An autosomal dominant mutation of GATA2 has been identified in the largest group of patients with an inherited deficiency of dendritic cells. Affected individuals develop a progressive loss of all subsets of dendritic cells (conventional and plasmacytoid) and monocytes, as well as reduced numbers of B and NK lymphoid cells, a condition that has been termed DCML deficiency. Although Tcell numbers are normal in these patients, their function becomes impaired as dendritic cells are lost. The loss of products of several hematopoietic lineages, but not all, suggests redundancy of the function of GATA2 in unaffected lineages. The basis for the progressive decline in products of the affected lineages is unknown, but is thought to reflect a role for GATA2 in maintaining stemcell progenitors that seed these populations. Given the deficiency of all dendritic and monocyte cells, the immune defects in these individuals are diverse, as are pathogen susceptibilities. These patients also have a substantial risk of hematologic malignancies.
Two inherited defects in interferon regulatory factor 8 (IRF8) are the first to be described that are associated with specific defects in the development of dendritic cells. In both variants, the mutation is in the DNAbinding domain of the transcription factor. In an autosomal recessive form, there is loss of monocytes and all types of circulating dendritic cells; all conventional and plasmacytoid dendritic cells are absent. Because dendritic cells are the primary antigenpresenting cells for naive T cells, their deficiency results in impaired development of effector T cells, and patients with these defects are susceptible to a range of severe opportunistic infections early in life, including those caused by intracellular bacteria, viruses, and fungi. They also develop a striking increase in the number of circulating immature granulocytes; this is thought to be due to diversion of myeloid precursors down the granulocytic pathway in the absence of the monocyte–dendritic cell developmental pathway. In contrast, in patients with autosomal dominant inheritance of a dominantnegative mutant allele of IRF8, there is a less severe phenotype, one that is characterized by a more selective deficiency of the CD1cpositive subset of dendritic cells (thought to be the equivalent of the CD11bpositive subset of mouse
Fig. 13.11 Defects in complement components are associated with susceptibility to certain infections and the accumulation of immune complexes. Defects in the early components of the alternative pathway and in C3 lead to susceptibility to extracellular pathogens, particularly pyogenic bacteria. Defects in the early components of the classical pathway predominantly affect the processing of immune complexes (see Section 10-20) and the clearance of apoptotic cells, leading to immune-complex disease. Deficiency of mannose-binding lectin (MBl), the recognition molecule of the mannose-binding lectin pathway, is associated with bacterial infections, mainly in early childhood. Defects in the membrane-attack components are associated only with susceptibility to strains of Neisseria species, the causative agents of meningitis and gonorrhea, implying that the effector pathway is important chiefly in defense against these organisms.
dendritic cells). This results in heightened susceptibility to intracellular bacteria, particularly atypical Mycobacterium spp., without the myeloproliferative syndrome seen in patients with the autosomal recessive variant.
and tissue damage.