Immune Deficiencies Associated With Phagocytosis

There is an association between allotypic forms of the FcyR and disease. Individuals expressing the FcyRIIa-R131 receptor are more susceptible to infections with encapsulated bacteria. Encapsulated bacteria evoke a response consisting of IgG2 antibodies. The FcyRIIa-R131 receptors cannot bind IgG2-coated bacteria. The FcyRIIa-H131 allotype is the only functional FcyR capable of binding IgG2 antibodies (Deo et al., 1997).

A normal function of tissue macrophages is the removal and destruction of aged red cells from circulating blood. In Gaucher's or Newmann-Pick's disease, there is a defect in the function of enzymes degrading sphingolipids. Because of the defect, red blood cell debris accumulates within the macrophage. The accumulated lipid inhibits the function of protein kinase C that is necessary for the membrane transduction of external stimuli that activate or regulate the macro-

phage. Because the macrophage cannot respond to functional stimuli, resistance to infection can be impaired (Burrell etal., 1992).

A rarely reported disease is the lazy leukocyte syndrome or leukocyte adhesion deficiency (LAD). In these patients, adhesion of neutrophils to the endothelium or other cells and phagocytosis are impaired. The genetic defect is found in two forms. In LAD-1, the defect is associated with the complement receptor type 3 (CR3; Mac-1, CD1 lb/CD18) found on monocytes, neutrophils, NK cells, and dendritic cells. There is a mutational defect in transcription of the CD18 B chain. In these patients, phagocytosis and killing are impaired (Fischer, 1990).

In subjects with LAD-2, the defect results from the absence or reduction of sialyl-Lewis X carbohydrate that is necessary for binding of E- and P-selectin (Fischer and Arnaiz-Villena, 1995). Thus, transendothelial migration of neutrophils is impaired.

MPO deficiencies are common autosomal recessive deficiencies that occur in 1:4000 adults. Usually, the defect has no effect on host defense and there is no increased frequency of infections (Fischer and Arnaiz-Villena, 1995).

Recurrent infections are found in patients with chronic granulomatous disease (CGD). These individuals reveal an increased frequency of deep tissue infections and a failure to resolve inflammatory reactions mediated by neutrophils. Consequently, there is granuloma and scarring in tissue. Despite aggressive therapy, the disease is often fatal.

Phagocytes from CGD patients can ingest opsonized bacteria but fail to generate sufficient superoxide for production of hydrogen peroxide. Several different genetic defects are associated with the disease. In the X-linked form that accounts for 66% of all cases, a 91-kDa transmembrane protein is absent, mutated, or truncated. This protein is part of the complex with cytochrome b588 used to generate superoxide. In the autosomal recessive form of the disease, the cytochrome system is intact. The defect resides in the failure to phosphorylate a 47-kDa component of the NADPH system that activates neutrophils (Fischer, 1990; Dinauerand Orkin, 1992).

Subjects with CGD have recurrent infections with catalase-producing streptococci orE. coli. Bacterial catalase reduces the small amount ofH202 produced by the macrophage, thus preventing intracellular killing. Catalase can act perox-idatively by oxidizing a hydrogen donor with H202 or catalytically by dismutation of H202 to H20 and 02. Other bacterial species that lack catalase (e.g., S. pneumoniae) are killed normally by phagocytes fromCGD patients (Fischer, 1990).

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