Fig. 13.13 Defects in phagocytic cells are associated with persistence of bacterial infection. Defects in neutrophil development caused by congenital neutropenias result in profound defects in antibacterial defense. impairment of the leukocyte integrins with a common β2 subunit (CD18) or defects in the selectin ligand sialyl-lewisX, prevent phagocytic cell adhesion and migration to sites of infection (leukocyte adhesion deficiency). inability to transmit signals through toll-like receptors (tlRs), due to defects in MyD88 or iRaK4, for example, impairs the proximal sensing of many infectious agents by innate immune cells. the respiratory burst is defective in chronic granulomatous disease, glucose-6-phosphate dehydrogenase (G6PD) deficiency, and myeloperoxidase deficiency. in chronic granulomatous disease, infections persist because macrophage activation is defective, leading to chronic stimulation of CD4 t cells and hence to granulomas. Vesicle fusion in phagocytes is defective in Chediak–Higashi syndrome. these diseases illustrate the critical role of phagocytes in removing and killing pathogenic bacteria.
cyclic neutropenia; how the mutant elastase causes a 21day cycle in neutropenia is still a mystery. A rare autosomal dominant form of SCN is caused by mutations in the oncogene GFI1, which encodes a transcriptional repressor that acts on ELA2. This finding arose from the unexpected observation that mice lacking the protein Gfi1 are neutropenic due to overexpression of Ela2.
Autosomal recessive forms of SCN have also been identified. Deficiency of the mitochondrial protein HAX1 leads to increased apoptosis in developing myeloid cells, resulting in a severe neutropenia referred to as Kostmann’s disease. The heightened sensitivity of developing neutrophils to apoptosis is highlighted by SCN associated with genetic defects in glucose metabolism. Patients with recessive mutations in the genes encoding the glucose6phosphatase catalytic subunit 3 (G6PC3) or the glucose6phosphate translocase 1 (SLC37A4) also demonstrate increased apoptosis during granulocyte development that results in neutropenia. Acquired neutropenia associated with chemotherapy, malignancy, or aplastic anemia is also associated with a similar spectrum of severe pyogenic bacterial infections. Finally, neutropenia can also be a feature of other primary immunodeficiency diseases, including CD40 ligand deficiency, CVID, XLA, Wiskott–Aldrich syndrome, and GATA2 deficiency. Some patients exhibit formation of autoantibodies that lead to accelerated destruction of neutrophils.