Using DR52c/Ni2+ mimotope tetramers to detect Ni2+ reactive CD4+ T cells in patients with joint replacement failure

Abstract

T cell mediated hypersensitivity to nickel (Ni²⁺) is one of the most common causes of allergic contact dermatitis. Ni²⁺ sensitization may also contribute to the failure of Ni²⁺ containing joint implants, and revision to non-Ni²⁺ containing hardware can be costly and debilitating. Previously, we identified Ni²⁺ mimotope peptides, which are reactive to a CD4⁺ T cell clone, ANi2.3 (Vα1, Vβ17), isolated from a Ni²⁺ hypersensitive patient with contact dermatitis. This T cell is restricted to the major histocompatibility complex class II (MHCII) molecule, Human Leukocyte Antigen (HLA)-DR52c (DRA, DRB3*0301). However, it is not known if Ni²⁺ induced T cell responses in sensitized joint replacement failure patients are similar to subjects with Ni²⁺ induced contact dermatitis. Here, we generated DR52c/Ni²⁺ mimotope tetramers, and used them to test if the same Ni²⁺ T cell activation mechanism could be generalized to Ni²⁺ sensitized patients with associated joint implant failure. We confirmed the specificity of these tetramers by staining of ANi2.3T cell transfectomas. The DR52c/Ni²⁺ mimotope tetramer detected Ni²⁺ reactive CD4⁺ T cells in the peripheral blood mononuclear cells (PBMC) of patients identified as Ni²⁺ sensitized by patch testing and a positive Ni²⁺ LPT. When HLA-typed by a DR52 specific antibody, three out of four patients were DR52 positive. In one patient, Ni²⁺ stimulation induced the expansion of Vβ17 positive CD4⁺ T cells from 0.8% to 13.3%. We found that the percentage of DR52 positivity and Vβ17 usage in Ni²⁺ sensitized joint failure patients are similar to Ni sensitized skin allergy patients. Ni²⁺ independent mimotope tetramers may be a useful tool to identify the Ni²⁺ reactive CD4⁺ T cells.

Keywords: CD4(+) T cells; HLA; Joint implants; Metal allergy; Metal toxicology; Tetramer.