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Professional Version

Primary Immunodeficiencies in Animals

By

Ian Rodney Tizard

, BVMS, BSc, PhD, DSc (Hons), DACVM, Department of Veterinary Pathobiology, College of Veterinary and Biomedical Sciences, Texas A&M University

Reviewed/Revised Jan 2024

Deficiencies in Innate Immunity

Destruction of invading bacteria by phagocytosis is a central feature of innate immunity and inflammation. Phagocytic cells are found either in the tissues (histiocytes, synovial macrophages, Kupffer cells, etc) or in the bloodstream (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 microbial invaders; adherence of microorganisms to the plasma membrane of the phagocyte; ingestion of the organisms into a phagosome; and subsequent activation of the respiratory burst and lysosomal enzymes in the phagosome, leading to microbial death and destruction.

Defects in Phagocytosis in Animals

Defects in phagocytic activity can be due to acquired or congenital defects in any of the above processes or simply to a deficiency of phagocytic cells themselves. Defects 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 a persistent loss of leukocytes. Some of the conditions in which secondary infections can be lethal include the following:

Congenital abnormalities that lead to impaired phagocytosis are well documented in animals. 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. This is a consequence of a failure of leukopoiesis in the bone marrow. Deficiencies of opsonins, chemotactic abilities, and myeloperoxidase have also been recognized in dogs. Other congenital abnormalities include the following:

The underlying genetic causes of these defects are unknown; some of the affected dogs have lower-than-normal levels of IgM and IgG, and their leukocytes have a bactericidal defect.

Trapped neutrophil syndrome is an inherited canine disease in which neutrophils produced by the bone marrow cannot gain access to the bloodstream to reach infected tissues.

Leukocyte Adhesion Deficiency in Animals

Leukocyte adhesion deficiency is an autosomal recessive primary immunodeficiency. It has been described in humans, Irish Setters, and Holstein calves. The deficiency results from the absence of an adhesive glycoprotein expressed on leukocytes. Clinically, it is characterized by recurrent bacterial infections, impaired pus formation, and delayed wound healing. Infected animals usually develop pyrexia, anorexia, and weight loss. Response to treatment with antimicrobials is usually poor.

Extreme, persistent leukocytosis may occur (> 100,000 WBC/mL) and consists predominantly of mature neutrophils. The deficiency prevents blood leukocytes from binding to vascular endothelial cells. As a result, they cannot migrate from blood vessels to enter the tissues, so they cannot contribute to the local defense of tissues against infections.

Complement Deficiencies in Animals

A congenital deficiency of complement component 3 (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 humans 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 decreased C3 levels. A congenital deficiency in the C1 inhibitor has been recognized in humans and occurs rarely in dogs and pigs. 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

Immunoglobulin Deficiencies in Animals

Immunoglobulin deficiencies may also be acquired or congenital. Acquired deficiencies occur in neonates that do not receive adequate maternal antibodies (failure of passive transfer) or in older animals due to drugs and infections that inhibit B cell immunoglobulin synthesis.

Failure of passive transfer occurs in mammals that use colostrum as their major source of maternal antibodies. Newborn animals that do not receive sufficient colostrum often succumb to fatal bacterial or viral infections of the intestinal or respiratory tracts. Failure of passive transfer can occur when a newborn 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.

Hypogammaglobulinemia of clinical significance can be associated with any disorder that interferes with antibody synthesis. Tumors, such as 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 and because regulatory pathways inhibit immunoglobulin production. Animals with myelomas that produce monoclonal antibodies may have secondary infections. Some viruses, such as canine distemper Canine Distemper and canine or feline parvovirus Canine Parvovirus Canine parvovirus is a highly contagious virus that commonly causes GI disease in young, unvaccinated dogs. Presenting signs include anorexia, lethargy, vomiting, and diarrhea, which is often... read more , can damage the immune system so severely that B cells are destroyed and antibody production ceases. Overgrowth by commensal fungi such as Pneumocystis spp may then occur.

Congenital hypogammaglobulinemia has been recognized either alone or in combination with defects in cell-mediated immunity (combined immunodeficiency Combined Immunodeficiency Diseases Destruction of invading bacteria by phagocytosis is a central feature of innate immunity and inflammation. Phagocytic cells are found either in the tissues (histiocytes, synovial macrophages... read more ). 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-Peis.

Cattle with IgG subclass deficiency are usually clinically normal. 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 allergies. IgA deficiency of Beagles appears to be due to a defect in its secretion because IgA-positive cells are present in normal numbers. Some German Shepherds have lower IgA levels than other breeds and a higher prevalence of intestinal infections. IgA deficiency in Shar-Peis is highly variable; some have negligible serum and secretory levels, whereas some have normal serum levels and low or negligible secretory levels. Like German Shepherds, affected Shar-Peis may develop allergic disease. Longterm treatment with broad-spectrum antimicrobials 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 a newborn. Puppies with this condition develop recurrent respiratory infections at 1–6 months but usually recover by 8 months. Affected foals frequently develop clinical signs of hypogammaglobulinemia (usually respiratory infections) at ~6 months old when their maternal antibody reaches a very low level. After another 3–5 months, they begin to produce immunoglobulins. Appropriate antimicrobial treatment and supportive care is often sufficient.

Deficiencies in Cell-Mediated Immunity in Animals

Deficiencies in cell-mediated immune responses are associated with thymic aplasia, an absent or very small thymus. This has been observed in dogs, cats, and cattle, as well as mice. This condition in laboratory mice has been used to create inbred strains of athymic mice (commonly known as nude mice because they lack hair) that are widely used in immunologic research.

Combined Immunodeficiency Diseases in Animals

If both humoral and cell-mediated immune responses are deficient, they are classified as combined immunodeficiencies (CIDs). These result from inherited defects in the earliest lymphocyte progenitors. An autosomal recessive CID has been identified in Arabian foals, Corgis, and Basset Hounds. It results from a defect in DNA repair enzymes and prevents the production of functional antigen receptors.

Affected dogs are frequently clinically normal during the first several months of life but become progressively more susceptible to microbial infections as maternal antibody wanes. Puppies with CIDs are usually clinically normal until 6–12 weeks.

Arabian foals with CIDs frequently succumb to adenovirus pneumonia or other infections when ~2 months old. The foals are persistently lymphopenic. Precolostral serum samples have no detectable IgM antibody. Immunoglobulin levels are normal at first but then progressively decline when compared with levels in healthy foals. At necropsy, the thymus may be difficult to identify and structurally abnormal. Lymphocytes are depleted in lymph nodes, Peyer patches, and spleen.

A PCR assay can confirm CIDs in foals and the presence of the mutated gene in heterozygote animals. As a result of such testing, the prevalence of equine CIDs has declined markedly.

Selective Immunodeficiencies in Animals

Many inherited immunodeficiency diseases have yet to be fully analyzed, so their causative mutations remain unknown. For example, Rottweiler puppies have a breed predilection for severe and often fatal canine parvovirus Canine Parvovirus Canine parvovirus is a highly contagious virus that commonly causes GI disease in young, unvaccinated dogs. Presenting signs include anorexia, lethargy, vomiting, and diarrhea, which is often... read more infections. Their resistance to other infections is essentially normal, and the basis of this selective immunodeficiency is unknown.

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

Focal and systemic aspergillosis Aspergillosis in Animals Aspergillosis is a sporadic fungal infection due to several environmentally ubiquitous Aspergillus spp. A fumigatus is believed to be the most common; however, multiple other species... read more Aspergillosis in Animals , as well as mycoses due to related fungi, affect certain breeds of dogs. German Shepherds and shepherd crosses are prone to develop focal aspergillosis in the nasal passages. Systemic aspergillosis is observed almost exclusively in German Shepherds. It is characterized by fungal pyelonephritis, osteomyelitis, and discospondylitis. The organism can be isolated readily from blood and urine. This is usually a consequence of the IgA deficiency in this breed.

Diagnosis of Primary Immunodeficiencies in Animals

Recurrent persistent infections in young animals suggest some form of immunodeficiency. A complete differential leukocyte count will reveal whether the cells are present in appropriate numbers. Turbidity tests are relatively easy to perform and are used to measure immunoglobulin levels and so diagnose failure of passive transfer of immunity. They may also provide useful diagnostic information. The amount of precipitate that forms can be easily measured in a spectrophotometer and, in effect, gives a direct reading of the amount of immunoglobulin present. Specific immunoglobulin deficiencies can be detected by means of a quantitative immunoassay such as radial immunodiffusion.

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

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