Genetic defects of apoptosis and primary immunodeficiency

Abstract

Programmed cell death is important for maintaining lymphocyte homeostasis. Several human-inherited diseases with impaired apoptosis have been identified at the genetic level: autoimmune lymphoproliferative syndrome, caspase-8 deficiency state, and X-linked lymphoproliferative syndrome. These diseases feature excess lymphocyte accumulation, autoimmunity, or immunodeficiency. Elucidating their molecular pathogenesis has also provided new insights into the signaling mechanisms regulating apoptosis and lymphocyte activation.

Figure 1

ALPS and CEDS illustrate signaling pathways for lymphocyte apoptosis and activation. In the death-inducing signaling complex (DISC) (center of figure), death receptor stimulation, here typified by trimerized Fas, leads to recruitment of FADD adapter molecules, which in turn recruits the initiator caspases-8 (and/or caspase-10). Oligomerization causes caspase-8/-10 activation and cleavage of downstream effector caspases. Caspase-8 cleavage of BID, a pro-apoptotic member of the BCL-2 family, feeds into a mitochondrial amplification loop in which apoptosome formation oligomerizes and activates caspase-9. During cytokine-withdrawal-induced apoptosis (left side of figure), interruption of IL-2-stimulated signaling leads to decreased activation of the RAF/MEK/ERK pathway. This causes increased expression of BIM, another pro-apoptotic member of the BCL-2 family, which in turn triggers mitochondrial depolarization. Released cytochrome c from depolarized mitochondria assembles with Apaf-1 and caspase-9 to form the apoptosome. Both the death receptor- and cytokine withdrawal-induced apoptosis pathways converge following activation of initiator caspases: these cleave and activate downstream effector caspases, which in turn cleave intracellular substrates, causing cell death. In the activation receptor induced signalosome (ARIS) (right side of figure), immunoreceptor stimulation leads to caspase-8-dependent recruitment of the CARMA1-BCL10-MALT1 (CBM) complex with the IKK complex. Caspase-8 linker and enzymatic function are required for optimal downstream NF-κB induction for lymphocyte activation. Mutations in the indicated signaling components that cause ALPS or CEDS are indicated. Death domains (DD), death effector domains (DED), and caspase recruitment domains (CARD) in relevant proteins containing these structures are as indicated.