The Immune System and Autoimmune
Diseases
Linda Aronson,
PetShrink,
(978) 838 0143; Fax 978 838 0216
www.petshrink.com
Introduction to the immune system
The immune system
is designed to protect the body from disease causing pathogens and other
foreign substances. It is an amazingly complex system, and we are probably only
just beginning to appreciate its many parts and functions. For example, recent research has shown
changes in the immune cells in human patients suffering from severe mental
illness. It is hoped these changes can
form the basis for a diagnostic test for these illnesses and allow for earlier
intervention. In this paper I will
merely hope to give an overview of the parts of the system involved in
preventing infection, and the ways in which the system can fail.
The body has a
number of lines of defense. The skin is
a wonderful barrier. The gut-associated
lymphoid tissue (GALT) is the biggest immune organ in the body, and about 70%
of the body’s immune system is to be found in the intestinal lining. The digestive tract must strive to exclude
unwanted pathogens while allowing nutrients to enter the body and coexisting
with commensal (good) bacteria that help digest food and make necessary enzymes
and vitamins, while preventing overgrowth by toxic bacteria and fungi. Acid in the stomach kills many
microorganisms, while the mucus lining of the gut contains antibodies to
neutralize others. Enzymes, especially
those in bile and saliva, detoxify some pathogens while others break down food
substances into their smallest elemental units.
Coordinated waves keep food moving through the gut. In the developed world the delicate balance
of the gut is often disrupted and inflammatory bowel disease is becoming
increasingly common in our dogs. In
humans there have been studies demonstrating that improved hygiene and the loss
of intestinal parasites which have coexisted for millennia may be responsible
and replacing them with benign parasites may be curative. There may also be mutations in the genes that
control innate immune recognition, adaptive immunity and epithelial
permeability all of which may contribute to the inflammatory response as well
as food allergies. The respiratory and
genitourinary tracts are similarly protected by a combination of mechanical and
chemical barriers.
The skin, lungs and
intestines (as well as circulating white blood cells) are populated by specific
peptides – small portions of protein - (e.g. cathelicidins) that act as natural
antibiotics. They help to contain fast
moving infections until the immune system can mount a fully orchestrated
attack. While bacteria have been able to
develop resistance to artificial antibiotics, they have never been able to develop
immunity to these peptides. It is hoped
that boosting this natural defense system may provide a successful means of
combating antibiotic resistant infections such as MRSA (methicillin resistant Staph. Aureus); necrotizing fasciitis
(the flesh eating bacteria); or toxic shock syndrome.
If the physical
barriers to infection fail, the next line of defense is provided by the innate
immune system, which identifies infectious agents by their pattern or structure
and provides an immediate but non specific response (inflammation, release of
chemicals to bring various immune cells or which kill invading organisms). If pathogens evade this system there is a
final adaptive immune system which is specific for particular pathogens and
antigens, but which takes several days to gear up initially to a new infectious
organism. However, once a particular microbe
has been encountered specific antibodies are formed against it, and can be
called into action on subsequent exposures. Antigens are molecules that generate
an antibody response. Both innate and adaptive immune systems have
humoral components found in the body fluids – primarily blood and lymph, and
cellular ones.
The complement
system is the primary component of the innate humoral response; it so called
because it complements antibodies in killing pathogens. A biochemical cascade of over 20 different
enzymes attacks the surface of microbes to which antibodies have attached. As
well as releasing chemicals that eat the organism, the cascade also attracts
other immune cells, increases the permeability of blood vessels facilitating
their access to the organism, as well as marking it for destruction. The cellular component consists of various
types of white blood cells: phagocytes (macrophages, neutrophils and dendritic
cells), mast cells, eosinophils, basal cells and natural killer (NK) cells. Phagocytes engulf and digest smaller
pathogens. They circulate throughout the
body, but are attracted by substances released by the complement cascade. Neutrophils usually represent the majority of
white cells in the blood, while macrophages are usually found in the tissues. They also scavenge dead cells, and present
cells to antibodies. Dendritic cells are
phagocytes in skin, nose, lungs and gastrointestinal tract where they have
contact with the external environment.
Mast cells are found in connective tissues and mucous membranes and they
regulate the inflammatory response.
Over-activity results in allergic and anaphylactic reactions. Basophils and eosinophils are also
circulating in the blood stream and their primary role is defense against
parasites, although they also have a role in allergies. NK cells destroy tumor
cells and those infected with viruses.
The adaptive immune
system allows for a stronger immune response and also provides immunological
memory so that an antigen that has already been encountered will produce a
faster and more focused response. It is
the adaptive immune system that must be able to tell self from non-self.
Lymphocytes are the cellular component of the adaptive immune system. There are two major types, B cells are formed
in the bone marrow and are involved in the humoral response. They are also known as immunoglobulins – IgG,
IgM, IgA, IgD and IgE. T cells originating in the thymus produce the
cell-mediated response involving the lymph nodes, thymus, spleen, GALT, tonsils
and mucus secretion. Both types have
receptors that recognize specific targets.
The B-cell receptor recognizes whole pathogens. T-cells only recognize small fragments of
pathogens that have been processed and presented by other (MHC) molecules. There are two major types: killer T cells
kill cells infected with pathogens as well as those that are damaged or
dysfunctional. Each T cell recognizes a
single antigen. Helper T cells, having
recognized the antigen, release chemicals to stimulate and increase the
activity of B cells, killer T cells and macrophages, and regulate both innate
and adaptive immune systems. A third
class of T cells, suppressor T cells dampen the immune response if it becomes
overactive or out of regulatory control.
Activation of the B
and T cells causes them to reproduce and their progeny become long-lived memory
cells ready to mount an immune response to any subsequent encounters with the
pathogen. Newborn puppies have not been
exposed to pathogens and lack this active memory. They have however, received passive immunity
from their dams. A particular kind of
antibody – IgG - is transported across the placenta providing the neonate puppy
with immunity to antigens encountered by the dam. The first milk, colostrum, also contains
antibodies (all classes) against primarily bacterial infections, as well as
lymphocytic cytokines – which are immune regulators; interleukins that control
inflammatory response; interferon which inhibits viral reproduction; and other
substances that support an effective immune response. These large molecules can only cross the
intestinal wall for the first 24-48 hours so it is important that the puppy
receives colostrum. If the bitch has
none, hyperimmune plasma can be tubed in during this time slot to provide
passive immunity. The puppy does not
make antibodies or memory cells in response to these antibodies, and the
immunity gradually wanes over the first weeks of the puppy’s life,
unfortunately persistence is highly variable.
Long term active immunity is obtained by activation of B and T cells
when they encounter an infection or artificially through vaccination.
Disorders of immunity
The immune system
is a complex one that is both specific and adaptive to the dog’s changing
environment. Its complexity
unfortunately makes it susceptible to failure.
There are basically three potential problems. In immunodeficiency one or more of the
components are inactive. Ability to
respond is reduced in the young and elderly.
Malnutrition, particularly the lack of sufficient protein, iron, copper,
zinc, selenium, Vitamins A, C, E, B6 or folic acid, is one
cause. Environmental toxins, genetic or
acquired diseases, and certain cancers can also result in immunodeficiency. Hypersensitivity is the result of an
excessive response that results in damage of the body’s own cells. There are four classes. Anaphylactic reactions are often associated
with allergy and can range from mild to fatal. They are caused by IgE released
from mast cells and basophils. Cytotoxic
hypersensitivity results from IgG or IgM antibodies attaching to the body’s own
cells and marking them for destruction.
Type III is caused by the deposition of immune complexes of antigens,
compliment proteins and IgG and IgM antibodies in the tissues. Type IV hypersensitivity includes many
autoimmune and infectious diseases as well as contact dermatitis and is
mediated by T cells, monocytes and macrophages. Autoimmune reactions are a specific
form of over-reactivity in which the immune system fails to distinguish self
from non-self resulting in it attacking parts of its own body. Specialized
cells in the bone marrow and thymus normally eliminate any lymphocytes that
present with self antigens.
Different hormones can stimulate or suppress the immune system. Estrogen hormones can stimulate both innate
and adaptive immune systems, which is why some autoimmune diseases are more
common in bitches and occur after she is sexually mature. It appears that testosterone may suppress the
immune system, while progesterone prevents the bitch rejecting the fetuses as
foreign, but also dampens the general immune response. Prolactin and growth hormone also affect the
immune system in a complex fashion. Declining
levels of hormones in older animals may contribute to a reduced immune response
in older animals. The immune system
regulates thyroid activity and vice versa.
Stress impairs immune reaction, while rest enhances it. Malnourished fetuses and neonates will suffer
a lifelong impairment, while certain foods – especially essential fatty acids
as well as some other foods and herbs can stimulate it.
Drugs can also be used to manipulate the
immune system. Immunosuppressive drugs
are used to control autoimmune diseases and to reduce inflammation as well as
to prevent rejection of transplanted organs.
Glucocorticoid drugs are the most potent anti-inflammatory drugs, but
they have serious side-effects. Other
drugs, such as azathioprine, are cytotoxic and suppress the immune response by
indiscriminately killing rapidly dividing cells such as activated T cells, but
also those in other organs causing toxic effects. A third class of drug inhibits the signals
that activate T cell response, cyclosporine does this. Antibiotics enhance
immune response, but will not be considered here. Neither will the various strategies employed
by pathogens to elude the immune response at all levels.
Autoimmune Diseases
At this time we are only beginning to
untangle the causes of these diseases.
In the majority of cases there appears to be a genetic factor necessary,
but disease will not be seen without some external trigger. Sometimes we can pinpoint this – a vaccine,
drug, toxin or illness (usually viral or bacterial) – but often the trigger is
not identified. Hormones and stress are
also triggers for disease. Are
autoimmune diseases more common now or are we better at detecting them? The answer is probably both. Certainly, we
and our dogs live in an increasingly artificial environment laden with
chemicals; food is laced with ingredients that are anything but natural. I come across repeated instances of
households where owners and their animals have an assortment of different
ailments that are all autoimmune in nature.
However, veterinarians and owners are also more aware of the
problem. Over and over I hear that an
unexplained problem is probably autoimmune with no real idea of what disease is
suspected. Just because a problem
responds to immunosuppressive drugs doesn’t mean that it was the result of
autoimmune disease.
Certain immune-suppressant viruses
(retroviruses and parvoviruses) have been implicated as causing bone marrow
failure, the immune mediated blood diseases (autoimmune hemolytic anemia – AIHA
- and immune-mediated thrombocytopenia – ITP), lymphoma, leukemia,
dysregulating humoral and cell-mediated immunity, liver and kidney failure, and
autoimmune endocrine disorders – thyroiditis, hypoadrenocorticism (Addison’s
disease) and diabetes. Viral disease and
recent vaccination with single or combined modified live viruses are also
triggers for immune-mediated blood disease, bone marrow failure and organ
dysfunction. The killed rabies vaccine
and bacterial leptospirosis vaccine more commonly trigger immediate or delayed
vaccinosis reactions. The bacterial (Ehrlichia,
Anaplasma, Rocky Mountain Spotted Fever)
Protozoal (Babesia) and spirochetal (Lyme
disease) tick borne diseases suppress the host immune system and decrease the
numbers of antibodies making the animal susceptible to secondary infection,
while inducing autoimmune diseases of the blood (AIHA and ITP), gut (IBD),
muscles (myositis), eye (uveitis), joints (polyarthritis) and in the case of
Lyme a protein losing disease of the kidney -the latter two closely mimic
systemic lupus erythematosus (SLE). When the apparent autoimmune disease has
been addressed titers for the tick borne diseases are often found to be sky
high, as these organisms can adapt and survive within the body for years or
even permanently. Skin “allergies” are
also indicative of an immune system gone awry.
Drugs associated with exacerbating or
triggering autoimmune disease include potentiated sulfonamides
(trimethoprim-sulfa and related antibiotics), monthly heartworm drugs
(especially those combined with flea preventatives) and anticonvulsant
drugs. As stress and the need for drugs
tend to go hand in hand virtually any drug is capable of acting as a trigger in
a susceptible individual.
Autoimmune thyroiditis
Hypothyroidism is arguably the most common
endocrine disease in dogs and in the majority of cases it is autoimmune in
nature. Because the thyroid hormones
regulate metabolic function in all the body’s cells even suboptimal function
can result in profound changes throughout the body that can be missed – written
off as puppy exuberance/ADD or normal aging – or mistaken for some other
disease. By the time the classical
presentation of obesity, lethargy, heat-seeking and alopecia is achieved
two-thirds of thyroid function or more has been lost. Monitoring thyroid function regularly through
comprehensive thyroid panels is one of the most important things we can do to
ensure good health for our dogs. Reduced
thyroid function results in depression of the immune response to other diseases. It often accompanies other autoimmune
disorders and any dog diagnosed with autoimmune disease should have a thyroid
panel run. Supplementing the thyroid usually
results in a better prognosis for these diseases as well as reducing the need
for other, often more expensive or toxic, drugs. Early signs are often behavioral in nature – increase
in fear, aggression or obsessive behaviors, as well as an inability to focus
and learn in young animals. Young
animals, unlike older dogs, often are uninterested in food, underweight and
hyperactive. Commonly seen signs
include:
____Excessive
shedding, patchy hair loss or “rat tail”
____Dry skin or dull, dry hair coat
____Recurrent infections (especially ear, skin and foot infections)
____Tendency to gain weight
____Heat seeking behavior (acts cold)
____Increased sleep time
____Hyperactivity
____Slow learning
____Seizures
____Worried look, tragic facial expression or looking “old”
____Reduced hearing, sight and scenting ability
____Chronic gastrointestinal symptoms
____Loss of muscle or bladder tone
____Head tilt
____Change in character of bark
____Exercise intolerance
____Infertility, false pregnancy or weak, dying or stillborn puppies
____Recurring eye infections
____Premature graying
Diagnosis via a
complete thyroid panel consisting minimally of serum levels of total and free
T3 (triiodothyronine) and T4 (thyroxine) preferably with levels of T3 , T4 and
thyroglobulin antibodies. Because dogs under 18 months, toy and giant breeds as well as sighthounds have
different thyroid requirements it is recommended that serum be sent to Hemopet
Diagnostics service for evaluation www.hemopet.org If a dog has low or suboptimal thyroid
function, treatment with L-thyroxine twice daily at a dose of 0.1mg/12-15 lbs
body weight should resolve any of the above problems.
Hypoadrenocorticism (Addison’s Disease)
See separate article.
Anemia per se is a clinical sign
not a disease, and is simply a decrease in the number of red blood cells (RBCs)
or the amount of hemoglobin, resulting in a decrease in the oxygen-carrying
capacity of the blood. Anemia can be caused by blood loss, decreased production
of new RBCs, or an increase in the rate of their destruction - hemolytic
anemia.
Senescent RBCs acquire markers on
the cell surface that are recognized and are removed from circulation usually
by the spleen and/or liver. Similarly
markers appear on RBCs in cases of AIHA.
These markers can be true autoantibodies, as in primary AIHA, or can be
secondary to drugs (the immune stimulator and wormer levamisole, certain
antibiotics, and the anticonvulsant anti-arrhythmia drug phenytoin have been
implicated), infectious disease, cancer, blood parasites, or heavy metals
(lead, and zinc). AIHA results when red
cells are removed faster than they can be replaced. Antibodies can be warm (usually IgG reactive
at body temperature) or cold type (usually IgM when body temperature drops below
normal). As well as being removed by
spleen and liver, RBCs are destroyed in the blood vessels when the
immunoglobulins (usually IgG) activates compliment. RBCs may also clump as a result of bridges
formed between cells usually by IgM.
Clinical signs of AIHA can appear
gradually or suddenly and relate to the lack of oxygen reaching the tissues –
collapse/weakness, lethargy, anorexia, exercise intolerance and an increase in
the heart and respiratory rates. Mucous membranes (gums, eyelids, etc.) are usually
pale and heart murmurs may be heard. Vomiting and diarrhea are not uncommon. Lymph nodes are usually swollen. In more
severe cases a fever and "icterus" (jaundice) - a yellow
discoloration of the gums, eyes, and skin due to a buildup of bilirubin, one of
the products of hemoglobin breakdown – will be found. Anemia is confirmed by complete blood count
(CBC). A Coombs test and clotting time
tests may also be used to confirm diagnosis although only about 60% of patients
with AIHA have a positive Coombs test.
Palpation and radiographs confirm enlargement of the spleen and
liver. In chronic cases the heart may be
enlarged. Anemia can be regenerative or
non regenerative. In the latter case,
there is immune mediated destruction of RBC precursors in the bone marrow.
In severe cases blood transfusion with cross-matched packed red cells or whole blood and intravenous fluids may be necessary. Corticosteroids are usually the first drug given and are started at very high immunosuppressive doses, the dose is very slowly tapered over many weeks or months to a low maintenance dose. Some affected dogs have to be kept on low steroid doses for the rest of their lives and most are susceptible to relapse. Other immunosuppressive drugs such as azathioprine (Imuran) or cyclophosphamide (Cytoxin) may be added. If the drugs have failed to produce significant improvement after 4 to 6 weeks splenectomy - the surgical removal of the spleen - may be recommended.
ITP is the destruction of platelets
also known as thrombocytes by the binding of antibodies to the platelets’
surface leading to their premature removal from circulation. ITP often accompanies AIHA. Platelets attach to cell walls when they are
damaged and help produce a clot to prevent blood loss either within the body or
through the skin and other external surfaces.
Generally we are unaware of all the minor breaches that occur all the
time. If platelet numbers drop
sufficiently low (<40,000) spontaneous hemorrhaging can occur usually into
the skin, g/i tract, respiratory or urinary systems. Typically presentation results from
hemorrhage into the skin (petechiation) causing small or large blood blisters,
excessive bleeding from minor traumas, vomiting, urinating or defecating blood,
lethargy, weakness or collapse – although these last three signs are more
likely if there is accompanying AIHA.
Other causes of clotting disorder - rat poison, hemophilia, von Willebrand’s
disease, bladder and prostate infection, cancer or intestinal parasites -
should be ruled out. CBC, Coombs test,
vWF and clotting tests are performed and bone marrow samples may also be
taken. Drug treatment is usually the
same as for AIHA. A single injection of
vincristine may be given in extreme cases as it will produce a large increase
in platelet numbers three days later.
Transfusion of whole blood or platelet rich plasma may also be
indicated. Once platelet counts are
normal ovariohysterectomy (spaying) is recommended in intact bitches to prevent
hemorrhage during estrous. Due to the
genetic component in autoimmune diseases it is strongly recommended that affected
dogs should not be used in a breeding program.
SLE also often accompanies/causes
AIHA and/or ITP. It is a multi-systemic
autoimmune disease often simply referred to as lupus. It is the result of
autoantibodies to non-organ specific nuclear and cytoplasmic antigens as well
as cell and organ specific antigens. The
resulting immune complexes are deposited in multiple locations throughout the
body, but most commonly the glomerular membranes in the kidney, synovial
membranes in joints, the skin, mucous membranes, blood and brain. Complement is activated leading to
inflammation as well as direct toxic damage to surrounding structures. Clinical signs depend upon where the immune
complexes are located and the specificity of the autoantibodies. The signs of SLE may be acute (sudden onset)
or chronic but are almost always cyclic – wax and wane. A fluctuating fever
that does not respond to antibiotics is often seen. Joints may be swollen and painful resulting
in a stiff gait or shifting lameness.
Symmetrical or local skin lesions with redness, scaling, ulceration and
loss of hair are also common as are ulcerative lesions in the mouth and
junctions between haired skin and mucous membranes. Glomerulonephritis results from leaky
membranes in the glomeruli – filtration units of the kidney – leading to poor
filtration and loss of protein into the urine.
Heart murmurs and arrhythmias and pleural friction rubs are due to
inflammation of heart muscle and the sacs around heart and lungs. Muscle wasting and inflammation, enlarged
lymph nodes and spleen, low white cell counts, depression, seizures and changed
mentation round out the possible symptoms.
While a CBC and antinuclear
antibody test (ANA) should be run, along with appropriate diagnostic tests for
specific systems affected diagnosis is based on the number of major and minor
signs of SLE present. A false positive
ANA can result from a number of infectious diseases such as some of the tick
borne diseases, which also present with polyarthritis. While immunosuppressant drug therapy is the
cornerstone of treatment of SLE, treatment is also directed at the particular systems
affected by the disease where possible.
Prognosis is guarded especially where kidney disease is advanced or
there is secondary infection (pyelonephritis), septic arthritis in the joints
or septicemia in the blood.
Discoid lupus erythematosus may be
a benign form of SLE and causes dermatitis of the face - usually over the
bridge of the nose. Lesions are similar to and often mistaken for nasal solar
dermatitis (also known as collie nose) and pemphigus erythematosus. Tattooing the area may prevent sunburn.
Vogt-Koyanagi-Harada-like syndrome
(VKH) is extremely rare and may be autoimmune in origin. It causes depigmentation of the nose, lips,
eyelids, footpads, and anus and they fade to pink or white, and there is an accompanying
acute uveitis (inflammation of the eyes). Early treatment may prevent blindness, but the
pigment loss is usually permanent.
Immune-mediated polyarthritis can
be seen in SLE as above or as an independent finding. There are several
different diseases included under this umbrella term, but the major signs for
all of them include high fever, joint pain and swelling, and a lameness that
seems to shift from leg to leg. Lymph nodes may be enlarged. Rheumatoid
arthritis (RA) is the most severe form and X-rays of the joints will show
erosion of cartilage and eventually bone.
Rheumatoid factor can usually be found in the blood. X-rays in the milder non-erosive forms will
appear normal. Other blood work may be
normal or show abnormalities and what changes there are will not be
consistent. In uncomplicated
immune-mediated polyarthropathies, clinical remission can be achieved with
corticosteroids in about half the cases. For the rest, azathioprine or
cyclosporine is usually effective, and remission can be maintained with
corticosteroids. With the exception of
rheumatoid arthritis, the prognosis is generally good.
Muscle related autoimmune diseases
Myositis can be generalized –
polymyositis (affecting skeletal muscles of limbs and jaw; dermatomyositis also
has skin lesions) or focal affecting either the masticatory muscles (temporalis
muscle over the head and jaw muscles) or extraocular muscles around the
eye. The muscles affected are usually
stiff and painful and may be acutely swollen, but they atrophy over time.
Autoantibodies are directed against muscle fibers. Polymyositis may also be caused by infectious
diseases, certain cancers and some drugs, so muscle biopsy is needed to confirm
an autoimmune etiology. Focal myositis
is often diagnosed by response to immunosuppressive drugs. Corticosteroids should produce full remission
provided there has been no fibrosis of the muscles prior to treatment. One potential complication of polymyositis is
megaesophagus, an enlargement of the entrance to the esophagus which prevents
closing the trachea when swallowing food.
This can result in food entering the trachea and causing infection
(aspiration pneumonia).
Myasthenia gravis may rarely be
congenital but is usually an autoimmune disease resulting from autoantibodies
attaching to the acetylcholine receptors that transmit nerve signals to muscles
causing them to contract. The receptors
are destroyed and often the surrounding cell membrane as well. Dogs may present
with focal weakness of muscles in the esophagus, pharynx or around the eye or
with generalized muscle weakness so the dog cannot support its own weight. Megaesophagus and aspiration pneumonia are
common. Serum acetylcholine antibody
receptor titer is diagnostic as is response to the anticholinesterase drug
edrophonium (which prolongs the action of acetylcholine in the neuromuscular junctions). Treatment is with a related more long acting
drug called pyridostigmine. Prednisone
is usually given at immunosuppressive doses, but it may initially make the
weakness worse.
Other
In humans type 1 (insulin
dependent) diabetes mellitus (DM) is an inflammatory autoimmune disease
resulting in destruction of insulin producing beta cells in the islets of
Langerhans. Autoantibodies to insulin
have been found in the dog suggesting that DM is predominantly an autoimmune
disease in the dog. Pancreatitis may
also be a possible cause. The number of
cases of DM appears to have increased dramatically since kibbled foods became
the predominant form of canine nutrition, and as these must be 60% carbohydrate
as opposed to about 5% carbohydrate in the diet of most wild canids, metabolic
disease may also be responsible or at least a contributing factor. Kerratoconjunctivitis sicca (KCS) commonly
known as dry eye results from cessation of tear production and responds to the
cyclosporine suggesting an immune mediated etiology. Vitiligo may represent an autoimmune
destruction of the cells that produce the pigment melanin. In time it is likely other autoimmune
diseases will be added to the list.