Hapten and danger hypotheses of IDIN immune mechanism. (1) Native drug in the bloodstream enters neutrophils, liver macrophages, and other cells. (2) Drug is oxidized to reactive metabolite(s). (3) Reactive drug (hapten) forms a covalent link with endogenous proteins, forming drug–protein adducts. (4) Drug–protein adducts are taken up by antigen- presenting cells (APCs) and peptide-drug presented in context of class II HLA to T helper (TH) cells that engage through T-cell receptor (TCR): Signal 1. (5) Stressed neutrophils or other cells release danger signals that activate APCs. (6) B7 on activated APCs engages CD28 on TH cell for co-stimulus that is Signal 2. (7) The activated TH cell provides signals to B cells to produce drug-dependent neutrophil antibodies against drug/hapten and to stimulate hapten-specific cytotoxic T cells (Tc): Immune response. (8) Drug-dependent neutrophil antibodies bind drug–protein adducts on neutrophil membrane that cause neutrophil destruction/clearance. (9) In the absence of danger signals, there is no Signal 2, resulting in immune tolerance.
