Cross-sensitization to haptens: formation of common haptenic metabolites, T cell recognition of cryptic peptides, and true T cell cross-reactivity

Abstract

To analyze T cell cross‐reactivity to para‐compounds, we established CD4+ T cell hybridomas from mice immunized with adducts of self‐globin and one of three different para‐compounds: p‐aminophenol, p‐phenylenediamine, or Bandrowski's base. Some of the hybridomas obtained reacted not only to the immunizing antigen, but also to metabolically related para‐compounds, bound to the same protein, thus suggesting formation of common metabolites. Other hybridomas cross‐reacted to globin adducts of metabolically unrelated para‐compounds, which denotes them as truly cross‐reactive cells whose TCR failed to distinguish among the different haptens. One of these hybridomas also reacted against a non‐haptenated, cryptic peptide of hemoglobin but not to the full‐length native protein. As this hybridoma reacted even more strongly to the respective peptide after it was haptenated, recognition of the native, cryptic peptide was apparently due to true cross‐reactivity. To conclude, true T cell cross‐reactivity to haptens does occur, as well as the formation of a common reactive metabolite, and T cell recognition of cryptic self‐peptides may underlie cross‐sensitization to chemicals.

A Comprehensive Listing of Bioactivation Pathways of Organic Functional Groups

“…69). It is noteworthy to point out that reductive metabolism of the nitro group to the corresponding reactive nitroso metabolite has also been proposed as an alternate mechanism of bioactivation leading to toxicity [47]. Chloramphenicol has been reported to be a suicide substrate for cytochrome P450 [464]; its mechanism of inactivation may be similar to that hypothesized below.…”

“…Following several challenges with the immunogen, the antiserum is screened for the antibody titer using an enzyme-linked immunosorbent assay (ELISA). The antibody then can be used to identify haptenized protein via Western blot analysis [47][48][49]. While this method can be a very powerful technique for the identification and characterization of cellular constituents that have undergone covalent modification by a reactive metabolite, it is generally a low-throughput and a time consuming method for the detection of reactive intermediates; and finally, (5) metabolite identification: An understanding of metabolic pathways and the biochemical mechanisms by which metabolites are synthesized can give insight to the potential of a compound to yield a reactive species [39].…”

Sulfonamide allergy and cross-reactivity

“…Wulferink et al [27] observed murine T-cell responses to globin adducts of metabolically unrelated compounds. Metabolite-protein complexes were recognized by T cells as cryptic self-peptides, even though the metabolites themselves were completely dissimilar.…”

Protein–Hapten Binding: Challenges and Limitations for In Vitro Skin Sensitization Assays

“…It is a long-standing hypothesis that sensitization can only occur if the sensitizing chemical (or hapten) binds to a skin protein (Landsteiner and Jacobs, 1936; Dupuis and Benerzra, 1982). However, some investigators in the field would refute the hypothesis that covalent binding is a prerequisite for sensitization in favor of noncovalent modes of protein-hapten association (7) or the modification of normal self-protein processing resulting in the generation of cryptic epitopes (8). It is therefore vital for the future development of in silico and in vitro methodologies that we understand fully the links between protein -hapten binding and ability to cause sensitization.…”