Exploring allergic and irritant contact dermatitis : biomarkers, mechanisms, and allergen uptake

Contact dermatitis (CD) is a common disease resulting from direct skin contact with allergens or irritants and greatly affects the life quality of suffering individuals. It is categorized into two main forms, namely allergic CD (ACD) and irritant CD (ICD), depending on the triggering agent. Despite having distinct underlying mechanisms, the clinical presentation of ACD and ICD can provoke resembling clinical manifestations, particularly in chronic cases, which hampers the clinical discrimination and subsequent disease management strategies. Furthermore, while the pathogenesis of ACD and ICD is better understood, effective therapeutics remain elusive. Additionally, the ongoing introduction of novel materials in industrial and consumer products, including metal nanoparticles, underscores the need for continuous evaluation of their skin absorption and potential to induce ACD. The overall aim of this thesis was to elucidate pathomechanisms of CD, offering new insights into its pathology, identifying disease classifiers, and comprehensively characterizing the absorption and distribution patterns of metal-based allergens in human skin.

Transcriptomic profiling of human skin biopsies obtained from positive patch test reactions to allergens and irritants was conducted in Paper I-III. In Paper I, integrative transcriptomic analysis and machine-learning approaches were utilized to identify disease-specific signatures for robust disease classification. By analyzing the transcriptomic profiles of positive patch test reactions to four allergens and two irritants with distinct properties, 28 disease-classifying gene sets with high prediction accuracy were identified. Notably, the proposed biomarker gene sets were validated in an independent patient group (n=31), and their potential clinical applicability was confirmed through performance testing in external datasets. In Paper II, time-dependent changes in the transcriptomic signature of ACD induced by nickel were investigated, revealing leukocyte compositional alterations in the late phases (48 and 96h) of nickel exposure. Specifically, deconvolution algorithms and enrichment analyses suggested infiltration and activation of various innate immune cells including natural killer (NK) cells, mast cells, and inflammatory macrophages. Notably, the transcriptomic profiling results from both Paper I and II indicated that NK cell activation might distinguish ACD from ICD. In Paper III, dysregulation of the short non-coding microRNA (miRNA), and its regulatory impact on the post-transcriptional expression in ACD and ICD was explored. The results revealed miRNA-mRNA pairs enriched for processes relevant to CD, identifying miR-155-5p, miR-142-3/5p and miR-497-5p as potential key regulators of the inflammatory process of ACD. Paper IV and V assessed the hazards of skin exposure to the metal nanoparticles, specifically CoNPs, in individuals with cobalt contact allergy, identifying CoNPs as a hazardous material capable of inducing ACD. Furthermore, the uptake and distribution of CoNPs in the skin were evaluated in Paper V, showing minimal uptake of CoNP compared to the standard test substance of cobalt contact allergy.

Overall, the findings from these studies provide novel insights into the molecular pathways involved in CD, encompassing the delineation of key cellular players and associated pathways, regulatory mechanisms, and proposal of robust disease classifiers of ACD and ICD. Additionally, the results underscore the potential hazards of allergens in nanoparticulate form as a potent inducers of elicitation responses in contact allergic individuals.

List of scientific papers

I. Fortino V*, Wisgrill L*, Werner P, Suomela S, Linder N, Jalonen E, Suomalainen A, Marwah V, Kero M, Pesonen M, Lundin J, Lauerma A, Aalto-Korte K, Greco D, Alenius H, Fyhrquist N. Machine-learning-driven biomarker discovery for the discrimination between allergic and irritant contact dermatitis. Proc Natl Acad Sci U S A. 2020 Dec 29;117(52):33474- 33485. Epub 2020 Dec 14. *These authors contributed equally.
https://doi.org/10.1073/pnas.2009192117

II. Wisgrill L, Werner P, Jalonen E, Berger A, Lauerma A, Alenius H, Fyhrquist N. Integrative transcriptome analysis deciphers mechanisms of nickel contact dermatitis. Allergy. 2021 Mar;76(3):804-815. Epub 2020 Aug 12.
https://doi.org/10.1111/all.14519

III. Werner P, Wisgrill L, Riskumäki M, Jalonen E, Vendelin J, Suomela S, Lauerma A, Alenius H, Fyhrquist N. Identification of novel miRNA-mRNA regulatory networks in contact dermatitis by integrated microarray analysis. Allergy. 2021 Apr;76(4):1257-1261. Epub 2020 Sep 20.
https://doi.org/10.1111/all.14578

IV. Midander K*, Werner P*, Isaksson M, Wisgrill L, Lidén C, Fyhrquist N, Julander A. Cobalt nanoparticles cause allergic contact dermatitis in humans. Br J Dermatol. 2022 Oct 28:ljac043. Epub ahead of print. *These authors contributed equally.
https://doi.org/10.1093/bjd/ljac043

V. Werner P, Schaier M, Braun G, Julander A, Midander K, Isaksson M, Köllensperger G*, Wisgrill L*, Fyhrquist N. Integrative transcriptomic analysis and assessment of skin permeation of cobalt nanoparticles and cobalt salts in human skin by RNAseq and LA-ICP-TOFMS. 2024. *These authors contributed equally. [Manuscript]