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Primary Immunodeficiencies

By Ian Tizard, BVMS, PhD, DACVM, University Distinguished Professor of Immunology; Director, Richard M. Schubot Exotic Bird Health Center, Department of Veterinary Pathobiology, College of Veterinary Medicine and Biomedical Sciences, Texas A&M University

Defects in Innate Immunity

Phagocytosis is a central feature of innate immunity. Phagocytic cells are found underlying the mucous membranes and skin and in the bloodstream, spleen, lymph nodes, meninges, synovial membrane, bone marrow, and around blood vessels throughout the body. Phagocytes are either in the tissue (histiocytes, synovial macrophages, Kupffer cells, etc) or in the blood (neutrophils and monocytes). Phagocytes have receptors for immunoglobulins and complement on their surfaces that assist in the engulfment (opsonization) of foreign material coated with specific antibody (opsonins) or complement, or both. Phagocytosis involves chemotaxis of the phagocyte toward foreign, noxious, or damaged tissues; adherence of microorganisms to the plasma membrane of the phagocyte; incorporation of the organisms into a phagosome; and activation of the respiratory burst and lysosomal enzymes in the phagosome, leading to microbial death and destruction.

Deficiencies in Phagocytosis:

Deficiencies in phagocytic activity can be due to acquired or congenital defects in any of these steps, or simply to a deficiency of phagocytic cells themselves. They often manifest as an increased susceptibility to bacterial infections of the skin, respiratory system, and GI tract. These infections respond poorly to antibiotics. Secondary phagocytic deficiencies include disorders that lead to profound and chronic depressions of WBCs. Feline leukemia virus infection, feline panleukopenia virus infection, feline immunodeficiency virus infection, tropical canine pancytopenia, idiopathic granulocytopenias, drug-induced granulocytopenias (antineoplastic drugs, estrogens, anticonvulsants, sulfonamides, etc), and myeloproliferative disorders are some of the conditions in which secondary infections can develop as life-threatening complications.

A cyclic decrease of all cellular elements, most notably neutrophils, occurs in the peripheral blood and lowers the resistance to infection of certain lines of gray Collies and Collie crosses.

Congenital abnormalities that lead to impaired phagocytosis are well documented in people. Deficiencies of opsonins, complement factors, chemotactic abilities, and myeloperoxidase have been recognized in people but not in other animals. Chediak-Higashi syndrome results from a defect in phagosomal function and has been recorded in cats, mink, cattle, and orcas. Chronic granulomatous disease has been recognized as an X-linked defect in some Irish Setters (canine granulocytopathy syndrome). Some lines of Weimaraners develop bacterial septicemias (usually manifested by bone and joint infections) as puppies. The underlying causes of these defects are unknown; some of the affected dogs have lower than normal levels of IgM and IgG, and their WBCs have a bactericidal defect.

Leukocyte Adhesion Deficiency:

Leukocyte adhesion deficiency is an autosomal recessive primary immunodeficiency. It has been described in people, Irish Setters, and Holstein cows. The deficiency results from the absence of an integrin, an essential surface glycoprotein expressed on leukocytes. Clinically, it is characterized by recurrent severe bacterial infections, impaired pus formation, and delayed wound healing. Infected animals usually have severe pyrexia, anorexia, and weight loss. Response to antibiotic therapy is usually poor. Extreme, persistent leukocytosis may occur (>100,000 WBCs/mL) and consists predominantly of mature neutrophils. The integrin deficiency prevents blood leukocytes from leaving blood vessels and entering the tissues, so they cannot contribute to the defense of tissues against infections.

Complement Deficiencies:

A congenital deficiency of C3 has been described in Brittany Spaniels. These dogs developed recurrent bacterial infections, especially skin diseases and pneumonias. Although complement is necessary for opsonization and neutrophil chemotaxis, bacterial infections do not always develop in people or laboratory animals with complement deficiencies, because the existence of multiple pathways provides a way to activate the system even if one pathway is blocked. Diagnosis is based on a blood test showing reduced C3 levels.

A congenital deficiency in the C1 inhibitor has been recognized in people and occurs rarely in dogs. This can lead to uncontrolled complement activation and inflammation. Affected animals have recurrent bouts of facial edema.

There is no specific treatment for complement deficiencies. Vaccination and antibiotics are used to prevent and treat infection. As with all inherited diseases, subsequent breeding programs must be carefully assessed to prevent the reappearance of the disease in future generations.

Deficiencies in Adaptive Immunity

Humoral Immunodeficiencies:

These deficiencies may be acquired or congenital. Acquired deficiencies are seen in neonates that do not receive adequate maternal antibodies (failure of passive transfer) or in older animals due to conditions that decrease active immunoglobulin synthesis. Failure of passive transfer occurs in species that use colostrum as the major source of maternal antibodies. It is commonly associated with recurrent infections in calves, lambs, and foals. Failure of passive transfer can occur when the young animal fails to nurse properly during the first several days of life or when the dam’s colostrum contains low levels of specific antibodies. Defects in the absorption of immunoglobulin from ingested milk may also occur. Immunoglobulin levels <400 mg/dL in a postnursing serum sample indicate a failure of passive transfer in foals. Premature weaning of calves is a problem in dairy herds and is a leading cause of failure of passive transfer in dairy calves. Newborn animals that do not receive sufficient maternal antibodies often succumb to fatal bacterial or viral infections of the GI and respiratory tracts.

Hypogammaglobulinemia of clinical significance can be associated with any disorder that interferes with antibody synthesis. Tumors, such as plasma cell myelomas or lymphosarcomas that secrete large amounts of monoclonal antibody, can be associated with profound antibody deficiencies. This is because the tumor cells outcompete normal immunoglobulin-producing cells, or because regulatory pathways inhibit immunoglobulin production. Animals with tumors that produce monoclonal antibodies may have severe secondary infections. Some viral infections, eg, canine distemper and canine parvovirus, may damage the immune system so severely that antibody production is virtually stopped.

Congenital hypogammaglobulinemia has been recognized either alone or in combination with defects in cell-mediated immunity (combined immunodeficiency, see below). Deficiencies in IgG subclasses have been seen in some breeds of cattle; IgM deficiency has been described in horses; and IgA deficiencies have been described in Beagles, German Shepherds, and Chinese Shar-Pei. Cattle with IgG subclass deficiency are usually asymptomatic. Older foals with IgM deficiencies develop respiratory infections. Dogs with IgA deficiency, like their human counterparts, are prone to chronic skin infections, chronic respiratory infections, and possibly allergies. IgA deficiency of Beagles appears to be due to a defect in the secretion of IgA, because IgA-positive cells are present in normal numbers. Some German Shepherds have lower IgA levels than other breeds and a higher incidence of intestinal infections. IgA deficiency in Shar-Pei is highly variable; some have negligible serum and secretory levels, and some have normal serum levels and low or negligible secretory levels. Like German Shepherds, affected Shar-Pei have more problems than expected with allergies. Dogs with these immunodeficiency syndromes may have a higher than usual incidence of autoimmune diseases and autoantibodies, such as autoimmune hemolytic anemia, thrombocytopenia, and systemic lupus erythematosus. Longterm treatment with broad-spectrum antibiotics is required and is often unsatisfactory.

Transient hypogammaglobulinemia has been recognized most frequently in foals and puppies. It may be more common in Spitz-type puppies than in other breeds. It results from a delayed onset of immunoglobulin production in the newborn and is associated with defects in both TH function and the B cell response to foreign antigens. Puppies with this condition develop recurrent respiratory infections at 1–6 mo of age but recover by 8 mo. Affected foals frequently develop clinical signs of hypogammaglobulinemia (usually respiratory infections) at ~6 mo of age when their maternal antibody reaches a very low level. After another 3–5 mo they begin to produce immunoglobulin. Appropriate antibiotic treatment and supportive therapy is often sufficient.

Deficiencies in Cell-mediated Immunity:

Deficiencies in cell-mediated immune responses are associated with thymic aplasia, an absent or very small thymus. This has been seen in some inbred lines of dogs, cats, and cattle; these animals were deficient in cell-mediated immune functions, as well as having pituitary dysfunction.

Combined Immunodeficiency Diseases:

If both humoral and cell-mediated immune responses are deficient, they are classified as combined immunodeficiencies (CID). These result from inherited defects in the earliest lymphocyte progenitors. An autosomal recessive CID has been identified in Arabian foals and Basset Hounds. It results from a defect in DNA repair enzymes and prevents the production of functional antigen receptors. Sporadic cases of CID have also been seen in Toy Poodle, Rottweiler, and mixed-breed puppies. Affected dogs are frequently asymptomatic during the first several months of life but become progressively more susceptible to microbial infections as maternal antibody wanes. Puppies with CID are clinically normal until 6–12 wk of age. The most common cause of death from CID is canine distemper as a consequence of routine immunization with modified-live virus distemper vaccine. Arabian foals with CID frequently succumb to adenovirus pneumonia or other infections when ~2 mo old. The foals are persistently lymphopenic. Precolostral serum samples have no detectable IgM antibody. Immunoglobulin levels are normal initially but then progressively decrease compared with levels in normal foals. At necropsy, the thymus is difficult to identify and is architecturally abnormal. Lymphocyte numbers are depleted in the lymph nodes, Peyer's patches, and spleen. A PCR test can confirm CID in foals and the presence of the gene in heterozygote animals. As a result of such testing, the prevalence of equine CID has declined significantly.

Selective Immunodeficiencies:

A large number of immunodeficiency diseases have yet to be fully analyzed, so their precise mechanisms remain unknown. For example, Rottweiler puppies have a breed predilection for severe and often fatal canine parvovirus infections (see Canine Parvovirus). Their resistance to other infections is essentially normal, and the basis of this selective immunodeficiency is unknown.

Persian cats have a predilection toward severe, and sometimes protracted, dermatophyte infections (see Dermatophytosis). In some Persian cats, the fungal infections invade the dermis and cause granulomatous disease (mycetomas).

Mink with the Aleutian coat color mutation are susceptible to chronic parvovirus infection and so develop Aleutian disease (see Aleutian Disease (Plasmacytosis)). Other strains of mink are susceptible to infection with this virus but do not develop clinical disease. This is due to inherited Chediak-Higashi syndrome.

Focal and systemic aspergillosis (see Aspergillosis), and mycoses due to related fungi, affect certain types of dogs. Long-nosed breeds, in particular German Shepherds and Shepherd-crosses, are prone to develop focal aspergillosis in the nasal passages. Systemic aspergillosis is seen almost exclusively in German Shepherds. It is characterized by fungal pyelonephritis, osteomyelitis, and discospondylitis. The organism can be isolated readily from blood and urine.

Diagnosis of Primary Immunodeficiencies

Recurrent persistent infections in young animals suggest some form of immunodeficiency. A complete differential leukocyte count will reveal whether all leukocyte types are present in appropriate numbers. Immunoglobulin deficiencies can only be detected by means of a quantitative immunoassay such as radial immunodiffusion, although turbidity tests such as those used for the diagnosis of failure of passive transfer are relatively easy to perform and may provide useful diagnostic information.

Primary immunodeficiencies as genetic diseases are generally not treatable and, if diagnosed, steps should be taken to ensure that parent animals that carry defective traits are no longer used for breeding.