The Immune System and Autoimmune Diseases
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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.
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.
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:
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
____Worried look, tragic facial expression or looking “old”
____Reduced hearing, sight and scenting ability
____Chronic gastrointestinal symptoms
____Loss of muscle or bladder tone
____Change in character of bark
____Infertility, false pregnancy or weak, dying or stillborn puppies
____Recurring eye infections
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.
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.