Diseases Involving Immune Complexes
(Type III reactions) |  |
| Immune complex disorders are among the most common of the immunologic diseases. They may be idiopathic or of secondary origin. The site of deposition of the immune complexes determines the nature of the disease. |
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Glomerulonephritis (
Glomerular Disease) is caused by deposition of antigen-antibody complexes in the subendothelial or subepithelial surface of the glomerular basement 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. |
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Hypersensitivity pneumonitis is caused by deposition of immune complexes in the alveoli; it is most common in large animals that are exposed 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). Hypersensitivity pneumonitis is characterized by the onset
of respiratory distress 4-6 hr after exposure to moldy hay. The most effective treatment is removal of the source of the antigen; otherwise, corticosteroid therapy may help. |
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Systemic lupus erythematosus (SLE) occurs in dogs, is rare in cats, and has been reported in large animals. It has 2 immunologic features: immune complex disease and a heightened antibody responsiveness with a tendency to produce autoantibodies. Therefore, it is a combination of Type II and III diseases. Antibodies to nucleic acid are the diagnostic hallmark of SLE, but in some individuals, antibodies to RBC, platelets, lymphocytes, clotting factors, immunoglobulin
(rheumatoid factors), and thyroglobulin also may be present. These autoantibodies, in particular those to nucleic acids, are not always pathogenic by themselves. Rather, they should be considered markers of the disease. Although combinations of autoantibodies and self-antigens may contribute to the total pool of immune complexes, they are not the sole source of immune complexes. Usually, either the immune complex or the autoantibody aspect of the disease predominates in a given
animal. Immune complex deposition around small blood vessels leads to synovitis, dermal reactions, oral erosions and ulcers, myositis, neuritis, meningitis, arteritis, myelopathy, glomerulonephritis, and pleuritis. Glomerulonephritis is one of the major life-threatening complications of SLE in cats but not in dogs. Psychosis, a major sign of SLE in people, is also seen in animals with SLE. Autoimmune hemolytic anemia or thrombocytopenia, or both, are the most common autoantibody
manifestations of SLE in animals. |
| SLE is characterized by the presence of antinuclear antibodies (ANA), and tests for these or the associated LE 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 should 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 mo after all clinical signs have disappeared. 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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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 are seen 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 SLE 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 (if implicated in the cause) or 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. (See also
periarteritis nodosa, below.) |
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Purpura hemorrhagica of horses is a form of nonthrombocytopenic purpura (
Congenital Thrombocytopenia) that often is a sequela of an earlier
Streptococcus
equi
respiratory infection; it is mediated by immune complexes of antibody and streptococcal antigen in vascular basement membranes.
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Anterior uveitis (
Anterior Uvea) often involves immune-complex-mediated reactions; it frequently occurs in the recovery stage of infectious canine hepatitis (
Infectious Canine Hepatitis: Introduction) due to the reaction of serum antibodies with uveal endothelial cells that contain canine adenovirus 1. Similarly, equine recurrent uveitis (
Equine Recurrent Uveitis: Introduction) or anterior uveitis of horses may be associated with immunologic reactions to
Leptospira
or
Onchocerca
spp
. Uveitis caused by
Toxoplasma
and feline infectious peritonitis virus infections of cats also has an immunologic basis. |
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Canine rheumatoid arthritis 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 prominent lesion is a progressive
erosion of cartilage and subchondral bone in the area of synovial attachments, which results in loss of articular cartilage and collapse of the joint space. Angular deformities often occur, and luxation of the joint is a frequent sequela. Deformities are most frequent in the carpal, tarsal, and phalangeal joints, and less frequent in the elbow and stifle. Synovial fluid changes indicate a sterile, inflammatory synovitis, with increased total cell count and a high proportion of
neutrophils in the synovial fluid cell population. The condition is believed to be due to deposition of immune complexes in the synovia. |
| A rheumatoid arthritis also has been recognized in cats. It tends to occur in older male cats and frequently is associated with feline leukemia virus infection. The development of disease in cats is much more insidious than in dogs. |
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Plasmacytic-lymphocytic synovitis, possibly a variant of rheumatoid arthritis, occurs in medium and large breeds of dogs. Although multiple joints often are involved, the disease has a predisposition for the stifles. The most common clinical sign is hindlimb lameness and anterior drawer motion of the stifles. Lymphocytes and polymorphonuclear neutrophils predominate in the synovial fluid, although in some cases the fluid is essentially normal. Gross inspection of the
joint reveals a yellowish proliferation of the synovial membrane and stretching or rupture of the cruciate ligaments. |
| Canine rheumatoid arthritis and plasmacytic-lymphocytic synovitis respond poorly to systemic glucocorticoids alone. Cyclophosphamide and azathioprine frequently are used with glucocorticoids to treat these disorders; NSAID (eg, aspirin, carprofen, etodolac, meloxicam) may help bring relief. |
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Idiopathic polyarthritis 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 systemic lupus erythematosus; joint disease 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 is inflammatory in nature but 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 mo. Dogs that do not respond well to such therapy
(>50%) are treated with more potent immunosuppressive drugs such as azathioprine or cyclophosphamide in addition to glucocorticoids. Gold salts may be helpful in augmenting glucocorticoid therapy in some animals. |
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Periarteritis nodosa (polyarteritis nodosa, necrotizing polyarteritis) is a rare, idiopathic disease of domestic animals that usually occurs as a secondary immunologic manifestation 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 hypertensive arterial reaction to these bacteria or to
their vaccines. It has been reported in cats, although it is often mistaken for the noneffusive form of feline infectious peritonitis. |
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Immune-mediated meningitis is believed to occur in dogs. The condition also has been called periarteritis nodosa, although its relationship to the human syndrome is uncertain. A steroid-responsive meningitis has been seen in adolescent or young adult Beagles, Boxers, German Shorthaired Pointers, and Akitas, but is very rare in other pure and mixed breeds. The clinical signs in Beagles, Boxers, and German Shorthaired Pointers consist of cyclic bouts of fever, severe neck
pain and rigidity, reluctance to move, and depression. Each attack lasts 5-10 days, with intervening periods of complete or partial normalcy lasting ≥1 wk. During attacks, protein and neutrophils in the CSF are increased. The lesion is an arteritis, primarily of the meningeal vessels, but occasionally of other organs as well. The disease is often self-limiting over several months; attacks become milder and less frequent. Glucocorticoid therapy reduces 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 a litter of young Bernese Mountain Dogs. The disease in this litter was somewhat cyclical, but the resolution in intervening periods was less than in the disorder of Beagles, German Shorthaired Pointers, and Boxers. CSF abnormalities resembled those of the disease in other breeds. The condition was less self-limiting and required longterm, high-dose glucocorticoid therapy to keep the animals comfortable. |
| A syndrome of meningitis, often associated with polyarthritis, is seen in Akitas as young as 12 wk old. The dogs show severe (but somewhat cyclical) bouts of fever, depression, cervical pain and rigidity, and generalized stiffness. Affected dogs grow at a slower rate and often appear unthrifty. The condition responds poorly to glucocorticoid and combination immunosuppressive therapy, and most dogs are euthanized as young adults. In older Akitas, a milder and more drug-responsive
form of the disease is seen, which may be associated with pemphigus foliaceus, uveitis, and plasmacytic-lymphocytic thyroiditis. |
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