Excessive activity of the adaptive immune system can lead to inappropriate immune responses collectively called hypersensitivities. In general, inappropriate innate immune responses do this by triggering inflammation that leads to collateral damage to nearby tissues or organs, or by producing vastly excessive amounts of inflammatory cytokines. Excessive adaptive immune responses, in contrast, can cause damage by multiple mechanisms. One simple classification divides these hypersensitivity reactions into four distinct types. Each involves very different mechanisms. Type I hypersensitivity is mediated by IgE antibodies and mast cells; Type II by IgG and/or IgM antibodies and complement; Type III by immune complexes, complement and neutrophils; and Type IV by T lymphocytes.
Type I Hypersensitivity
Type I, or immediate hypersensitivity, encompasses IgE-mediated responses to foreign antigens. These reactions may be minor and local or may be severe and generalized. In its most extreme form, type 1 hypersensitivity or allergy is expressed as a lethal shock syndrome called anaphylaxis. Anaphylaxis is an acute systemic manifestation of the interaction of an antigen (allergen) binding to IgE on mast cells and basophils. The antigen binding triggers the mast cell to release a complex mixture of inflammatory mediators, including:
eosinophil chemotactic factors
platelet activating factor
Some of these molecules directly affect both the vascular system, causing vasodilation and increased vascular permeability, and the smooth muscles, causing contraction. Other mediators attract eosinophils to the reaction site.
The severity of anaphylaxis depends on the type of antigen, the amount of IgE produced, the amount of antigen received, and the route of exposure. If the animal has been previously sensitized by exposure to an allergen (antigen) and produces high levels of IgE antibodies, then injection of the sensitizing antigens directly into the bloodstream can result in anaphylactic shock and related allergic reactions such as hives, urticaria, and facial-conjunctival edema. If the sensitizing allergen enters through the mucous membranes or the skin, allergic reactions tend to be more localized. Antigens that can trigger anaphylactic and allergic reactions are numerous and include the venom of stinging and biting insects, some vaccines, drugs, foods, and blood products.
Systemic Anaphylaxis (Generalized Anaphylactic Reactions)
Anaphylactic shock occurs in sensitized animals within seconds to minutes after exposure to the allergen. In most domestic species, the lungs are the primary target organs, and the portal-mesenteric vasculature is a secondary target; this is reversed in dogs. Mast cell degranulation releases histamine and other mediators that cause constriction of bronchial airways or pulmonary veins, pooling of blood and edema in the pulmonary vascular bed, and severe respiratory distress. Mast cell degranulation in the portosystemic vasculature causes venous dilation and pooling of blood in the intestine and liver. Clinical signs may be localized or generalized and include:
restlessness and excitement
pruritus around the head or site of exposure
In dogs, the major organ affected by anaphylactic shock is the liver, and signs are associated with constriction of hepatic veins, resulting in portal hypertension and visceral pooling of blood. GI signs rather than respiratory signs are more apt to be seen in dogs. Immediate treatment, in addition to treating respiratory distress, consists of the systemic administration of epinephrine. Additional treatments include intravenous fluids to control shock and corticosteroids if needed. Ancillary support of blood pressure and respiration may also be necessary.
Urticarial reactions Urticaria (hives) of the skin and subcutis and acute edema of the lips, conjunctiva, and skin of the face (facial-conjunctival angioedema) are less severe forms of Type I hypersensitivity. Hives are the least severe reaction and may not be associated with other clinical abnormalities. Facial-conjunctival edema is more severe and can be associated with mild to moderately severe systemic anaphylaxis. Urticarial reactions and facial-conjunctival edema occur in most species and usually resolve spontaneously within 24 hours. Not all urticarial reactions are mediated by Type I hypersensitivity.
Localized Allergic Reactions
Allergic rhinitis, manifest by serous nasal discharge and sneezing, is less common in domestic animals than in people. Often, it is seasonal, correlating with pollen exposure. Nonseasonal rhinitis may be associated with exposure to ubiquitous allergens, such as molds, animal danders, bedding, and feeds. Recurrent airway obstruction Recurrent Airway Obstruction in Horses Recurrent airway obstruction (RAO) is a common, performance-limiting, allergic respiratory disease of horses characterized by chronic cough, nasal discharge, and respiratory difficulty. Episodes... read more in horses is probably a response to chronic exposure to molds present in hay and poorly ventilated stables. Recent research on "equine asthma" has defined a type of the condition in which there is predominantly a neutrophilic response in the airway. Summer snuffles is a seasonal allergic rhinitis occurring in Guernsey or Jersey cattle placed on certain types of flowering pastures in late summer and early autumn.
Allergic rhinitis can be diagnosed tentatively by the following:
identification of eosinophils in the nasal exudate
demonstration of a favorable response to antihistamines
disappearance of signs when the offending allergen is removed, or
occasionally, its seasonal nature
Skin testing is not an accurate means to identify the causes of nasal allergies in animals.
Chronic allergic bronchitis has been diagnosed in dogs. A dry, harsh, hacking cough that is easily precipitated by exertion or by pressure on the trachea is a characteristic clinical sign. The disease may be seasonal. It is not usually associated with other signs of illness. The bronchial exudate is rich in eosinophils and free of bacteria. Chest radiographs are normal, and there may or may not be a low-grade peripheral eosinophilia. The condition is treated with bronchodilators and expectorants (aminophylline and potassium iodide or guaifenesin). Glucocorticoids will alleviate clinical signs, especially when their use can be limited to certain seasons or to low-dose, alternate-day therapy. Avoidance of the offending allergen(s) usually is not possible.
Allergic bronchiolitis is most common in cats. It is manifest by a low-grade cough, wheezing, some dyspnea, and increased peribronchiolar density on radiographs, and it may be mistaken for other conditions such as allergic asthma or lungworm disease. Early in the course of the disease, clinical signs can be reduced by antihistamine therapy, but if the disease increases in severity, moderate to high dosages of corticosteroids may be necessary. The offending allergen usually is not identified.
Pulmonary infiltration with eosinophilia occurs most frequently in dogs but has been recognized in all species. It is associated with diffuse inflammatory infiltrates in the lungs and a pronounced peripheral eosinophilia; frequently, serum globulins are increased. Unlike allergic bronchitis, affected animals are often dyspneic or tire easily with exercise. The bronchial exudate contains numerous eosinophils. The specific offending allergen is rarely identified. Glucocorticoids are the treatment of choice. A similar syndrome is also associated with resident or migratory parasitic infections of the lungs in young animals.
Allergic asthma occurs most frequently in cats, in which the signs are similar to those in people. It occurs more frequently in summer and in some cats can be triggered by going outdoors. Indoor cats can also get asthma, often from reaction to dust mite allergens. Individual attacks can be transient and mild or can be protracted and severe (status asthmaticus). Mild attacks may manifest as wheezing and coughing; in severe attacks, there may be expiratory dyspnea, hyperinflation of the lungs, aerophagia, cyanosis, and frantic attempts to obtain air. Eosinophils are found in bronchial wash fluids of asthmatic cats.
Intestinal allergies ( food allergies Food Allergy ) are principally seen in dogs and cats, particularly kittens. Allergic gastritis is manifest by vomiting, which occurs 1 to >12 times weekly within 1–2 hours of eating. The vomitus may be tinged with bile. In cats, vomiting may be the sole sign; dogs may also have intermittent loose feces. Cats and dogs with allergic gastritis are usually healthy except for vomiting.
Allergic enteritis is associated with a mild inflammation of the small intestine but with little or no eosinophilia. Feces usually are normal in volume and frequency but vary from semiformed to watery. They may be extremely odorous, especially in cats. Affected animals may be excessively thin despite good appetite. Skin lesions and poor coat are commonly associated with food allergies in cats but less commonly in dogs. The allergy often develops following episodes of viral, bacterial, or protozoal enteritis, a phenomenon known as allergic breakthrough.
Eosinophilic enteritis, the most severe form of allergic intestinal disease, manifests by moderate to severe inflammation of the intestines and a pronounced eosinophilia. Diarrhea, weight loss, and poor coat condition are usually evident. The prevalence of allergic colitis is greater in cats than in dogs, although in general it is not common. In dogs, it is often associated with frequent defecation and soft, mucus-laden and sometimes bloody feces; in cats, it most frequently manifests by more normal feces coated or spotted with fresh blood.
Atopic dermatitis Atopic Dermatitis is a complex, pruritic, chronic skin disorder that occurs in many species but has been studied mostly in dogs. Some animals with atopic dermatitis may have a genetic predisposition that leads to excessive production of reaginic (IgE) antibodies. It has been estimated that ~10% of all dogs suffer from atopy, with a breed predisposition in terriers, Dalmatians, and retrievers. There is increasing evidence that dogs with atopic dermatitis have a skin barrier defect and that most allergens enter through the skin. Atopic dogs often chew at their feet and axillae. Excessive sweating is especially noticeable in hairless areas. The severity of the skin lesions are greatly increased by licking, scratching, flea infestation, and secondary bacterial or yeast infection. Atopic skin lesions in cats are either miliary (small scabs) and widespread or are larger and more localized. Localized lesions are often pruritic.
In cats, food allergens probably are a more common cause of skin lesions than are inhaled allergens. Sweet itch Biting Midges Culicoides sensitivity in a horse. The biting midges, “no-see-ums,” or punkies belong to the family Ceratopogonidae. The most common biting midges are Culicoides spp. They are associated... read more is a seasonal allergic dermatitis of horses associated with certain insect bites, especially night-feeding Culicoides. Intensely pruritic lesions appear along the dorsum from the ears to tail head and perianal area. Similar allergic skin reactions to insect bites can be seen around the ears and face of cats and dogs. (For diagnosis and treatment, see Atopic Dermatitis Atopic Dermatitis .)
Type II Reactions
Type II hypersensitivity reactions occur when an antibody binds to antigens located on the surface of cells. This bound antibody can then activate the classical complement pathway, resulting in cell lysis, or phagocytosis. Many different antigens may trigger this cell destruction, but an infection in a genetically predisposed animal appears to be a major triggering pathway. Cross-reactive antibodies can develop during infections. These cross-reactive antibodies directed toward an infectious agent may also bind to normal tissue antigens and trigger antibody-mediated cytotoxicity. Pathogens such as Babesia or Haemobartonella, which parasitize cells, trigger an immune response that destroys those cells as part of the protective mechanism. As another example, drug metabolites can bind to erythrocytes and create a new epitope that stimulates an antibody response, thereby causing destruction of the cells by antibody and complement.
The most common manifestations of Type II hypersensitivity involve blood cells. These include hemolytic anemia if RBCs are involved, leukopenia involving WBCs, or thrombocytopenia involving platelets. Under some circumstances, a cytotoxic attack on vascular epithelial cells will cause a vasculitis with local vascular leakage.
Bovine Neonatal Pancytopenia
In 2007, a dramatic hemorrhagic disease affecting calves appeared in Europe; upon investigation it was found to result from the use of a bovine viral diarrhea vaccine. The vaccine virus was grown in bovine kidney cells. As a result, it stimulated antibody formation in some recipient cows directed against the cell’s MHC molecules. These antibodies were concentrated in their colostrum. When their calves suckled, the ingested antibodies destroyed the calf’s bone marrow stem cells and resulted in a massive and lethal pancytopenia. The offending vaccine has been withdrawn.
Type III Reactions
Antigen-antibody complexes (immune complexes) deposited in small blood vessels fix complement in situ and cause acute inflammation. Activation of complement by immune complexes results in production of complement byproducts that are chemotactic for neutrophils. The neutrophils are unable to ingest the complexes that are stuck in the blood vessel walls and they release their granule contents in the tissue. These granules contain toxic enzymes that cause severe tissue damage. The most frequently affected sites of immune complex deposition are the joints, skin, kidneys, lungs, and brain.
The prerequisite for the development of immune-complex disease is the persistent presence of soluble antigen and antibody. These form insoluble immune complexes that become trapped on the basement membrane of small blood vessels. The deposited immune complexes then activate the classical complement pathway. Complement fragments attract neutrophils and are also directly vasoactive, triggering a vasculitis. These antigens may persist for a number of reasons, including chronic infections and certain cancers, especially lymphoreticular neoplasms. Chronic antigen exposure may also occur with inhaled antigens, and, in such cases, immune complexes can form in the alveolar walls. Lastly, some animals respond to self-antigens, which then act as a source of chronic antigen exposure. In many cases, the origin of the antigen within these immune complexes cannot be determined.
The location of the immune complexes is largely determined by the route by which antigen enters the body. Inhaled antigens give rise to a pneumonitis, antigens that enter through the skin cause local skin lesions, and antigens that access the bloodstream form immune complexes that are deposited in renal glomeruli or joints. Clinical signs are therefore variable but may include:
cutaneous signs (such as erythema multiforme)
polyarthritis (shifting-leg lameness or painful, swollen joints)
Other signs include ataxia, behavior change, proteinuria, isosthenuria, polydipsia, polyuria, or nonspecific signs such as vomiting, diarrhea, or abdominal pain. Diagnosis is based on the elimination of more common causes of clinical signs. Supporting evidence to confirm the diagnosis includes establishing a temporal relationship if a drug or infectious agent is suspected as the cause, identifying chronic infections or malignancies, and performing histopathology and immunohistochemistry on biopsies to identify immune-mediated vasculitides or nephritis.
Therapy should include supportive treatment, removal of the causative agent, or treatment of the underlying disorder, such as appropriate antibiotic therapy for bacterial infections, surgical drainage of abscesses or infected tissue, therapy for heartworm disease, and the withdrawal of the offending drugs. Immunosuppressive therapy may be needed to prevent the continued deposition of immune-complexes.
Membranoproliferative glomerulonephritis is caused by immune complexes that form within the bloodstream and are filtered out in the glomeruli ( see Glomerular Disease in Small Animals Glomerular Disease in Small Animals Glomerular disease is a well-recognized cause of chronic kidney disease (CKD) in dogs, may produce acute kidney injury in dogs, and is also occasionally seen in cats with CKD. These animals... read more ). In effect, the insoluble complexes collect on the glomerular basement membrane. Depending on their size, they may be deposited on the subendothelial or subepithelial surface of the membrane. Secondary glomerulonephritis occurs as a side effect of chronic infectious, neoplastic, or immunologic disorders. Animals with idiopathic glomerulonephritis (>50% of cases) usually have signs of renal disease, whereas secondary glomerulonephritis is often a relatively minor part of a more serious disease.
When inhaled antigens meet circulating antibodies in the walls of the lung alveoli, immune complexes form in the alveolar walls and trigger acute inflammation. Hypersensitivity pneumonitis Hypersensitivity Pneumonitis in Cattle Hypersensitivity pneumonitis is a condition that appears to be similar to farmer’s lung disease in people and occurs in both acute and chronic forms in adult cattle. The human and bovine forms... read more is most common in large animals exposed over a long time to antigenic dusts. The most potent antigens of this type are those contained in the spores of thermophilic actinomycetes from moldy hay. Inhalation of these spores causes farmer's lung disease in humans and a similar condition in cattle. Hypersensitivity pneumonitis is characterized by the onset of respiratory distress 4–6 hours after exposure to moldy hay. The most effective treatment is removal of the source of the antigen; otherwise, corticosteroid therapy may help.
Vasculitis mediated by immune complexes occurs in animals, especially dogs and horses. Lesions are most prevalent in the dermis of the distal limbs and mucous membranes of the mouth, particularly the palate and tongue (dogs) and lips (horses). Involvement of the nose, ears, eyelids, cornea, and anus is less common. Early lesions develop as reddened areas that rapidly form shallow erosions. A scab quickly forms over dermal erosions. Edema of the limbs is common in horses and a less frequent but equally striking sign in dogs. Vasculitis is a feature of systemic lupus in some animals but most often is idiopathic. Drug-induced vasculitis has been well recognized in dogs. The vasculitis is detected on histopathologic and immunohistopathologic examination of superficial and deep biopsies taken from the margins of lesions.
Vasculitis is treated by withdrawal of offending drugs and, if necessary, by immunosuppressive drug therapy. Glucocorticoids used alone or in combination with other agents such as azathioprine or cyclophosphamide are usually used to treat non-drug-induced cases.
(Polyarteritis Nodosa, Necrotizing Polyarteritis)
Periarteritis nodosa is a rare disease of domestic animals caused by deposition of immune complexes and inflammation in walls of small and medium-sized arteries. Among farm animals, it is most common in pigs, usually associated with erysipelas and streptococcal infections, and is attributed to a type III reaction to these bacteria or to their vaccines. It has been reported in cats, although it may be mistaken for the noneffusive form of feline infectious peritonitis.
Canine Rheumatoid Arthritis
Canine rheumatoid arthritis results from excessive, uncontrolled inflammation around joints. It manifests initially as a shifting lameness with soft-tissue swelling around involved joints. Within weeks or months, the disease localizes in individual joints, and characteristic radiographic changes develop. The earliest radiographic changes consist of soft-tissue swelling and a loss of trabecular bone density in the area of the joint. Lucent cyst-like areas frequently are seen in the subchondral bone. The most prominent lesion is a progressive erosion of cartilage and subchondral bone in the area of synovial attachments, resulting in loss of articular cartilage and collapse of the joint space. Angular deformities often occur, and luxation of the joint is a frequent sequel. Deformities are most frequent in the carpal, tarsal, and phalangeal joints and less frequent in the elbow and stifle.
The primary lesion in canine rheumatoid arthritis is nonsuppurative, proliferative synovitis. This is followed by joint erosion and eventually leads to fibrous ankylosis.
An erosive arthritis has also been recognized in cats. It tends to occur in older, male cats and frequently is associated with infection with feline syncytia-forming virus. The development of this disease in cats is much more insidious than in dogs.
Canine rheumatoid arthritis responds poorly to systemic glucocorticoids alone. Immunosuppressive agents with anti-inflammatory activity such as cyclophosphamide and azathioprine are used with glucocorticoids to treat this disorder; NSAIDs such as aspirin, carprofen, etodolac, or meloxicam may bring relief.
Plasmacytic-lymphocytic synovitis is possibly a variant of rheumatoid arthritis. It occurs in medium-sized and large dogs. Although multiple joints often are involved, the disease has a predisposition for the stifle. The most common clinical signs are hindlimb lameness and anterior drawer motion of the stifles. Lymphocytes, plasma cells, and neutrophils are present in the synovial fluid, although in some cases the fluid is essentially normal. Examination of the joint shows synovial proliferation and stretching or rupture of the cruciate ligaments. Treatment is as for canine rheumatoid arthritis, above.
Arthritis of unknown etiology is most common in large dogs, particularly German Shepherds, Doberman Pinschers, retrievers, spaniels, and pointers. In toy breeds, it is most frequent in Toy Poodles, Yorkshire Terriers, and Chihuahuas, or mixes of these breeds. There is no evidence of a primary chronic infectious disease process or of systemic lupus erythematosus. Arthritis is often the sole manifestation.
Diagnosis is based on the history of cyclic antibiotic-unresponsive fever, malaise, and anorexia, with stiffness or lameness. Bony changes are not seen on radiographs until the disease is well established. Even then, radiographic changes are mild and can mimic degenerative joint disease. Synovial fluid contains leukocytes but is sterile.
The disease may be controlled with daily high-dose glucocorticoids followed by low-dose, alternate-day therapy. Treatment usually can be discontinued after 3–5 months. Dogs that do not respond well to such therapy (>50%) may be treated with more potent immunosuppressive drugs such as azathioprine or cyclophosphamide in addition to glucocorticoids. Gold salts help augment glucocorticoid therapy in some animals.
Other Type III Reactions
Purpura hemorrhagica of horses is a severe nonthrombocytopenic purpura Primary Immune-mediated Thrombocytopenia (ITP) in Animals Disorders of platelets can be divided into acquired or congenital thrombocytopenias and acquired or congenital functional disorders (thrombocytopathias), with acquired thrombocytopenia being... read more that often follows a Streptococcus equi infection; it occurs when immune complexes of antibody and streptococcal antigen are deposited in vascular basement membranes.
Anterior uveitis Anterior Uvea ("blue-eye") is an immune complex–mediated reaction that frequently occurs in the recovery stage of infectious canine hepatitis Infectious Canine Hepatitis . It results from the reaction of serum antibodies with uveal endothelial cells infected with canine adenovirus 1. Similarly, severe equine recurrent uveitis Equine Recurrent Uveitis is associated with immunologic reactions to Leptospira or Onchocerca spp. This periodic ophthalmia results from autoimmune attack. Antibodies against some serovars of Leptospira can cross-react with retinal antigens and so trigger severe ophthalmia. Uveitis caused by Toxoplasma and feline infectious peritonitis virus infections of cats may also have an immunologic basis.
Type IV Reactions
Cell-mediated immune reactions occur when antigen triggers type 1, cell-mediated responses. Multiple cytokines are produced, as well as activated macrophages and cytotoxic T cells. The infiltration of mononuclear cells and the release of inflammatory molecules from these cells results in the pathologic processes of cell-mediated immune reactions. The antigens usually responsible for the development of Type IV reactions include intracellular bacteria or parasites, some viruses, reactive chemicals, and (in certain situations) cellular autoantigens. The lesions commonly occur in the skin (allergic contact dermatitis) when the antigen comes into contact with the skin. Examples of antigens that cause type IV responses are metals such as nickel and chemicals that may be on lawns or carpets (these can cause contact dermatitis on the ventral abdomen of dogs that lie on their ventrum on such surfaces). The diagnosis is based on eliminating other causes of disease and on histology. The goals of treatment are to identify and eliminate the source of antigen responsible for the reaction and to provide anti-inflammatory or immunosuppressive therapy as required.
T cell–mediated granulomatous reactions may also occur around persistent infectious foci. These reactions to microorganisms such as mycobacteria, Coccidioides spp, Blastomyces spp, and Histoplasma spp, and possibly feline infectious peritonitis virus, may be a result of chronic cell-mediated immune reactions and localized macrophage activation. Although cell-mediated immunity effectively controls these types of infections in most animals, for poorly understood reasons, these same mechanisms are only partially effective in others. These granulomatous reactions are characterized by the development of a fibrous stroma and an infiltration of macrophages, giant cells, and lymphocytes around the persistent antigen.
Lymphocytic choriomeningitis, a viral infection Viral Infections Rats are more commonly kept as pets than mice. Both species are used extensively in research. Although a great deal of information has been accumulated on wild and laboratory rats and mice,... read more of mice, results from the destruction of virus-infected cells by T cells, leading to CNS damage and a choriomeningitis.
Old-dog encephalitis may also result from cell-mediated immune mechanisms directed against cells persistently infected with canine distemper Canine Distemper virus. The initiating canine distemper virus infection is usually clinically inapparent and may precede the development of encephalitis by many years.
Allergic Contact Hypersensitivity
Allergic contact hypersensitivity results from chemicals reacting with and modifying normal dermal proteins. The modified proteins trigger a cell-mediated immune response, which causes inflammation and damages the skin (eg, poison oak and poison ivy reactions in people). This reaction has been described in dogs, cattle, and horses and usually occurs as a result of contact with sensitizing chemicals incorporated in plastic food dishes, plastic collars, and drugs placed on the skin.
Along with primary and secondary immunodeficiencies, the third type of immunologically mediated disease involves the development of autoimmunity. This is an immune response directed against normal cellular components. These diseases are readily divided into organ-specific diseases affecting a single body organ or into diseases directed against widespread antigens and as a result affect multiple organ systems.
Autoimmune thyroiditis in dogs is characterized by destruction of the thyroid gland by an autoimmune process that has both humoral (Type II) and cell-mediated (Type IV) components. It is particularly prevalent in Doberman Pinschers, Beagles, Golden Retrievers, and Akitas. Hypothyroidism Hypothyroidism in Animals Hypothyroidism is thyroid hormone deficiency. It is diagnosed by clinical features such as lethargy, weight gain, obesity, haircoat changes, and low serum thyroid hormone concentrations. Management... read more may be the sole manifestation of the disease or may be a clinical or subclinical component of a broader autoimmune disorder such as systemic lupus erythematosus Systemic Lupus Erythematosus (SLE) Excessive activity of the adaptive immune system can lead to inappropriate immune responses collectively called hypersensitivities. In general, inappropriate innate immune responses do this... read more or panendocrinopathy.
Autoimmune adrenalitis has been reported in dogs. The adrenal glands are slowly destroyed by a plasmacytic-lymphocytic infiltrate. When sufficient glandular tissue is destroyed, the dogs develop Addison disease ( adrenocortical insufficiency Addison Disease Addison disease (hypoadrenocorticism) results from the lack of glucocorticoids, mineralocorticoids, or both. Isolated aldosterone insufficiency appears to be very rare, whereas isolated glucocorticoid... read more . The condition is sometimes associated with autoimmune thyroiditis (see above).
Immune-mediated Hemolytic Anemia (IMHA) and Thrombocytopenia
The production of autoantibodies against erythrocyte or platelet antigens leads to anemia and thrombocytopenia, the most common Type II reactions. Antibody and complement attach to RBCs either directly or indirectly via an absorbed antigen and then mediate RBC destruction, resulting in a severe, life-threatening anemia. Concurrent thrombocytopenia is found in 60% of cases. IMHA can be associated with systemic lupus erythematosus Systemic Lupus Erythematosus (SLE) Excessive activity of the adaptive immune system can lead to inappropriate immune responses collectively called hypersensitivities. In general, inappropriate innate immune responses do this... read more or with lymphoreticular malignancies. Drugs or infections may trigger episodes of hemolytic anemia or thrombocytopenia in many species. More often than not, the initiating cause is unknown.
Immune-mediated hemolytic anemia occurs in several clinical forms: peracute, acute or subacute, chronic, cold agglutinin disease, and red cell aplasia. Most cases are treatable, but relapses are common.
Peracute IMHA is seen mainly in middle-aged, larger breeds of dogs. Affected dogs are acutely depressed and have a rapid decrease in PCV within 24–48 hours, with bilirubinemia, variable icterus, and sometimes hemoglobinuria. Initially, the anemia is nonresponsive, but it may respond within 3–5 days. Thrombocytopenia may also be present. Antiglobulin tests are often negative, and spherocytes may or may not be present, but tube or slide agglutination of RBCs is marked. The autoagglutination is not dispersed by saline dilution, hence the term hemolytic anemia with in-saline agglutinins. The serum usually contains autoantibodies that cause agglutination of most donor RBCs.
The prognosis of peracute IMHA is poor even with prompt and vigorous therapy. The most effective therapy involves immediate use of high dosages of glucocorticoids plus cyclophosphamide, together with a compatible blood transfusion. If incompatible blood must be used, the animal should first be heparinized and maintained on heparin for 10 days. Even without transfusion, heparinization may be beneficial for the first 2 weeks or more. Bovine hemoglobin blood substitute and human immunoglobulins can be used as supportive therapy until immunosuppressive treatment reduces the destruction of RBCs.
Acute IMHA is the most common form of the disease, with a breed predilection in Cocker Spaniels. Initial signs are pallor, fatigue, and less commonly, icterus. Hepatosplenomegaly is a prominent sign. The WBC count may be increased due to bone marrow hyperplasia. Autoagglutination of RBCs is uncommon, and the antiglobulin test is generally positive. These animals usually respond well to glucocorticoid therapy. If a favorable response is not seen within 7–10 days, cytotoxic drugs (cyclophosphamide or azathioprine) should be added to the regimen.
Chronic IMHA differs from the acute form in that the PCV falls to a constant level and remains there for weeks or months. The bone marrow is either normal or hyperresponsive, and the antiglobulin test is often negative. Chronic IMHA is relatively more common in cats than in dogs. Usually, the anemia is responsive early in the course of disease but responds minimally or not at all by the time it becomes severe. Initial treatment is with glucocorticoids; if there is no response within 2 weeks, cytotoxic drugs may be added to the regimen.
Cold agglutinin disease is an IMHA of dogs and horses. Its cause is usually unknown but it may be secondary to infection, other autoimmune diseases, or neoplasia. The IgM autoantibodies can be agglutinating or nonagglutinating. Complete agglutination does not occur at body temperature but only when the blood is chilled; thus, it is more frequent in colder climates and seasons. Initial signs may be of a hemolytic disease; in the agglutinating type, vascular blockage may lead to necrosis of the nose, tips of the ears and tail, digits, scrotum, and prepuce. Diagnosis is based on a reversible autoagglutination that occurs only at 4°C. The direct antiglobulin reaction is usually negative for IgG, frequently positive for C3, and usually positive for IgM if the reaction is performed in the cold. Mortality is high. In the absence of an obvious initiating cause such as infection or neoplasia, the disease is best controlled with high doses of glucocorticoids in combination with cyclophosphamide.
Red cell aplasia Anemia Caused by Primary Bone Marrow Diseases in Animals is most common in dogs. It occurs in two forms, one in postweanling to adolescent puppies and the other in adults. Unlike in IMHA, the bone marrow shows a selective depression of erythroid elements; granulocytes and platelets are unaffected. Therefore, the peripheral anemia is unresponsive. The immune attack is directed against erythroid stem cells, and the antiglobulin test is usually negative. Treatment is usually as for chronic IMHA, but recovery may be very slow.
Immune-mediated thrombocytopenia Primary Immune-mediated Thrombocytopenia (ITP) in Animals Disorders of platelets can be divided into acquired or congenital thrombocytopenias and acquired or congenital functional disorders (thrombocytopathias), with acquired thrombocytopenia being... read more is common in dogs. It occurs more often in females than males. The most frequent clinical signs are hemorrhages of the skin and mucous membranes. Melena, epistaxis, and hematuria may be accompanying features and can cause profound anemia. Hemolytic anemia and thrombocytopenia sometimes occur together. Immune-mediated thrombocytopenia usually is diagnosed on the basis of low peripheral platelet counts despite a pronounced megakaryocytosis in the marrow. Occasionally, megakaryocytes may be selectively absent from the marrow. Tests for antiplatelet antibodies are difficult to conduct, so diagnosis is usually made on clinical presentation and response to therapy.
Animals with immune-mediated thrombocytopenia that show only petechial and ecchymotic hemorrhages, with no significant blood loss and megakaryocytes in the marrow, may be treated initially with glucocorticoids. The clinical signs should abate and the platelet count begin to rise after 5–7 days. If the platelet count has not increased significantly by 7–10 days, cyclophosphamide, azathioprine, or vincristine can be added to the glucocorticoid regimen.
In animals with megakaryocytes in the marrow and severe blood loss, a more rapid response to therapy is desirable. Such animals are treated with a single injection of vincristine combined with daily glucocorticoids; a favorable response usually occurs after 3–5 days. If the blood loss is life-threatening, platelet-rich whole blood should be administered. If the platelet count has risen by day 7, remission is maintained on glucocorticoids alone. If there is no response after 7 days, a second dose of vincristine is given. If the platelet count is still low after 2 weeks, vincristine is discontinued and either cyclophosphamide or azathioprine is added.
Animals with thrombocytopenia and no megakaryocytes respond much more slowly to glucocorticoids, or to glucocorticoids and vincristine. Preferred treatment for these animals is with prednisolone and cyclophosphamide, and a response should not be expected earlier than 1–2 weeks after beginning therapy. Treatment may be discontinued in most animals with immune-mediated thrombocytopenia 1–3 months after the platelet count returns to normal. Some animals have a persistent thrombocytopenia despite drug therapy, or they can be maintained in remission only with chronic, high-dose treatment. The alternatives are to allow the animal to live with the thrombocytopenia if signs are minimal or to use longterm combination drug therapy with glucocorticoids and either vincristine, azathioprine, or cyclophosphamide. Splenectomy is seldom curative by itself but may allow use of lower and safer dosages of immunosuppressive drugs.
Autoimmune Skin Diseases
In autoimmune skin diseases, affected animals make autoantibodies against the intracellular cement proteins in the epidermis. This promotes local proteolysis, leading to separation of the epidermal cells (acantholysis) and development of vesicles within the skin.
Pemphigus foliaceus is the most common of these diseases, occurring more often in dogs than in cats and horses. It is characterized by the development of erosions, ulcerations, and thick encrustations of the skin and mucocutaneous junctions. The absence of lesions in the mouth, and the widespread thick, crusty nature of the skin lesions, tend to differentiate pemphigus foliaceus from the much rarer pemphigus vulgaris. Autoantibodies in the skin react with intracellular cement (desmoglein), resulting in its degradation and separation of the cornified and uncornified cell layers. Immunosuppression is required to treat the disease. High doses of glucocorticoids are used initially, but low-dose, alternate-day therapy is used once the disease is under control. More potent immunosuppressive drugs such as cyclophosphamide or azathioprine may be used with glucocorticoids in cases unresponsive to steroids alone. Animals that respond poorly to initial therapy, or that require high dosages of drugs to control lesions, have a poor longterm prognosis.
Pemphigus vulgaris is a less common autoimmune skin disease than pemphigus foliaceus. It is characterized by vesicle formation along the mucocutaneous junctions of the mouth, anus, prepuce, and vulva, and in the oral cavity. Other areas of the skin are only mildly involved. Because the epidermis of animals is relatively thin (compared with human skin), these blisters rupture rapidly and form erosions; consequently, characteristic bullae are seldom seen. The vesicles develop as a result of suprabasilar acantholysis. Secondary bacterial infection often complicates the lesions, and if untreated, the disease is often fatal. It is treated with high doses of glucocorticoids alone or in combination with other drugs such as cyclophosphamide, azathioprine, or gold salts. Pemphigus vulgaris is difficult to maintain in remission, and the longterm prognosis of affected animals is fair to poor.
Bullous pemphigoid is a rare canine skin disease recognized most often in Collies and Doberman Pinschers. Lesions are often widespread but tend to be concentrated in the groin. The involved skin resembles a severe scald. Bullae also develop; they are subepidermal and may be full of eosinophils. Autoantibodies to the basal lamina can be detected in immunohistopathologic sections. The treatment of choice is prednisolone and azathioprine used in combination; remission is frequent, but continual drug therapy at relatively high dosages may be required to keep the disease under control. The longterm prognosis is poor.
Myasthenia gravis is an autoimmune disease in which autoantibodies directed against the acetylcholine receptors of muscle cells cause receptor degradation or blockage and thus block neuromuscular transmission. The disease is characterized by extreme generalized muscle weakness, accentuated by mild exercise. Megaesophagus due to paralysis of esophageal muscles is a frequent primary or accompanying complaint in dogs. Thymomas are often associated with myasthenia gravis in people but are uncommon in domestic species. Administration of a short-acting anticholinesterase (edrophonium chloride) produces a dramatic increase in muscle strength. Treatment is with a long-acting anticholinesterase. Chronic immunosuppressive drug therapy for this disease is logical. Autoantibodies to the acetylcholine receptors can be detected in the serum of affected animals by an indirect immunohistopathologic assay using normal muscle as a substrate.
Immune-mediated meningitis occurs in adolescent or young adult Beagles, Boxers, German Shorthaired Pointers, and Akitas but is rare in other pure and mixed breeds. The clinical signs consist of:
cyclic episodes of fever
severe neck pain and rigidity
reluctance to move
Each attack lasts 5–10 days, with intervening periods of complete or partial normality lasting about a week. During attacks, protein and neutrophils in the CSF are increased. The primary lesion is a meningeal arteritis, but occasionally other organs are affected as well. The disease is often self-limiting, so that over several months attacks become milder and less frequent. Glucocorticoids reduce the severity of attacks. In some animals, the disease becomes chronic and only partially amenable to therapy.
A more severe form of this meningitis has been reported in young Bernese Mountain Dogs. The disease in this breed is somewhat cyclical, but the resolution in intervening periods is shorter than in other species. CSF abnormalities resemble those seen in other breeds. The condition requires longterm, high-dose glucocorticoid therapy.
A syndrome of meningitis, often associated with polyarthritis, is seen in young Akitas. The dogs show severe episodes of fever, depression, cervical pain and rigidity, and generalized stiffness. Affected dogs grow slowly and often appear unthrifty. The condition responds poorly to glucocorticoid and immunosuppressive therapy. Most affected dogs are euthanized as young adults. A milder and more drug-responsive form of the disease has been reported in older Akitas and may be associated with pemphigus foliaceus, uveitis, and plasmacytic-lymphocytic thyroiditis.
Keratitis sicca Nasolacrimal and Lacrimal Apparatus The tear production and drainage system is vital for health of the outer eye. Tear glands within the orbit (lacrimal and in some species Harder gland) as well as the superficial tear gland of... read more is a "dry eye" syndrome that occurs in dogs. It can occur in either a primary form or secondary to chronic use of sulfonamides. It results from immune-mediated destruction of the lacrimal glands and is similar to Sjögren syndrome of people. Affected dogs may respond favorably to cyclosporine eye drops.
Systemic Lupus Erythematosus (SLE)
This complex autoimmune disease occurs in dogs, is rare in cats, and has been reported in large animals. It has two consistent immunologic features: immune complex disease and a tendency to produce multiple autoantibodies. Clinically, it reflects a combination of Type II and III mechanisms. Antibodies to nucleic acids (called antinuclear antibodies, ANA) are the diagnostic hallmark of SLE, but in many individuals, antibodies to RBCs, platelets, lymphocytes, clotting factors, , and thyroglobulin are also present. The presence of ANA can be diagnostic of the disease. Either the immune complex or the autoantibody component of the disease tends to predominate in a given animal. Immune complex deposition around small blood vessels may lead to:
oral erosions and ulcers
Glomerulonephritis is one of the major, life-threatening complications of SLE in cats. Autoimmune hemolytic anemia or thrombocytopenia, or both, are the most common presentations of SLE in animals.
SLE is characterized by the presence of ANA, and tests for these or the associated lupus cells may help in diagnosis. However, some healthy animals may have ANA, and not all animals with SLE have detectable ANA in their blood. Diagnosis of SLE must therefore be based on the entire clinical syndrome—not just on the presence or absence of ANA.
SLE usually can be treated with glucocorticoids. Initially, they are used in high daily doses, and when remission occurs, alternate-day, low-dose therapy is used. Drug treatment should be continued for 2–3 months after all clinical signs have resolved. Cyclophosphamide or azathioprine, or both, are used in combination with glucocorticoids in animals with SLE that is difficult to control with glucocorticoids alone.
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Also see pet health information regarding types of immune system disorders in dogs Disorders Involving Anaphylactic Reactions (Type I Reactions, Atopy) in Dogs In a Type I reaction, the animal has been previously exposed to an antigen and produces an excess of antibodies. If this antigen appears in the blood, the reaction can be either body-wide (such... read more and types of immune system disorders in cats Disorders Involving Anaphylactic Reactions (Type I Reactions, Atopy) in Cats In a Type I reaction, the animal has been previously exposed to an antigen and produces an excess of antibodies. If this antigen appears in the blood, the reaction can be either body-wide (such... read more .