Nickel allergy – immunologic inflammatory pathways

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Review of: Nickel sulfate promotes IL-17A producing CD4+ T-cells by an IL-23 dependent mechanism regulated by TLR4 and Jak-STAT pathways

Original article: Bechara, R, Antonios, D, Azouri, H, Pallardy, M, Nickel sulfate promotes IL-17A producing CD4+ T-cells by an IL-23 dependent mechanism regulated by TLR4 and Jak-STAT pathways. The Journal of Investigative Dermatology. 2017 Jun 17.

Reviewed by: Jacqueline Chen, BA. MSI & Brittanya A. Limone, MS, BS. MSIV

  • Allergic contact dermatitis (ACD) is classically described as a Type IV hypersensitivity reaction, however, the distinctive characteristics of a nickel-induced allergic contact dermatitis (Ni-ACD) lead to immunologic mechanisms that not only encompass a Th1 response but involve additional inflammatory cells, cytokines, and pathways.
  • In Ni-ACD, dendritic cells (antigen presenting [accessory] cells) play a critical role. Dendritic cells bind the antigenic nickel absorbed in the skin and then present it to T-cells at local lymph nodes, coordinating T-cell differentiation through cytokine messengers.
    • The two most crucial cytokine signals include:
      • IL-12p70 which promotes a T-helper Cell 1 type (Th1) response
      • IL-23 which stimulates the development of T-helper Cell 17 type (Th17) cells
    • Notably, the presence of IL-17A produced by Th17 cells correlates with the clinical reaction in nickel allergic patients. An injection of anti-IL-17 neutralizing antibodies may limit the severity of the contact hypersensitivity.
    • The IL-23/IL-12p70 balance determines the primary immunologic mechanism of the hypersensitivity reaction.
      • Increases in the IL-23/IL12p70 balance lead to a greater Th1 cell polarization
      • Decreases in the IL-23/IL-12p70 ratio produce a stronger Th17 cell response.
    • Brechara et al identified 5 specific modulators of T-cell differentiation that are important in the development of Ni-ACD through alterations in the IL-23/IL-12p70 balance.
      • IFN-γ
        • Produced by Th1 cells.
        • Greatly increases the IL-23 levels produced by nickel sulfate (NiSO4)-treated dendritic cells.
        • The increase in the IL-23/IL-12p70 ratio favors Th17 cell development.
      • Jak-STAT pathway
        • Inhibition of the Jak-STAT pathway increases IL-23.
        • Alternatively, activation of the pathway will increase IL-12p40 and IL-12p70 levels and decrease the IL-23/IL-12p70 balance.
        • This decrease in the IL-23/IL-12p70 balance favors a Th1 cell response.
      • TLR4, p38MAPK and NFkB pathways
        • Activation of these pathways is essential for nickel-induced production of IL-23, IL-12p40 and IL-12p70.
        • Since both IL-23 and IL-12 cytokines are produced, the IL-23/IL-12p70 balance remains high.
      • In summary, Ni-ACD is a complex immunologic disease involving not only a cell-mediated Th1 response but also Th17 cell development with alterations in IFN- γ levels and TLR4, Jak-STAT, p38MAPK, and NF-kβ immunologic pathways.

Article: link to publishers site

Researchers are investigating the role of piercings and the development of nickel allergy – please consider to take the Loma Linda University Nickel Allergy Survey:

Nickel allergy survey