Abstract
Although nickel hypersensitivity is known as a delayed-type hypersensitivity mediated by nickel-specific T cells, it is greatly influenced by other immune cells. Here we show that splenic natural killer cells (NK cells) directly or indirectly respond to nickel by secretion of IFN-gamma. Using enzyme-linked immunosorbent spot (ELISPOT) assays, we found that nickel-reactive cells readily secreted IFN-gamma when splenocytes were cultured in the presence of varying concentrations of nickel sulfate (NiSO(4)) for 24 h. However, nickel-reactive IL-2- or IL- 4-secreting cells were infrequent during the 24-h culture with NiSO(4). Immune responses to nickel were innate, not adaptive, in nature since the frequency of nickel-reactive IFN-g-secreting cells did not increase upon previous exposure to NiSO(4) and recombination activating gene (RAG)-1-deficient mice contained nickel-reactive IFN-gamma-secreting cells. The involvement of NK cells in the innate response to NiSO(4) was confirmed since we could observe a significant reduction of the frequency of nickel-reactive cells in NK cell-depleted mice. Furthermore, the number of IFN-gamma secreting cells was significantly reduced in the ELISPOT assays when NKG2D was blocked by anti-NKG2D antibody. These results suggest that there is an early and rapid innate immune response to nickel, which is mediated by NK cells and the NKG2D receptor. The significance of the innate response to nickel is that it may contribute to development of the late T cell-mediated delayed type hypersensitivity against nickel.
Highlights
Nickel is commonly found in coins, jewelry, and many other surrounding materials, but nickel is the most common occupational as well as environmental contact allergen (Basketter et al, 1993; Zug et al, 2008)
Since the enzyme-linked immunosorbent spot (ELISPOT) assay was performed by 24-h stimulation with NiSO4 and naive T cells usually require at least a few days for immune response, it was expected that only memory nickel-reactive T cells could respond to nickel ions and secrete cytokines
We measured the numbers of IL-2, IL-4, and IFN-γ-secreting cells since T cells participating in the immune response to nickel could be either T helper 1 (Th1) or Th2 cells (Artik et al, 2001; Sebastiani et al, 2002)
Summary
Nickel is commonly found in coins, jewelry, and many other surrounding materials, but nickel is the most common occupational as well as environmental contact allergen (Basketter et al, 1993; Zug et al, 2008). Whereas the description of nickelspecific antibodies is rare probably due to the diversity of proteins conjugated to nickel ion, several groups reported the presence of nickel-specific T cells (Kapsenberg et al, 1987; Silvennoinen-Kassinen et al, 1991; Sebastiani et al, 2002; Gamerdinger et al, 2003). Those nickel-specific CD4+ and CD8+ T cells may explain the immunological pathogenesis of nickel contact dermatitis and immune response to nickel-containing metal implants since nickel-specific T cells have been repeatedly detected in sensitized human and animals. The immune response to nickel is regarded as an example of delayed type hypersensitivity model, especially if nickel was applied subcutaneously (Ishii et al, 1995)
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