Norketamine [BSA]

Nickel (Ni) is a widely distributed metal in the environment and an important pollutant because of its many industrial applications. With increasing incidences of Ni contamination, Ni toxicity has become a global public health concern and recent evidence suggests that Ni adversely affects the immune system. Hence, this paper reviews the literature on immune-related effects of Ni exposure, the immunotoxicological effects of Ni, and the underlying mechanism of Ni immunotoxicity. The main focus was on the effect of Ni on the development of organs of immune system, lymphocyte subpopulations, cytokines, immunoglobulins, natural killer (NK) cells, and macrophages. Moreover, Ni toxicity also induces inflammation and several studies demonstrated that Ni could induce immunotoxicity. Excessive Ni exposure can inhibit the development of immune organs by excessively inducing apoptosis and inhibiting proliferation. Furthermore, Ni can decrease T and B lymphocytes, the specific mechanism of which requires further research. The effects of Ni on immunoglobulin A (IgA), IgG, and IgM remain unknown and while Ni inhibited IgA, IgG, and IgM levels in an animal experiment, the opposite result was found in research on humans. Ni inhibits the production of cytokines in non-inflammatory responses. Cytokine levels increased in Ni-induced inflammation responses, and Ni activates inflammation through toll like (TL)4-mediated nuclear factor-kappa B (NF-kappa B) and signal transduction cascades mitogen-activated protein kinase (MAPK) pathways. Ni has been indicated to inactivate NK cells and macrophages both in vitro and in vivo. Identifying the mechanisms underlying the Ni-induced immunotoxicity may help to explain the growing risk of infections and cancers in human populations that have been exposed to Ni for a long time. Such knowledge may also help to prevent and treat Ni-related carcinogenicity and toxicology.

Aims/hypothesis Mucosal-associated invariant T (MAIT) cells are innate-like T cells that recognise derivatives of bacterial riboflavin metabolites presented by MHC-Ib-related protein 1 (MR1) molecules and are important effector cells for mucosal immunity. Their development can be influenced by the intestinal microbiome. Since the development of type 1 diabetes has been associated with changes in the gut microbiome, this can be hypothesised to lead to alterations in circulating MAIT cells. Accordingly, peripheral blood MAIT cell alterations have been reported previously in patients with type 1 diabetes. However, a comprehensive analysis of the frequency and phenotype of circulating MAIT cells at different stages of type 1 diabetes progression is currently lacking. Methods We analysed the frequency, phenotype and functionality of peripheral blood MAIT cells, as well as gamma delta T cells, invariant natural killer T (iNKT) cells and natural killer (NK) cells with flow cytometry in a cross-sectional paediatric cohort (aged 2-15) consisting of 51 children with newly diagnosed type 1 diabetes, 27 autoantibody-positive (AAb(+)) at-risk children, and 113 healthy control children of similar age and HLA class II background. The frequency of MAIT cells was also assessed in a separate cross-sectional adult cohort (aged 19-39) of 33 adults with established type 1 diabetes and 37 healthy individuals of similar age. Results Children with newly diagnosed type 1 diabetes displayed a proportional increase of CD8(-)CD27(-)MAIT cells compared with healthy control children (median 4.6% vs 3.1% of MAIT cells, respectively, p = 0.004), which was associated with reduced expression of C-C chemokine receptor (CCR)5 (median 90.0% vs 94.3% of MAIT cells, p = 0.02) and beta 7 integrin (median 73.5% vs 81.7% of MAIT cells, p = 0.004), as well as decreased production of IFN-gamma (median 57.1% vs 69.3% of MAIT cells, p = 0.04) by the MAIT cells. The frequency of MAIT cells was also decreased in AAb(+)children who later progressed to type 1 diabetes compared with healthy control children (median 0.44% vs 0.96% of CD3(+)T cells, p = 0.04), as well as in adult patients with a short duration of type 1 diabetes (less than 6 years after diagnosis) compared with control individuals (median 0.87% vs 2.19% of CD3(+)T cells, p = 0.007). No alterations in gamma delta T cell, iNKT cell or NK cell frequencies were observed in children with type 1 diabetes or in AAb(+) children, with the exception of an increased frequency of IL-17A(+)gamma delta T cells in children with newly diagnosed diabetes compared with healthy control children (median 1.58% vs 1.09% of gamma delta T cells, p = 0.002). Conclusions/interpretation Changes in the frequency and phenotype of circulating MAIT cells were detectable before, at the onset and after diagnosis of type 1 diabetes in cross-sectional cohorts. Our results suggest a possible temporal association between peripheral blood MAIT cell alterations and the clinical onset of type 1 diabetes.