Immunodeficiency (2).pdf

IMMUNODEFICIENCY VETS2007 Chiara Palmieri ([email protected]) Immunodeficiency may be defined as impairment in function of part or parts of the immune system that renders the immunodeficient patient more susceptible to infectious diseases. Two broad categories exist: 1) primary immunodeficiency:...

IMMUNODEFICIENCY VETS2007 Chiara Palmieri ([email protected]) Immunodeficiency may be defined as impairment in function of part or parts of the immune system that renders the immunodeficient patient more susceptible to infectious diseases. Two broad categories exist: 1) primary immunodeficiency: when there is a mutation in a gene encoding a molecule of the immune system. Such diseases are inherited and congenital. 2) secondary immunodeficiency: occurs in an adult animal that had previously normal immune function and may be related to age, infection, medical therapy or the presence of chronic disease. PRIMARY IMMUNODEFICIENCY These disorders are relatively rare, although there are some very well studied animal primary immunodeficiencies for which the precise genetic basis is known. Spontaneously arising primary immunodeficiencies are most common and best described in dogs and horses. The primary immunodeficiency diseases can affect immune system development at different levels. A mutation that inhibits the development of both T and B lymphocytes (e.g. SCID) will have much more consequences for the animal than a mutation that selectively impairs the production of complement factor C3 or IgA. The range of immunodeficiency disorders encompasses:         Failure of the pluripotent stem cell Failure of committed stem cells Failure of T-cell development Failure of B-cell development Failure of B-cell maturation to plasma cells Failure of production of selected immunoglobulin class/es Failure to produce functional phagocytic cells Failure of production of one or more complement molecules There are certain clinical and historical features of disease that might suggest the presence of an underlying primary immunodeficiency in any animal. These include:        Disease affecting one particular breed Disease occurring in young littermate animals with onset shortly after the expected time of loss of maternally-derived immunity Chronic recurrent infections Infection of multiple body sites Failure of infection to respond to standard antimicrobial therapy Infection with environmental saprophytes Persistent lymphopaenia or hypogammaglobulinaemia  Failure to respond to vaccination Inherited defects in innate immunity They include defects in the various stages of phagocytosis as well as complement deficiencies. (a) Chediak Higashi syndrome The Chediak Higashi syndrome presents as abnormal granulation of the neutrophil cytoplasm. This autosomal recessive disorder is associated with defective neutrophil function and increased susceptibility to infection and is caused by a mutation in the LYST gene, which encodes a molecule involved in the fusion of lysosomal membranes. The disease occurs in the blue smoke Persian cat, in Hereford, Japanese and Brangus cattle, Aleutian mink, white tigers, killer whales and man. The defect produces abnormally large secretory lysosomes in neutrophils, monocytes, eosinophils and pigmented cells. The leukocyte granules of affected animals are more fragile than those of normal animals, rupturing spontaneously and causing tissue damage. These leukocytes have defective chemotactic responsiveness, reduced motility and reduced intracellular killing. Cytotoxic T cells fail to excrete their granzyme-rich lysosomes. There is an increased susceptibility to respiratory infections and neonatal septicaemia, as well as to tumours and viral infections. Affected animals may have diluted coat colour and poorly pigmented irises due to fusion of melanosomes (melanin granules), which are related to lysosomes. Haemorrhages may occur following trauma as the mutation also affects lysosomes within platelets. (b) Leukocyte adhesion deficiency (see the lecture on acute inflammation) (c) Pelger-Huet anomaly Inherited disorder characterised by a failure of the granulocyte nuclei to segment into lobes. The neutrophils therefore appear to be very immature. The anomaly is usually detected when an animal is observed to have a persistent left shift that cannot be reconciled with its good health. Although neutrophils closely resemble band forms, their nuclear chromatin is condensed, reflecting their maturity. Neutrophils are less able to migrate from blood vessels in vivo, most likely due to inflexible nuclei. In humans, the anomaly is due to a mutation in the gene coding the lamin B, a nuclear membrane receptor that interacts with chromatin to determine the shape of the nucleus. This anomaly has been observed in Arabian horses, cats and various dog breeds. (d) Complement deficiencies   Canine C3 deficiency Porcine factor H deficiency: factor H is a critical component of the alternative complement pathway; it normally inactivates C3b as soon as it is generated and so prevents excessive alternative pathway activation. If animal fails to make factor H, C3b will be generated in an uncontrolled fashion. This deficiency has been identified in Yorkshire pigs. Alterations are typically seen in renal glomeruli with capillary basement membrane thickening due to massive deposition of C3. The disease is commonly referred to as porcine dense deposit disease. Inherited defects in the adaptive immune system (a) Severe combined immunodeficiency SCID is well described in Arabian horses, where the disease reflects a small base pair deletion in the DNA protein kinase gene. This gene is essential for the recombination of VDJ regions in the formation of TCRs and BCRs. In the absence of both TCRs and BCRs, affected foals cannot respond to antigens and fail to produce functional T or B cells. If they suckle successfully, they will acquire maternal immunoglobulins. Once these have been catabolised, however, these foals cannot produce their own antibodies and eventually become agammaglobulinaemic. Affected foals are therefore born healthy but begin to sicken by 2 months of age. All die by 4 to 6 months as a result of overwhelming infection by a variety of low-grade pathogens. On necropsy, the spleens of these foals lack germinal centres and periarteriolar lymphoid sheaths. Their lymph nodes lack lymphoid follicles and germinal centres and there is cellular depletion of paracortex. The thymus in these animals may be difficult to find. Canine SCID is recognised in the Basset hound, Cardigan Welsh corgi and Jack Russell terrier. In the first two breeds, the underlying pathogenesis involved a mutation in the common γ chain of the receptors for the cytokines IL2, IL4, IL7, IL9, IL15, while in the Jack Russell terrier is caused by a mutation in the DNA protein kinase gene. (b) Selective immunoglobulin deficiency: these deficiencies have been variably described in dogs, horses and cattle. In dogs, selective deficiencies of IgA have been observed in several breeds, but German Shepherd are especially predisposed to a range of infectious disorders, including mycoses, anal furunculosis, deep pyoderma and small intestinal bacterial overgrowth. This suggests that they may have deficiencies in mucosal immunity. (c) Common variable immunodeficiency This condition is characterised by a failure of B cells to make antibodies. Described in horses with trace serum levels of IgG and IgM and very low IgA. T cell numbers are normal but B cells are undetectable. On necropsy, there are no B cells in lymphoid organs, blood or bone marrow. (d) Hereditary parakeratosis Certain Black pied Danish and Friesian cattle carry an autosomal recessive trait of thymic and lymphocytic hypoplasia. Affected calves are born healthy, but by 4 to 8 weeks they begin to experience severe skin infections. If untreated, they die within a few weeks, and none survive for longer than 4 months. Affected calves have exanthema, hair loss on the legs, and parakeratosis around the mouth and eyes. There is depletion of lymphocytes in the GALT and atrophy of the thymus, spleen and lymph nodes. These animals are T-cell deficient and have depressed cell-mediated immunity but normal antibody response. If these calves are treated by oral zinc oxide or zinc sulphate, they recover the ability to mount normal cell mediated responses. These animals have a zinc deficiency: zinc is an essential component of the thymic hormone thymulin required for a normal T cell response. SECONDARY (acquired) IMMUNODEFICIENCY They can affect animals of any breed and are relatively common. Secondary immunodeficiency affects adult animals that have had normal immune function until they undergo some form of physiological or pathological changes Immunosenescence Age-related decline in immune function; normal physiological change in older animals. In general, there is a relative decrease in circulating CD4+ cells and a relative increase in CD8+ cells with an overall reduced CD4:CD8 ratio. These circulating T cells are predominantly memory cells with relatively few naïve cells remaining in older animals. Medical immunosuppression: induced when immunosuppressive therapy is used to control autoimmune disease or when chemotherapy is used in the management of cancer. Specific infections The best example is FIV infection. FIV is a T lymphotropic retrovirus that infects lymphocytes and APCs. Infected cats have an acute phase of mild illness during which there is a progressive decline in blood CD4+ cells. The cat will then become asymptomatic, but during this second phase of disease there is continued decline in circulating CD4+ cells, which may occur over several years. During the third stage of disease there is a recurrence of mild illness, which progress to more severe terminal stage similar to human AIDS with a chronic multisystemic disease that may include gingivostomatitis, respiratory tract infection, enteritis, dermatitis, weight loss, pyrexia and lymphadenomegaly. Chronic disease Any animal afflicted by chronic infectious, inflammatory or neoplastic disease is likely to have a degree of secondary suppression of the immune system and increased susceptibility to infection. Some infectious agents (e.g. CDV, canine and feline parvovirus, FIV and FeLV, PCV-2, BVDV) may cause direct depletion of lymphoid tissue. Stress Chronic stress is also immunosuppressive and follows an elevation in endogenous glucocorticoid production. A similar effect is seen in hyperadrenocorticism (Cushing disease) in which there is circulating lymphopaenia and increased susceptibility to secondary infection. Animals housed indoors in high-density rearing units or animals transported for long distances in close confines are considered at risk of stress-induced immune suppression. Malnutrition Severe malnutrition leads to increased susceptibility to infection due to impairment of T-cell function, but with sparing of B-cell activity and immunoglobulin production. These affects are thought to be related to leptin, an adipokine related to body fat mass. An animal suffering malnutrition will have loss of body adipose tissue reserve and reduced concentration of leptin, that is immunostimulatory and pro-inflammatory.