Haptenation: Chemical Reactivity and Protein Binding

Abstract

Low molecular weight chemical (LMW) allergens are commonly referred to as haptens. Haptens must complex with proteins to be recognized by the immune system. The majority of occupationally related haptens are reactive, electrophilic chemicals, or are metabolized to reactive metabolites that form covalent bonds with nucleophilic centers on proteins. Nonelectrophilic protein binding may occur through disulfide exchange, coordinate covalent binding onto metal ions on metalloproteins or of metal allergens, themselves, to the major histocompatibility complex. Recent chemical reactivity kinetic studies suggest that the rate of protein binding is a major determinant of allergenic potency; however, electrophilic strength does not seem to predict the ability of a hapten to skew the response between Th1 and Th2. Modern proteomic mass spectrometry methods that allow detailed delineation of potential differences in protein binding sites may be valuable in predicting if a chemical will stimulate an immediate or delayed hypersensitivity. Chemical aspects related to both reactivity and protein-specific binding are discussed.

The GARD platform for potency assessment of skin sensitizing chemicals_suppl

“…NF-κB subunits (RelB or p52) were predicted key hubs in all reactivity groups except in MA chemicals. In summary, there seem to be common mechanistic responses to chemical exposures per se such as cell cycle and DNA damage-related, but the pathway analysis results also support the hypothesis that different chemical reactivity classes induce distinct signaling pathways as observed earlier by us (Albrekt et al, 2014) and in other experimental systems (Cottrez et al, 2015;Migdal et al, 2013;Natsch et al, 2015;Chipinda et al, 2011). Several pathways are linked to processes known to be relevant in skin sensitization.…”

“…Although DCs are not the primary target for protein modification in vivo, we hypothesized that different protein reactivity classes influence the DC transcriptome differentially. Protein reactivity is one of the most important features of chemicals defining their skin sensitizing capacity and potency with certain limitations (Chipinda et al, 2011). Protein reactivity-specific patterns were detectable as revealed by the comparison of the most significantly regulated transcripts induced by the reactivity groups MA, SB, and SN.…”

The lymphocyte transformation test in allergic contact dermatitis: New opportunities

“…Although the majority of skin sensitizing chemicals are inherently electrophilic, it is now appreciated that as many as one third of all contact allergens require either metabolic (pro-haptens) or abiotic activation such as auto-oxidation (pre-haptens) for the formation of hapten-protein conjugates (Chipinda et al, 2011). It is assumed that such conjugates form spontaneously in vitro in tissue culture with proteins such as human serum albumin (HSA) and that prehaptens may undergo auto-oxidation in culture media.…”

Modelagem in chemico: as bases mecanísticas entre a reatividade e a toxicidade

“…As moléculas de alto peso molecular são reconhecidas pelo organismo na forma como se encontram, e assim ativam a resposta imune. Por outro lado as moléculas de baixo peso molecular se ligam direta ou indiretamente a uma proteína e são internalizadas processadas ou metabolizadas e dispostas para que o organismo as reconheça, essas são chamadas de haptenos (Chipinda et al, 2011). Os mecanismos de sensibilização dérmica e respiratória apesar de ter passagens semelhantes, diferem entre si em vários aspectos.…”