IMMUNODEFICIENCIES RESULTING IN DEFECTIVE HOMEOSTASIS OF THE IMMUNE SYSTEM
DEFECTS IN THE CYTOLYTIC PATHWAY
The homeostasis of immune responses requires prevention of excessive lymphocyte activation. The mechanism by which such regulation occurs includes activation-induced cell death of T lymphocytes, which requires the activation of apoptotic pathways. Defects in critical components of these pathways result in susceptibility to hemophagocytic lymphohistiocytosis (HLH), which is usually triggered by an intercurrent viral infection caused by viruses such as EBV or cytomegalovirus. HLH is characterized by massive infiltration of organs, such as the liver, spleen, bone marrow, and central nervous system, by activated CD8 lymphocytes and macrophages, as well as a massive overproduction of IFN-γ and TNF-α. Severe pancytopenia is typical of this syndrome and is caused in part by phagocytosis of blood cells by activated macrophages and in part is secondary to the infiltration of bone marrow by activated macrophages (histiocytes).