Defects in Innate Immunity

Innate immunity constitutes the first line of defense against infectious organisms. Two important mediators of innate immunity are phagocytes and complement, both of which also participate in the effector phases of adaptive immunity. Therefore, congenital disorders of phagocytes and the complement system result in recurrent infections. Complement deficiencies were described in Chapter 12. Deficiencies have been described in the classical and alternative complement pathways as well as in the lectin pathway. They typically present with recurrent bacterial infections, particularly by encapsulated bacteria and also Neisseria species, and often also contribute to susceptibility to autoimmune disorders, particularly systemic lupus erythematosus.

In this section of the chapter, we discuss some examples of congenital phagocyte disorders (Table 20-2) and inherited defects in Toll-like receptor (TLR) pathways and in the IL-12/IFN-y pathway. Phagocyte defects generally result in infections of the skin and respiratory tract with bacteria or fungi, the latter predominantly involving

TABLE 20-2 Congenital Disorders of Innate Immunity

Disease

Functional Deficiencies

Mechanism of Defect

Chronic granulomatous disease

Defective production of reactive oxygen species by phagocytes; recurrent intracellular bacterial and fungal infections

Mutation in genes of phagocyte oxidase complex; phox-91 (cytochrome b588 a subunit) is mutated in X-linked form

Leukocyte adhesion deficiency type 1

Defective leukocyte adhesion and migration linked to decreased or absent expression of p2 integrins; recurrent bacterial and fungal infections

Mutations in gene encoding the p chain (CD18) of p2 integrins

Leukocyte adhesion deficiency type 2

Defective leukocyte rolling and migration linked to decreased or absent expression of leukocyte ligands for endothelial E-and P- selectins, causing failure of leukocyte migration into tissues; recurrent bacterial and fungal infections

Mutations in gene encoding a GDP-fucose transporter required for the synthesis of the sialyl Lewis X component of E- and P- selectin ligands

Leukocyte adhesion deficiency type 3

Defective leukocyte adhesion and migration linked to defective inside-out signaling and therefore defective integrin activation

Mutations in gene encoding KINDLIN-3

Chediak-Higashi syndrome

Defective vesicle fusion and lysosomal function in neutrophils, macrophages, dendritic cells, natural killer cells, cytotoxic T cells, and many other cell types; recurrent infections by pyogenic bacteria

Mutation in LYST leading to defect in secretory granule exocytosis and lysosomal function

Toll-like receptor signaling defects

Recurrent infections because of defects in TLR and CD40 signaling and defective type I interferon production

Mutations in NEMO, UNC93B, MyD88, kBa, and IRAK-4 compromise NF-kB activation downstream of Toll-like receptors

IRAK-4, IL-1 receptor-associated kinase 4; LYST, lysosomal trafficking protein; NEMO, NF-kB essential modulator.

Aspergillus and Candida species. Deep-seated abscesses and oral stomatitis are also common. Defects in TLR signaling and in type I interferon signaling may contribute to recurrent pyogenic infections as well as to severe viral infections; defects in IL-12 and the IFN-y pathway are linked to susceptibility to intracellular pathogens, particularly mycobacterial infections.

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