Immunological Mechanisms of Metal Allergies and the Nickel-Specific TCR-pMHC Interface

Riedel, Franziska; Aparicio‐Soto, Marina; Curato, Caterina; Thierse, Hermann‐Josef; Siewert, Katherina; Luch, Andreas

doi:10.3390/ijerph182010867

Cited by 27 publications

(38 citation statements)

References 240 publications

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“…Once sensitized, clinical symptoms, such as allergic contact dermatitis (ACD) occur, even after otherwise relatively harmless chemical exposures ( Peiser et al, 2012 ; Esser and Martin, 2017 ; Martin et al, 2018 ). To date, only a few chemical-induced T cell epitopes, mainly for model proteins or peptides, have been elucidated ( Martin et al, 2004 ; Thierse et al, 2005 ; Meng et al, 2018 ; Pichler, 2019 ; Riedel et al, 2021 ). Experimental hardships linked to inefficient epitope generation and the rarity of antigen-specific T cells have delayed the development of T cell-based assays ( Martin et al, 2010 ; Ogese et al, 2020 ; Hammond et al, 2021 ; Riedel et al, 2021 ).…”

Section: Introductionmentioning

confidence: 99%

“…To date, only a few chemical-induced T cell epitopes, mainly for model proteins or peptides, have been elucidated ( Martin et al, 2004 ; Thierse et al, 2005 ; Meng et al, 2018 ; Pichler, 2019 ; Riedel et al, 2021 ). Experimental hardships linked to inefficient epitope generation and the rarity of antigen-specific T cells have delayed the development of T cell-based assays ( Martin et al, 2010 ; Ogese et al, 2020 ; Hammond et al, 2021 ; Riedel et al, 2021 ). However, alternative in vitro tests that include T cells are urgently needed for improved diagnosis and predictive purposes by worldwide regulatory authorities ( Corsini et al, 2018 ).…”

Section: Introductionmentioning

confidence: 99%

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Frequencies and TCR Repertoires of Human 2,4,6-Trinitrobenzenesulfonic Acid-specific T Cells

et al. 2022

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Allergic contact dermatitis is a widespread T cell-mediated inflammatory skin disease, but in vitro monitoring of chemical-specific T cells remains challenging. We here introduce short-term CD154/CD137 upregulation to monitor human T cell responses to the experimental sensitizer 2,4,6-trinitrobenzenesulfonic acid (TNBS). Peripheral blood mononuclear cells (PBMC) from healthy donor buffy coats were TNBS-modified and incubated with unmodified PBMC. After 5 and 16 h, we detected TNBS-specific activated CD154+CD4+ and CD137+CD8+ T cells by multi-parameter flow cytometry, respectively. Activated cells were sorted for restimulation and bulk T cell receptor (TCR) high-throughput sequencing (HTS). Stimulation with TNBS-modified cells (3 mM) induced CD154 expression on 0.04% of CD4+ and CD137 expression on 0.60% of CD8+ memory T cells, respectively (means, n = 11–17 donors). CD69 co-expression argued for TCR-mediated activation, which was further supported by TNBS-specific restimulation of 10/13 CD154+CD4+ and 11/15 CD137+CD8+ T cell clones and lines. Major histocompatibility complex (MHC) blocking antibodies prevented activation, illustrating MHC restriction. The high frequencies of TNBS-specific T cells were associated with distinct common changes in the TCR β-chain repertoire. We observed an overrepresentation of tryptophan and lysine in the complementarity determining regions 3 (CDR3) (n = 3–5 donors), indicating a preferential interaction of these amino acids with the TNBS-induced epitopes. In summary, the detection of TNBS-specific T cells by CD154/CD137 upregulation is a fast, comprehensive and quantitative method. Combined with TCR HTS, the mechanisms of chemical allergen recognition that underlie unusually frequent T cell activation can be assessed. In the future, this approach may be adapted to detect T cells activated by additional chemical sensitizers.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Frequencies and TCR Repertoires of Human 2,4,6-Trinitrobenzenesulfonic Acid-specific T Cells

et al. 2022

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“…Metal allergy is a delayed type of hypersensitive reaction, the pathogenesis of which is mediated by a complex immune network of T-cell-mediated interactions [1][2][3]. However, the precise mechanisms by which metal allergy causes disease have not been fully elucidated.…”

Section: Introductionmentioning

confidence: 99%

Metal Allergy Mediates the Development of Oral Lichen Planus via TSLP-TSLPR Signaling

Yunizar

Watanabe

Liu

et al. 2022

JCM

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Metal allergy is a T-cell-mediated delayed type of hypersensitive reaction. The pathogenetic mechanisms underlying the allergy are unclear, although the condition has been reported to be related to oral lichen planus (OLP), despite an absence of immunological studies to support this relationship. In this study, histopathological samples of OLP patients were examined to compare the metal allergy-positive and -negative groups, with a focus on the network of epidermal keratinocytes and T cells induced by thymic stromal lymphopoietin (TSLP) and its receptor, TSLPR. Infiltration of T cells into the epithelium was revealed to be higher in the OLP lesions of metal allergy-positive patients than in those of metal allergy-negative patients. Moreover, TSLP-TSLPR signaling and TNF-α production were higher in the epithelial tissue samples of the metal allergy-positive patients than in the metal allergy-negative patients. Metal allergy is associated with both increased expressions of TSLP in keratinocytes and increased TNF-α levels in the epithelium. We propose that this would promote the accumulation of T cells at the lesion site, contributing to the formation of the disease. These results suggest that metal allergy may be an aggravating factor in the pathogenesis of OLP.

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“…Much progress has been made in the understanding of metal-induced T cell epitopes [ 38 , 39 , 40 , 41 ], which has been reviewed elsewhere [ 42 , 43 ]. Mechanisms of non-metallic chemical-induced T cell epitopes, including those of drug hypersensitivity reactions (DHRs), are illustrated in Figure 1 .…”

Section: Introductionmentioning

confidence: 99%

“…In the case of chemical allergens, modified self-structures exceed the threshold for functional T cell binding and induce unintended adaptive immune responses. These mechanisms are grounded in the extensive poly-specificity (also called cross-reactivity) of TCR [ 43 , 53 , 54 ].…”

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

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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.

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Immunological Mechanisms of Metal Allergies and the Nickel-Specific TCR-pMHC Interface

Cited by 27 publications

References 240 publications

Frequencies and TCR Repertoires of Human 2,4,6-Trinitrobenzenesulfonic Acid-specific T Cells

Frequencies and TCR Repertoires of Human 2,4,6-Trinitrobenzenesulfonic Acid-specific T Cells

Metal Allergy Mediates the Development of Oral Lichen Planus via TSLP-TSLPR Signaling

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

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