1. What is an autoimmune disease?
When a body encounters something
foreign in its environment it needs to be able to mount an immune response
against that substance to protect itself from potential harm. In order to
do this effectively it must be able to recognise what is self in order to
respond to non-self or foreign. In autoimmune diseases there is a failure
to recognise some part of self. Such autoimmunity may be restricted to a
single organ, a localized region or the whole animal. The consequences may
vary from minimal to catastrophic, depending on the extent to which the
body is affected. In autoimmune disease pathologic signs are seen as a
result of the autoimmune response. Frequently more than one autoimmune
disease will be seen in the same animal, as well as an increased
susceptibility to bacterial infection. There are four basic mechanisms
underlying autoimmune disease:
1. Antibody mediated diseases: a specific antibody exists
targeted against a particular antigen (protein) which leads to its
destruction and signs of the disease. Examples are: auto-immune mediated
hemolytic anemia, where the target is on the surface of the red blood
cell; myesthenia gravis where the target is the acetylcholine receptor in
the neuromuscular junction; hypoadrenocorticism (Addisons) where the
targets are the cells of the adrenal gland.
2. Immune-complex-mediated diseases: antibodies are produced
against proteins in the body, these combine into large molecules which
circulate around the body. In systemmic lupus erythematosus (SLE)
antibodies are formed against several components in the cells nucleus
(hence the anti-nuclear antibody test (ANA) for SLE). Most notably
antibodies are made against the bodys double stranded DNA, and form
circulating soluble complexes of DNA and antibody, which break down in
skin causing an increased sensitivity to ultraviolet light and a variety
of signs. As the blood is filtered through the kidneys the complexes are
trapped in the glomeruli and blood vessels, causing the kidney to leak
protein - glomerulonephritis. They also cause leakage in other blood
vessels, and there may be hemorrhaging, as well as accumulating in
synovial fluid and causing signs of arthritis and joint pain. Rheumatoid
arthritis results from immune complexes (IgM class antibody called
rheumatoid factor) against part of the animals own immune system (part
of its IgG molecules). These form complexes which are deposited in the
synovia of the joint spaces causing an inflammatory response, joint
swelling and pain. The collagen and cartilage of the joint breaks down and
is eventually replaced by fibrin which fuses the joints - ankylosis.
3. Antibody and T Cell-mediated diseases: T cells are one of two
types (the other being B-cells) which mediate immune reactions. Upon
exposure to a particular antigen they become programmed to search for and
destroy that particular protein in future. Once an animal has been exposed
to an antigen it will be able to mount a much faster response to it the
next time it encounters it. This is the basis of vaccination. Thyroiditis
(autoimmune hypothyroidism) seems to be of mixed etiology. Several target
antigens have been identified, including thyroglobulin the major hormone
made by the thyroid. Autoantibodies to antigens in the epithelial cells of
the thyroid have also been found. The thyroid becomes invaded by large
numbers of T and B cells as well as macrophages which are cells that
engulf and destroy other cell types. T cells specifically programmed for
thyroglobulin have been identified.
4. Diseases arising from a deficiency in complement: When an
antigen and antibody react they may activate a series of serum enzymes
(the complement system) whose end result is either the lysis (breakup) of
the antigen molecule or to make it easier for phagocytic cells like the
macrophages to destroy it. Animals with deficiencies in enzymes activated
early in the complement system develop autoimmune diseases like SLE.
2. Which diseases are there?
Those diseases of greatest concern in the bearded collie are:
Auto-immune mediated anemia (AIMA) also called autoimmune hemolytic
anemia (AIHA) and immune mediated hemolytic anemia (IMHA): antibodies
formed against antigens in the red blood cell membrane cause these cells
to burst open. The resulting anemia compromises the dogs ability to
provide sufficient oxygen for cell function throughout the body.
Immune-mediated thrombocytopenia (ITP): a dangerously low level of
platelets - either due to an increase in antibody and complement-mediated
phagocytosis of platelets in the spleen, bone marrow and liver, or
decreased production due to antibody and/or complement mediated
phagocytosis of platelet stem cells (megakaryocytes) in the bone marrow.
The low platelet levels lead to spontaneour bleeding, often nose bleeds or
petechiation (bleeding just under the skin and mucous membranes) are seen.
Blood in the stool, urine or vomit is less common. (Often seen with AIHA,
SLE and RA.)
Autoimmune thyroiditis (hypothyroidism) is generally found with the
other autoimmune diseases or may occur by itself. Loss of thyroid hormones
is manifested early by behavioral changes - aggression, hyperactivity,
anxiety/fear, compulsive behaviors, phobic behaviors; allergies and
reduced resistance to bacterial, viral, fungal and protozoal infection -
often manifest as skin and respiratory disorders. Seizure disorders are
also often related to low thyroid levels. As the disease progresses
lethargy, obesity, alopecia (loss of hair/poor haircoat especially on the
sides) and infertility are more common.
Hypoadrenocorticism (Addisons disease): The adrenal gland produces
hormones which regulate the level of sodium and potassium (mineralocorticoids)
and mediate the bodys response to physiologic and psychologic stress (corticosteroids).
The former are needed to maintain proper cell function, their loss is seen
as muscle weakness and eventually heart failure as the hearts muscle
cells can no longer produce the nervous impulses needed for the heart to
contract. Gastrointestinal function is also usually impaired, and weight
loss is frequently seen. Animals are less able to cope with mild, everyday
occurences and hide, refuse to eat and show other symptoms of stress.
SLE: Known as the great imitator can be hard to diagnose as it can
manifest as a disease of the skin/mucous membranes/nails, kidney and/or
joints as has already been described. SLE can also affect the brain
producing signs of cognitive dysfunction. It is also hard to diagnose
definitively as not all dogs with SLE have postive ANA titers.
Pemphigus folliaceus is a skin disease in which pustules are formed. In
beardies they seem to be more common on the feet, but can be restricted to
the face or appear patchily all over the dog. After the pustules burst the
skin appears crusty or scaly and loses its hair. The dog may chew on or
scratch the lesions increasing the damage and ulcers and serious skin
erosion may result. Although the antigen has not been specifically
identified, pemphigus is a result of autoantibodies directed against the
cell membrane of epithelial cells, causing them to become round and
separate instead of forming a solid sheet.
Rheumatoid Arthritis (RA) was described above.
Myasthenia gravis results in a loss of muscle function because nerve
signals are no longer received by the muscles. The dog loses muscle mass,
due to disuse, and becomes weak and reluctant to move. Enlargement of the
esophagus (megaesophagus) may result. This is often seen as regurgitation
of food as soon as it is swallowed, and frequently results in aspiration
of food into the lungs. Even when treated, dogs are liable to die of
aspiration pneumonia due to megaesophagus. Untreated dogs eventually lose
the use of swallowing and respiratory muscles.
Autoimune myositis is usually divided between polymyositis and
masticatory muscle myositis. In the former there is often generalized
weakness made worse by exercise. Most frequently the muscles over the top
of the head waste away. Fever and depression are common as is
megaesophagus. Concomittant SLE, RA and myasthenia gravis have been
reported. Masticatory muscle myositis, as the name implies, is limited to
the chewing muscles, antibodies are formed to a particular type of muscle
Inflammatory Bowel Disease (IBD) is neither a specific disease nor is
it clearly an autoimmune disease. In general, it is a catch-all for
animals with excessive numbers of inflammatory cells in the mucosa of the
stomach, small and/or large intestine for which no other cause can be
found and which result in vomitting and/or diarrhea. Although
autoantibodies have been found, it is likely that these have been formed
secondary to the initiating factor which exposed previously hidden
antigens by increasing the permeability of the g/i mucosa.
3. What causes autoimmune diseases?
Genetic: It has been shown in humans that particular major
histocompatibility complex (MHC) genes are associated with the incidence
of specific autoimmune diseases. MHC genes are present in all vertebrates,
and are unusual in that they are inherited as a unit, they encode for two
major categories of molecules that form part of cell membranes and cross
the entire membrane. In particular they have a role in selecting the
antigens recognised by T-cells.
An analysis of the pedigrees received of beardies affected by
hypoadrenocorticism in the last survey by the BCCA suggests that this
disease is caused by an autosomal recessive gene with incomplete
penetrance. A study, funded in part by donations from the BCCA, is being
sponsored by AKC-CHF. The researchers hope to identify a gene or genes at
one or more loci which correlate with hypoadrenocorticism. To date they
have received blood samples and pedigrees from well over 100 beardies
which are either affected with the disease or closely related to affected
dogs. Other breed clubs are now becoming involved in the project. Clearly
a blood test for the disease would enable us to reduce the incidence
Analysis of pedigrees from an extremely large population of Old English
sheepdogs and smaller populations of other breeds, has shown that (almost)
all cases of autoimmune disease occur in particular blood lines.
Vaccinosis reactions occur in the same blood lines. However, it is equally
clear that not all dogs within these groups will develop an autoimmune
disease, the majority will live normal, healthy lives, although some may
have sub-clinical autoimmune disorders.
Conclusion: It seems likely that a dog must have a genetic tendency in
order to develop an autoimmune disease. However, for overt disease to
manifest itself specific insults to the animals immune system must also
Other factors: We are gradually piecing together some of the
factors which can influence whether a dog will develop an autoimmune
disease. The health of its immune system in general seems to be a major
factor. Dogs are at far more risk when they are already stressed by
disease. For this reason it is imperative that we do not further stress a
sick dog by vaccinating it (more on this in the other talk). The reported
incidence of autoimmune disease is on the rise, and there is some debate
as to whether this is because it is really more common or because we are
better at detecting it. I believe that both factors are probably involved.
A couple of recent papers suggest that both an increase in pollution
and an increase in sanitation could be problematic.
Study 1: Over the last 25 years or more we have received (as have our
dogs) small daily doses of insecticides, weed killers and artificial
fertilizers in our drinking and bath water. Levels tend to be higher in
rural areas where wells are the water source. Most commonly found are
carbamate insecticides and triazine herbicides. The government in its
wisdom has looked at the effect (mostly looking for cancer) of each
chemical individually at low levels when given to lab rodents, and deemed
the levels in groundwater "safe". For the last five years a
group in Wisconsin have fed cocktails of these contaminants as they are
typically found in tap water to male mice via their drinking water. They
report a measurable effect on nervous, immune and endocrine systems.
Specifically they found the mice less able to mount an antibody response
to foreign proteins, increased or reduced levels of thyroid hormones
(depending on the mixture) and an increase in aggressive behavior. (They
only measured these 3 parameters so other effects on the body were not
tested for.) These results were found if the mice received mixtures but
not individual chemicals at these low levels. A study of 4 and 5 year old,
lowland living children in Mexico exposed to pesticides compared to a
highland group living where there is no pesticide use found increased
aggression, reduced stamina and impaired cognitive ability in the former
group - all symptoms of hypothyroidism although thyroid levels were not
measured in these groups. How about the pesticides we put on our dogs for
fleas and ticks, or the lawn and other garden chemicals?
Study 2: A recent article in New Scientist reports a small study from
the University of Iowa looking at IBD. It was noted by the group that the
reported incidence of IBD correlated with the elimination of intestinal
worms. They gave 6 people with chronic IBD a drink with eggs from
intestinal worms that dont normally affect people. Five went into
complete remission. A larger study is planned. Throughout history until
very recently our immune system has been used to the presence of worms in
the g/i tract, it seems their removal may have caused the immune system to
go into overdrive. It also makes me wonder about the effect of monthly
worming our dogs.
A number of drugs have been associated with the onset of autoimmune
disease these include but are not limited to: trimethoprim-sulfas (e.g
Tribrissen, antibiotics); nitrofurantoin (eg Macrodantin, antibiotic);
carprofen (Rimadyl - NSAID); phenylbutazone (eg Butazolidin, NSAID);
phenobarbital (anti seizure and sedative); primidone (eg Neurosyn,
anti-seizure); diethycarbamazine-oxybendazole (combination only, eg
Filaribits Plus, heartworm preventative with vermicide), milbemycin oxime
(eg Interceptor, heartworm preventative) and ivermectin (eg Heartguard,
heartworm preventative); auranofin/aurothioglucose (Ridaura/Solganal, gold
compound for arthritis and pemphigus). Stress is important, whether it is
environmental, psychological or physiological. Pregnancy is a stress, as
is lactation. Reproductive abnormalities may point to an underlying
autoimmune problem or prime the dogs immune system so that it is more
susceptible to other stresses. The same is true of many diseases - viral
diseases, lymphoma and bone marrow problems as well as failure of immunity
seem to be particularly dangerous, however. Food can also be a source of
chemicals which have been implicated in the acquisition of autoimmune
disease. Processing resulting in the loss of protective agents from the
diet as well, may also be a contributing factor.
Clearly we cannot protect our dogs - or ourselves - from all potential
risk factors, not least because there are still so many which have yet to
be identified. Running a complete thyroid panel every year or two on all
dogs used for breeding is at present still our best defense. However, we
should be careful to not stress our dogs immune systems. Never
vaccinate sick animals - or stress them unnecessarily. Dont worm and
vaccinate at the same time, avoid multivalent vaccines. At the same time
dont stress yourself by worrying about things over which you have no
control. It is important to remember that beardies are still one of the
healthier breeds. In any attempt to reduce the incidence of one problem
whether it is poor tail set, bad bites or autoimmune disease we must avoid
throwing out the baby with the bathwater, and maintain the loveable,
outgoing breed which has been entrusted to our stewardship.
Copyright © 1999 [ Linda Aronson DVM].
Author's note (January 2009):
They have done further research to confirm the initial report on IBD, one paper is:
Trichuris suis seems to be safe and possibly effective in the treatment of inflammatory bowel disease. Robert W. Summers, M.D., David E. Elliott, M.D., Ph.D., Khurram Qadir, M.D., Joseph F. Urban, Jr., Ph.D. , Robin Thompson, M.H.A. , Joel V. Weinstock, M.D. The American Journal of Gastroenterology, Volume 98 Issue 9, Pages 2034 - 2041. (
That paper is available on-line).
Pesticides in Mexico:
Guillette, E., et al., “An Anthropological Approach to the Evaluation of Preschool Children Exposed to Pesticides in Mexico,” Environmental Health Perspectives, 106(6):347-353, 1998.
As for the rats, there have been hundreds of papers since then confirming the finding in humans and other species.
I would suggest searching on google, and you will find dozens of more recent papers. I wrote that article back around 1999 2000, and there's been so much new research since.