Figure 8.

An updated model linking clozapine bioactivation and clozapine-induced inflammation in idiosyncratic drug-induced agranulocytosis (IDIAG). (1) Clozapine is oxidized by myeloperoxidase (MPO)-expressing cells to a reactive nitrenium ion that covalently modifies endogenous proteins, generating neoantigens. Depending on the essentiality and the role of the proteins modified, this causes cellular dysfunction, the release of damage-associated molecular patterns (DAMPs; including S100 and drug-modified proteins), along with other proinflammatory mediators, and activation of a stress response, propagated by cortisol/corticosterone. The stress response may also directly influence the generation of DAMPs and vice versa. (2) These signals initiate the chemotaxis and activation of immune cells such as other neutrophils that can sense DAMPs in several ways, including recognition by pattern recognition receptors, leading to inflammasome activation. Inflammasome signaling propagates a proinflammatory response through the increased release of proinflammatory cytokines (e.g., IL-1β, CXCL1) and acute phase proteins (e.g., α1AGP, CRP), as well as mobilization of peripheral immune cells. (3) The presentation of clozapine neoantigens in the context of specific HLA haplotypes on antigen-presenting cells are detected by T cells expressing cognate T cell receptors. In the presence of appropriate co-stimulatory signals, an adaptive immune response is initiated that, if unresolved through tolerance, leads to the targeted destruction of granulocyte precursors and the onset of IDIAG. The inhibition of myeloperoxidase with PF-1355 significantly attenuates clozapine-induced inflammation, ultimately reducing the chance of adaptive immune activation and progression to IDIAG.