Abnormalities in two components of innate immunity, phagocytes and the complement system, are important causes of immunodeficiency (Fig. 1).

Fig1. Congenital immunodeficiencies caused by defects in innate immunity. The figure lists immunodeficiency diseases caused by defects in various components of the innate immune system. NF-κB, NF-nu clear factor κB; NK, natural killer, TLR, toll-like receptors.

• Chronic granulomatous disease (CGD) is caused by mutations in genes encoding subunits of the enzyme phagocyte NADPH oxidase, which catalyzes the pro duction of microbicidal reactive oxygen species in lysosomes. Affected neutrophils and macrophages are unable to kill the microbes they phagocytose. The most common infections in CGD patients are bacteria that make the enzyme catalase, as well as Aspergillus and Candida species of fungi. Catalase-producing bacteria can degrade hydrogen per oxide, which is an alternative source of free radicals that CGD leukocytes could use to kill bacteria. The immune system tries to compensate for this defective microbial killing by calling in more macrophages and by activating T cells, which stimulate recruitment and activation of phagocytes. Therefore, collections of macrophages accumulate around foci of infections to try to control the infections. These collections resemble granulomas, giving rise to the name of this disease. The most common form of CGD is X-linked, caused by mutations in a subunit of the NADPH oxidase that is encoded by a gene on the X chromosome.

 • Leukocyte adhesion deficiency is caused by mutations in genes encoding integrins, enzymes required for the expression of ligands for selectins, or signaling molecules activated by chemokine receptors that are required to activate integrins. Integrins and selectin ligands are involved in the adhesion of leukocytes to other cells. As a result of these mutations, blood leukocytes do not bind firmly to vascular endothelium and are not recruited normally to sites of infection.

 • Deficiencies of almost every complement protein, and many complement regulatory proteins, have been described. C3 deficiency results in severe infections and may be fatal. Deficiencies of C2 and C4, two components of the classical pathway of complement activation, may result in increased bacterial or viral infection or increased incidence of systemic lupus erythematosus, presumably because of defective clearance of immune complexes. Deficiencies of complement regulatory proteins lead to various syndromes associated with excessive complement activation.

 • The Chédiak-Higashi syndrome is an immunodeficiency disease in which the lysosomal granules of leukocytes do not function normally. The immune defect affects phagocytes and natural killer (NK) cells and manifests as increased susceptibility to bacterial infection.

Rare patients have been described with mutations affecting TLRs or signaling pathways downstream of TLRs, including molecules required for activation of the nuclear factor κB (NF-κB) transcription factor. As mentioned earlier, several of these mutations make patients susceptible to only a limited set of infections. For example, mutations affecting MyD88, an adaptor protein required for signaling by most TLRs, are associated with severe bacterial (most often pneumococcal) pneumonias, and mutations affecting TLR3 are associated with recurrent herpesvirus encephalitis but apparently not other viral infections. 

مواضيع ذات صلة

Congenital Immunodeficiencies: Defects in Lymphocyte Maturation

Congenital (Primary) Immunodeficiencies

Neuroimmunology: Interactions Between the Immune and Nervous Systems

Disorders of Neutrophils

Cell Surface Receptors

Sepsis

Acute Inflammation

Diseases Caused by T Lymphocytes

Etiology, Examples, and Therapy of Immune Complex–Mediated Diseases

Examples and Treatment of Diseases Caused by Cell- or Tissue-Specific Antibodies

Mechanisms of Antibody-Mediated Tissue Injury and Disease

Hypersensitivity Disorders Caused by Immune Responses : Clinical Syndromes and Therapy