Genetic defects affecting any of the constituent proteins of the NADPH oxidase expressed in neutrophils and monocytes (see Section 32) can cause chronic granulomatous disease. Patients with the disease have chronic bacterial infections, which in some cases lead to the formation of granulomas. Deficiencies in glucose6phosphate dehydrogenase (G6PD) and myeloperoxidase (MPO) also impair intracellular bacterial killing and lead to a similar, although less severe, phenotype.
13-16 Mutations in the molecular regulators of inflammation can ‘autoinflammatory disease.’
There are a small number of diseases in which mutations in genes that control the life, death, and activities of inflammatory cells are associated with severe inflammatory disease. Although they do not lead to immunodeficiency, we have included them in this chapter because they are singlegene defects affecting a crucial aspect of innate immunity—the inflammatory response. These conditions represent a failure of the normal mechanisms that limit inflammation, and are known as autoinflammatory diseases: they can lead to inflammation even in the absence of infection (Fig. 13.14). Familial Mediterranean fever (FMF) is characterized by episodic attacks of severe inflammation, which can occur at various sites throughout the body and are associated with fever, an acutephase response (see Section 318), and severe malaise. The pathogenesis of FMF was a mystery until its cause was discovered to be mutations in the gene MEFV, which encodes a protein called pyrin, to reflect its association with fever. Pyrin and pyrin domaincontaining proteins are involved in pathways that lead to the apoptosis of inflammatory cells, and in pathways that inhibit the secretion of proinflammatory cytokines such as IL1β. It is proposed that an absence of functional pyrin leads to unregulated cytokine activity and defective apoptosis, resulting in a failure to control inflammation. In mice, an absence of pyrin causes increased sensitivity to lipopolysaccharide and a defect in macrophage apoptosis. A disease with similar clinical manifestations, known as TNFreceptor associated periodic syndrome (TRAPS), is caused by mutations in quite a different gene, that encoding the TNFα receptor TNFRI. Patients with TRAPS have reduced levels of TNFRI, which lead to increased levels of proinflammatory TNFα in the circulation because it is not regulated by binding to this receptor. The disease responds to therapeutic blockade with antiTNF agents such as etanercept, a soluble TNF receptor developed primarily to treat patients with rheumatoid arthritis (see Section 168). Mutations in the gene encoding PSTPIP1 (prolineserinethreonine phosphataseinteracting protein 1), which interacts with pyrin, are associated with another dominantly inherited autoinflammatory syndrome—pyogenic arthritis, pyoderma gangrenosum, and acne (PAPA). The mutations increase binding of pyrin to PSTPIP1, and it has been proposed that the interaction sequesters pyrin and limits its normal regulatory function.