Secondary Immunological Defects

Key Points

• Immunodeficiencies caused by damage to the immune system (secondary immunodeficiencies) are not uncommon in domestic animals.

• The most important causes of immunosuppression are viral infections. To survive within a host, viruses may cause profound immunodeficiency either by infecting and killing lymphocytes or by causing them to become cancerous.

• Other important causes of immunodeficiencies include stress, both physical and mental, some environmental toxins, malnutrition (both starvation and obesity), and old age.

The immune system, like any body system, is subject to destruction and dysfunction as a result of attacks by pathogenic and environmental agents. Among the most important of these agents are microorganisms, especially viruses, toxins, stress of various types, old age, and malnutrition.

Virus-Induced Immunosuppression

Viruses that affect the immune system may be divided into those that affect primary lymphoid tissues and those that affect secondary lymphoid tissues. Both types of virus can cause profound immunodeficiencies. For example, in chickens, the infectious bursal disease virus (IBDV) destroys lymphocytes in the bursa of Fabricius. IBDV is not completely specific for bursal cells; it also destroys cells in the spleen and thymus. These tissues usually recover, whereas the bursa atrophies. The resulting immunosuppression, as might be predicted, is most evident in young birds infected soon after hatching, at a time when the bursa is actively engaged in generating B cells.

One of the most important animal viruses that destroys secondary lymphoid organs is canine distemper. Canine distemper virus, although it can multiply in many different cell types, has a predilection for lymphocytes, epithelia, and nervous tissue. Its primary cellular receptor is CD150, expressed on activated B and T cells. The distemper virus spreads from its initial invasion sites in the tonsils and bronchial lymph nodes to the bloodstream, where it kills both T and B cells and causes a lymphopenia. Subsequently it invades secondary lymphoid organs such as the spleen, lymph nodes, mucosal lymphoid tissues, and bone marrow, where it destroys more cells. The virus also invades and destroys the thymus. The shedding of infected cells from these lymphoid organs enables the virus to reach epithelial tissues and the brain. Canine distemper virus triggers lymphocyte and macrophage apoptosis and produces profound immunosuppression. It also suppresses production of interleukin-1 (IL-1) and IL-2 while stimulating prostaglandin release by macrophages. As a result, lymphocyte responses to mitogens are depressed, immunoglobulin levels fall, and skin allograft rejection is suppressed. This immunosuppression accounts, in large part, for the clinical signs of canine distemper. For example, many dogs with distemper develop Pneumocystis pneumonia. (Pneumocystis is a fungus that occurs in the lungs. It does not cause disease in immunocompetent animals but produces a severe pneumonia in animals with suppressed immune function. Indeed, the development of Pneumocystis pneumonia is evidence of a significant immunodeficiency.) If germ-free dogs are infected by virulent distemper virus, they develop a relatively mild disease, presumably because secondary infection cannot occur.

Loss of lymphocytes is common in virus infections since viral survival and persistence may require immunosuppression (Figure 38-1). Thus a lymphopenia occurs in feline panleukopenia, canine parvovirus-2 infection, feline leukemia, and African swine fever. Bovine virus diarrhea virus (BVDV) causes destruction of both B and T cells in the lymph nodes, spleen, thymus, and Peyer’s patches. As in canine distemper, surviving B cells fail to make immunoglobulins and respond poorly to mitogens. Viral destruction of Peyer’s patches causes intestinal ulceration and leads to secondary bacterial invasion. Both persistently infected cattle and normal cattle infected with cytopathic BVDV have depressed neutrophil functions, and bacterial clearance from the blood is impaired. A related virus, border disease virus, preferentially infects CD8+ T cells and interferes with their cytotoxic and immunoregulatory functions.

FIGURE 38-1 The immunosuppressive effect of viruses. The effect of administering a mixed vaccine (containing canine distemper, canine adenovirus, canine parainfluenza, canine parvovirus-2, and leptospira) on the response of a puppy’s lymphocytes to the mitogen phytohemagglutinin. Control levels were 100%. (Redrawn from Phillips TR, Jensen JL, Rubino MJ, et al: Effects of vaccines on the canine immune system, *Can J Vet Res* 53:154–160, 1989.)

Herpesviruses are also immunosuppressive. For example, equine herpesvirus-1 causes a drop in T cell numbers and depresses cell-mediated responses in foals. Bovine herpesvirus-1 (BHV-1) also causes a drop in T cells and in the responses to T cell mitogens. Although BHV-1 stimulates bovine alveolar macrophages to express increased amounts of MHC class II and promotes antibody-mediated phagocytosis, it also depresses macrophage-mediated cytotoxicity and IL-1 synthesis. Parainfluenzavirus-3 and infectious bovine rhinotracheitis viruses have long been known to interfere with alveolar macrophage function. They inhibit phagosome-lysosome fusion, paving the way for secondary infections with Mannheimia hemolytica in stressed calves. Porcine reproductive and respiratory syndrome (PRRS) virus in pigs causes destruction of alveolar macrophages and predisposes affected animals to severe enzootic pneumonia. It also kills dendritic cells, a feature that may account for the ability of PRRS virus to persist in pigs for up to 6 months.

The effect of some viruses on the immune system may be relatively complex or anomalous. In maedi-visna, a neurological disease of sheep caused by a retrovirus, cell-mediated immune responses such as graft rejection are suppressed, whereas B cell responses are enhanced (Chapter 26). Some leukemia viruses may be selectively immunosuppressive, so that depression of the IgG response is greater than that of the IgM response. In equine infectious anemia, the IgG3 response is variably depressed, whereas synthesis of the other immunoglobulin classes remains unaffected.

The results of virus-induced lymphoid tissue destruction are readily seen. Animals are lymphopenic and have reduced lymphocyte responses to mitogens. For example, responses to phytohemagglutinin are depressed in influenza, measles, canine distemper, Marek’s disease, Newcastle disease, feline leukemia, bovine virus diarrhea, and lymphocytic choriomeningitis. Destruction of lymphoid tissues may also result in hypogammaglobulinemia or a reduced response to antigens. Thymic atrophy and lymphopenia are common manifestations of many virus infections, and before any primary immunodeficiency syndrome is diagnosed, rigorous steps must be taken to exclude the possibility that it is, in fact, secondary to a virus infection.

Retrovirus Infections in Primates

More than 40 lentiviruses have been isolated from nonhuman primates, especially African species. These simian immunodeficiency viruses include SIV_mac isolated from a rhesus macaque (Macaca mulatta) in a laboratory; SIV_agm from an African green monkey (Chlorocebus sabaeus); SIV_sm from a sooty mangabey (Cercocebus atys); SIV_mnd from a mandrill (Mandrillus sphinx); and most important, SIV_cpz from a chimpanzee (Pan troglodytes). SIV_cpz is the ancestor of HIV-1, whereas SIV_sm is the ancestor of HIV-2. All these isolates selectively invade CD4+ T cells. When SIV_mac infects rhesus macaques and other Asian species, it stimulates a strong but ineffective immune response. Viral replication continues and eventually causes an immunodeficiency syndrome similar to human AIDS. The infection is believed to be transmitted sexually. Clinical disease progression is slow, but the animals eventually develop lymphadenopathy, severe weight loss, chronic diarrhea, lymphomas, neurological lesions, and opportunistic infections by organisms such as Pneumocystis, Mycobacterium avium-intracellulare, Candida albicans, and Cryptosporidium parvum. The macaques are immunosuppressed as a result of depletion of CD4+ T cells, macrophages, and dendritic cells. The virus invades both T cells and macrophages using two cellular receptors, CD4 and either the receptor for the chemokine CCR5 or for CXCR4. About 25% of infected animals do not mount a significant response to SIV and die within 3 to 5 months as a result of a severe SIV encephalitis. Macaques that mount an immune response usually die 1 to 3 years after infection. Spontaneous recovery does not occur. The other SIVs cause persistent viremia but rarely result in disease in African primates. This is because they rapidly develop an antiinflammatory response that prevents chronic T cell activation and apoptosis.

Type D Simian Retroviruses

An acquired immunodeficiency syndrome (AIDS) develops in primates infected with one of several endogenous type D simian retroviruses (SRVs). These viruses, much more common than the lentiviruses, are transmitted by biting; vertical transmission rarely occurs. SRVs have a much broader tissue tropism than the SIVs and, in addition to lymphocytes and macrophages, can also infect fibroblasts, epithelial cells, and the central nervous system. The SRVs destroy both B and T cells, leading to death from opportunistic infections. The syndrome is associated with a profound drop in serum IgG and IgM levels and a severe lymphopenia. Monocyte function is unimpaired, but surviving lymphocytes do not respond to mitogens. Affected monkeys are also profoundly neutropenic. On necropsy, the monkeys have a generalized lymphadenopathy, hepatomegaly, and splenomegaly. There is a loss of lymphocytes from the T-dependent areas of the secondary lymphoid organs. B cell areas show an initial hyperplasia of the secondary follicles followed by the loss of these follicles and an absence of plasma cells. These histological changes are very similar to those seen in AIDS in humans. In many cases, normally innocuous agents such as Pneumocystis, cytomegalovirus, C. parvum, and C. albicans cause infection. Some affected monkeys develop tumors such as fibrosarcomas. About half of the infected animals develop neutralizing antibodies and survive the disease. The others die from septicemia or diarrhea with wasting.

Retrovirus Infections in Cats

Feline Leukemia

Feline leukemia virus (FeLV) is an oncogenic retrovirus that can cause both proliferative and degenerative diseases in cats (Figure 38-2). Three naturally occurring viral variants are recognized based on the structure of their gp70 protein. FeLV-A is the predominant, naturally transmitted variant. It is present in all FeLV-infected cats. The other variants are only found in association with FeLV-A. When FeLV-A combines with endogenous retroviral sequences (sequences that are stably integrated into the cat genome and are normally never expressed but are genetically transmitted), FeLV-B is formed. FeLV-B is found in about 50% of viremic cats and has a greater propensity than FeLV-A to cause tumors. FeLV-C is found in about 1% to 2% of infected cats and arises from FeLV-A through a mutation in the envelope gene. It is much more suppressive for bone marrow than FeLV-A.