| 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 (Addison’s) 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 cell’s nucleus (hence the anti-nuclear
antibody test (ANA) for SLE). Most notably antibodies are made
against the body’s 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 animal’s 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 dog’s 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 (Addison’s disease): The adrenal
gland produces hormones which regulate the level of sodium and
potassium (mineralocorticoids) and mediate the body’s 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
heart’s 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 fiber.
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 dramatically.
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
animal’s immune system must also be presented.
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 don’t
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 dog’s 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. Don’t worm and vaccinate
at the same time, avoid multivalent vaccines. At the same time
don’t 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].
All rights reserved
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.
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A fond thank you to Linda Aronson, DVM for the
use of this article. |
