine and perhaps by combining
so many multi-valent vaccines, are we perhaps confusing the immune system
whereby it starts attacking itself? From that point of view, the vaccine
companies now recommend a full booster every two years and a partial booster
every year. So already there is a trend to reduce the frequency of
vaccines. It is known that the immunity for most of the diseases that
we vaccinate against does last a lot longer than a single year.
Addison’s disease and hypothyroidism is diagnosed at the end of the disease
process. The trigger that needs to be identified in these dogs
is the one that started the disease process, which could have been years
before. Any vaccination given just before diagnosis would be unlikely to
have triggered the disease. Once we start diagnosing these dogs in the early
stages, initial trigger factors may become known to us.
If a dog has AIHA or IMTP, and was diagnosed within a month of receiving
a vaccination, we do warn the owner that it may have been the vaccine that
triggered the disease. The animal, however, would have the genetic
susceptibility there in the first place. Vaccination could potentially
cause a relapse in these dogs, so unless their anti-body titres suggest
that they are at significant risk we recommend that the dog is not vaccinated.
Anti-body titres, which show immunity levels to the diseases that we
vaccinate against, can be measured, so there may be no need to vaccinate.
For the vast majority of dogs, vaccination is not a problem, but for some
it maybe. Your dog’s yearly visit to the vet should be for a health check.
A vaccination should only be given if it is appropriate.
There may have been a propensity to over vaccinate both in the human
and veterinary field, but by over vaccinating the vast majority of the
population are protected from potentially fatal diseases, the unfortunate
downside is that a small population of animals are vulnerable to another
set of diseases.
Most boarding kennel owners require dogs to be vaccinated because it
is an environment where disease can occur. If your dog is blood tested
and has shown good protective titres, then certification can be provided
for the kennel.
Q Does the susceptibility of individuals to diseases such as parvo
vary?
A SG Yes. The most at risk are puppies after the maternal antibodies
wane, from 6-7 weeks especially, and older dogs whose immune system may
not be as functional. Also some individuals of middle age may be susceptible,
for example if they have not been vaccinated or have not come across the
virus in their environment, they will be as susceptible as a puppy. If a
dog has been regularly vaccinated for several years then their protective
titres can last for a considerable time. Puppies should definitely
be vaccinated at the right time and probably a booster, but thereafter, many
more people are blood testing first before deciding to vaccinate. If
there are adverse reactions to vaccines then the vet should submit the yellow
form to the vaccine company. The leptospirosis vaccine is a killed
vaccine and it doesn’t last as long as the other vaccines. Those dogs
at high risk, eg. that go out a lot or live near water pools, should be vaccinated
at least, annually. If the other protective titre levels are good then
a vaccination for leptospirosis only, can be given.
Q Do the titre levels in a dog change?
A SG Yes, titre levels do change. Titre levels can fall, but they
can also increase when the animal is exposed naturally to the virus, within
its own environment. Levels should be tested annually to ensure that
the dog has adequate protection.
Q Should a bitch with nail bed infection be bred from?
A SG It very much depends on what is causing the nail bed infection.
It could be fungal or bacterial, if it is auto-immune, then probably not,
but it would need to be definitively diagnosed. Auto-immune nail bed infection
would need to be diagnosed by performing a biopsy.
Q Should a dog with thyroiditis be treated before hypothyroidism develops?
A RD If the dog doesn’t have any clinical signs, then it is very
hard to treat, because any clinical improvement that medication could make,
when to all intents and purposes the dog is clinically normal, wouldn’t
be recognised. I would not suggest that the dog is put on thyroid replacement
therapy. If a dog has thyroiditis then it needs to be monitored very
closely until clinical signs develop. At the moment I don’t think
there is any justification in treating dogs until they have developed a
clinical problem. Medication will not alter the progression of the disease.
Q What are the side effects of prednisolone?
A SG Typical side effects are increased thirst, increased urination,
increase in appetite and muscle weakness. It can also have side effects
on the liver. Some dogs tolerate prednisolone better than others.
Once the dog has stabilised they will be gradually weaned off. This will
usually take about two months. Dogs that are unable to be weaned off
are usually put on every other day therapy to minimise the side effects.
NOTE
CIMDA is pleased to offer support to owners who have dogs with AI disease.
CIMDA (Canine Immune Mediated Disease Awareness), 73, Osidge Lane,
Southgate, London N14 5JL.. Tel: 020 8368 9148 : email:
jo@cimda.fsnet.co.uk
reprinted with kind permission from Josephine Tucker
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