Chronic immune activation associated with intestinal helminth infections results in impaired signal transduction and anergy

Helminthic parasites cause widespread, persistent infections in humans. The immigration of Ethiopians to Israel (a group denoted here by "Eth."), many of them infested with helminths and in a chronic immune-activation state, enabled us to investigate the effects of such immune activation on immune r esponses. We studied the immune profile and immune functions of 190 Eth. an d Israeli non-Eth. (Isr.) highly, partially, or non-immune-activated indivi duals. Immune cells from highly immune-activated individuals were defective in several signaling responses, all of which were restored gradually follo wing anti-helminthic treatment. These cells showed poor transmembrane signa ling, as seen by the phosphorylation of various tyrosine kinases and of the MAPK kinases, ERK1/2 and p38; deficient degradation of phosphorylated I ka ppa B alpha; increased expression of cytotoxic T lymphocyte-associated anti gen 4 (CTLA-4), which appears to block proliferative responses in these cel ls; decreased beta-chemokine secretion by CD8(+) cells after stimulation; a nd reduced proliferation to recall antigen stimulation. Highly immune-activ ated individuals also showed decreased delayed-type skin hypersensitivity r esponses to recall antigen before deworming. These findings support the not ion that chronic helminthic infections cause persistent immune activation t hat results in hyporesponsiveness and anergy. Such impaired immune function s may diminish the capacity of these individuals to cope with infections an d to generate cellular protective immunity after vaccination.