Proteomic analysis of haptenation by skin sensitisers: Diphencyprone and ethyl acrylate

Parkinson, Erika; Aleksić, Maja; Arthur, Rachael; Mota, Sergio Regufe da; Cubberley, Richard; Skipp, Paul

doi:10.1016/j.tiv.2019.104697

Cited by 10 publications

(10 citation statements)

References 45 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Despite the prevalence of skin/respiratory chemical allergies, our knowledge about the process of protein modification, a key event, is still limited. The current mechanistic knowledge is derived from studies carried out in solution using model peptides or isolated proteins and more recently ex vivo studies using cell lysates. , As an important first step toward understanding the complexity of protein haptenation in a complex living environment, we have studied the reactivity of PA toward a 3D reconstructed human epidermis. This study was performed using a novel approach combining the HRMAS NMR technique and the LC-MS/MS proteomic analysis.…”

Section: Discussionmentioning

confidence: 99%

“…These results could be compared with proteomic studies carried out on lysate of HaCaT cell line incubated with skin sensitizers. In the studies of Parkinson et al, , skin sensitizers such as 1-chloro-2,4-dinitrobenzene (DNCB), 5-chloro-2-methyl-4-isothiazol-3-one (MCI), cinnamaldehyde (CA), or diphenylcyclopropenone (DCP) were shown to haptenize cysteine residues (5 to 16%) on modified HaCaT cell proteins. As an example, DNCB that also reacted mainly with lysine residues (about 72%) was also found to modify significantly cysteine residues (about 20%).…”

Section: Discussionmentioning

confidence: 99%

“…To date our knowledge on the process of protein haptenation is still limited and mainly derived from studies performed in solution using either amino acids, model peptides, isolated proteins, or cell lysates. , It is therefore necessary to understand how chemical allergens interact with proteins in a complex living environment and if this might differ in the immune response. For a long time, it was supposed that the type of allergy was mainly associated with the route of exposure, i.e., the skin or the respiratory tract.…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Chemical Modifications Induced by Phthalic Anhydride, a Respiratory Sensitizer, in Reconstructed Human Epidermis: A Combined HRMAS NMR and LC-MS/MS Proteomic Approach

Khong

Berl

Kuhn

et al. 2021

Chem. Res. Toxicol.

View full text Add to dashboard Cite

Chemical skin and respiratory allergies are becoming a major health problem. To date our knowledge on the process of protein haptenation is still limited and mainly derived from studies performed in solution using model nucleophiles. In order to better understand chemical interactions between chemical allergens and the skin, we have investigated the reactivity of phthalic anhydride 1 (PA), a chemical respiratory sensitizer, toward reconstructed human epidermis (RHE). This study was performed using a new approach combining HRMAS NMR to investigate the in situ chemical reactivity and LC-MS/MS to identify modified epidermal proteins. In RHE, the reaction of PA appeared to be quite fast and the major product formed was phthalic acid. Two amide type adducts on lysine residues were observed and after 8h of incubation, we also observed the formation of an imide type cyclized adducts with lysine. In parallel, RHE samples topically exposed to phthalic anhydride ( 13 C)-1 were analyzed using the shotgun proteomics method. Thus, 948 different proteins were extracted and identified, 135 of which being modified by PA, i.e., 14.2% of the extracted proteome. A total of 211 amino acids were modified by PA and validated by fragmentation spectra. We thus identified 154 modified lysines, 22 modified histidines, 30 modified tyrosines, and 5 modified arginines. The rate of modified residues, as a proportion of the total number of modifiable nucleophilic residues in RHE, was rather low (1%). At the protein level, modified proteins were mainly type I and type II keratins and other proteins which are abundant in the epidermis such as protein S100A, Caspase 14, annexin A2, serpin B3, fatty-acid binding protein 5, histone H2, H3, H4, etc. However, the most modified protein, mainly on histidine residues, was filaggrin, a protein that is of low abundance (0.0266 mol %) and rich in histidine.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Chemical Modifications Induced by Phthalic Anhydride, a Respiratory Sensitizer, in Reconstructed Human Epidermis: A Combined HRMAS NMR and LC-MS/MS Proteomic Approach

Khong

Berl

Kuhn

et al. 2021

Chem. Res. Toxicol.

View full text Add to dashboard Cite

show abstract

“…These reactive sites are also assumed to be most likely modified in vivo . Alb has mainly been the target in such studies, as one of the major blood proteins that is also in high abundance in the skin ( Aleksic et al, 2007 ; Jenkinson et al, 2010 ; Parkinson et al, 2014 ; Ndreu et al, 2020 ; Parkinson et al, 2020a ), but also Hb due to its potentials as an exposure biomarker ( Ndreu et al, 2020 ). Jenskinson et al (2010) demonstrated that hapten-Alb conjugates could induce T-cell proliferation in individuals sensitized to the hapten in the investigated conjugate, indicating that haptenation of Alb could be the culprit of CHS.…”

Section: Introductionmentioning

confidence: 99%

Haptenation of Macrophage Migration Inhibitory Factor: A Potential Biomarker for Contact Hypersensitivity

et al. 2022

View full text Add to dashboard Cite

The immunological response in contact hypersensitivity is incited by small electrophilic compounds, known as haptens, that react with endogenous proteins after skin absorption. However, the identity of hapten-modified proteins seen as immunogenic remains as yet largely unknown. In a recent study, we have for the first time identified a hapten-modified protein in the local lymph nodes of mice treated topically with the model hapten tetramethylrhodamine isothiocyanate (TRITC). The TRITC modification was located on the N-terminal proline of the protein macrophage migration inhibitory factor (MIF). The focus of the current study was to investigate the presence of the same hapten-protein conjugate in blood samples from mice treated topically with TRITC. Furthermore, TRITC modifications of the two major blood proteins, namely hemoglobin (Hb) and albumin (Alb), as well as TRITC modifications of MIF other than the N-terminal proline, were examined. Following incubation with different molar ratios of TRITC, a proteomic approach was applied to characterize conjugate formation of the three aforementioned proteins, using high resolution mass spectrometry (HRMS). The targeted screening of the TRITC-treated mice blood and lymph node samples for these sites led to the identification of only the same TRITC-MIF conjugate previously detected in the lymph nodes. No Hb and Alb conjugates were detected. Quantification of both the TRITC-modified and unmodified N-terminal peptide of MIF in blood and lymph node samples gave interesting insights of MIF’s role in murine contact hypersensitivity. Incubation of MIF with four different haptens encompassing different reactivity mechanisms and potencies, showed adduct formation at different amino acid residues, suggesting that MIF can be the preferred target for a wide variety of haptens. The present study provides essential progress toward understanding of hapten-protein conjugate formation in contact hypersensitivity and identifies hapten-modified MIF as a potential biomarker for this condition. Further investigation of MIF as a target protein can be a next step to determine if MIF is a biomarker that can be used to develop better diagnostic tools and targeted therapeutics for individuals with allergic contact dermatitis.

show abstract

“…In addition, rare epitopes can be important since T cells can be activated by single ligands [ 83 , 84 ]. While experimental research on the haptenome of sensitizing chemicals is ongoing [ 85 , 86 ], new insights into possible T cell epitopes are obtained that need to be experimentally validated, e.g., as outlined in the studies reviewed here.…”

Section: Introductionmentioning

confidence: 99%

In Vitro Monitoring of Human T Cell Responses to Skin Sensitizing Chemicals—A Systematic Review

Aparicio‐Soto

Curato

Riedel

et al. 2021

Cells

View full text Add to dashboard Cite

Background: Chemical allergies are T cell-mediated diseases that often manifest in the skin as allergic contact dermatitis (ACD). To prevent ACD on a public health scale and avoid elicitation reactions at the individual patient level, predictive and diagnostic tests, respectively, are indispensable. Currently, there is no validated in vitro T cell assay available. The main bottlenecks concern the inefficient generation of T cell epitopes and the detection of rare antigen-specific T cells. Methods: Here, we systematically review original experimental research papers describing T cell activation to chemical skin sensitizers. We focus our search on studies published in the PubMed and Scopus databases on non-metallic allergens in the last 20 years. Results: We identified 37 papers, among them 32 (86%) describing antigen-specific human T cell activation to 31 different chemical allergens. The remaining studies measured the general effects of chemical allergens on T cell function (five studies, 14%). Most antigen-specific studies used peripheral blood mononuclear cells (PBMC) as antigen-presenting cells (APC, 75%) and interrogated the blood T cell pool (91%). Depending on the individual chemical properties, T cell epitopes were generated either by direct administration into the culture medium (72%), separate modification of autologous APC (29%) or by use of hapten-modified model proteins (13%). Read-outs were mainly based on proliferation (91%), often combined with cytokine secretion (53%). The analysis of T cell clones offers additional opportunities to elucidate the mechanisms of epitope formation and cross-reactivity (13%). The best researched allergen was p-phenylenediamine (PPD, 12 studies, 38%). For this and some other allergens, stronger immune responses were observed in some allergic patients (15/31 chemicals, 48%), illustrating the in vivo relevance of the identified T cells while detection limits remain challenging in many cases. Interpretation: Our results illustrate current hardships and possible solutions to monitoring T cell responses to individual chemical skin sensitizers. The provided data can guide the further development of T cell assays to unfold their full predictive and diagnostic potential, including cross-reactivity assessments.

show abstract

Proteomic analysis of haptenation by skin sensitisers: Diphencyprone and ethyl acrylate

Cited by 10 publications

References 45 publications

Chemical Modifications Induced by Phthalic Anhydride, a Respiratory Sensitizer, in Reconstructed Human Epidermis: A Combined HRMAS NMR and LC-MS/MS Proteomic Approach

Chemical Modifications Induced by Phthalic Anhydride, a Respiratory Sensitizer, in Reconstructed Human Epidermis: A Combined HRMAS NMR and LC-MS/MS Proteomic Approach

Haptenation of Macrophage Migration Inhibitory Factor: A Potential Biomarker for Contact Hypersensitivity

In Vitro Monitoring of Human T Cell Responses to Skin Sensitizing Chemicals—A Systematic Review

Contact Info

Product

Resources

About