Multiple environmental antigens may trigger autoimmunity in psoriasis through T-cell receptor polyspecificity.

Introduction: Psoriasis is a T-cell mediated autoimmune skin disease. HLA-C*06:02 is the main psoriasis-specific risk gene. Using a Vα3S1/Vß13S1 T-cell receptor (TCR) from a lesional psoriatic CD8+ T-cell clone we had discovered that, as an underlying pathomechanism, HLA-C*06:02 mediates an autoimmune response against melanocytes in psoriasis, and we had identified an epitope from ADAMTS-like protein 5 (ADAMTSL5) as a melanocyte autoantigen. The conditions activating the psoriatic autoimmune response in genetically predisposed individuals throughout life remain incompletely understood. Here, we aimed to identify environmental antigens that might trigger autoimmunity in psoriasis because of TCR polyspecificity. Methods: We screened databases with the peptide recognition motif of the Vα3S1/Vß13S1 TCR for environmental proteins containing peptides activating this TCR. We investigated the immunogenicity of these peptides for psoriasis patients and healthy controls by lymphocyte stimulation experiments and peptide-loaded HLA-C*06:02 tetramers. Results: We identified peptides from wheat, Saccharomyces cerevisiae, microbiota, tobacco, and pathogens that activated both the Vα3S1/Vß13S1 TCR and CD8+ T cells from psoriasis patients. Using fluorescent HLA-C*06:02 tetramers loaded with ADAMTSL5 or wheat peptides, we find that the same CD8+ T cells may recognize both autoantigen and environmental antigens. A wheat-free diet could alleviate psoriasis in several patients. Discussion: Our results show that due to TCR polyspecificity, several environmental antigens corresponding to previously suspected psoriasis risk conditions converge in the reactivity of a pathogenic psoriatic TCR and might thus be able to stimulate the psoriatic autoimmune response against melanocytes. Avoiding the corresponding environmental risk factors could contribute to the management of psoriasis.

Contact sensitization to iron: A potentially underestimated metal allergen and elicitor of complications in patients with metal implants.

BACKGROUND: Little is known about sensitization to iron (Fe) in private, occupational, and medical settings, particulary implantology. OBJECTIVES: To investigate sensitization to metals, particularly to Fe, both in pre-implant individuals with presumed metal allergy and in patients with suspected metal implant allergy. To further characterize Fe-sensitized individuals. METHODS: Analysis of patch test reactions to an Fe (II) sulfate-containing metal series in 183 consecutive patients (41 pre-implant, 142 metal implant bearers). Test readings were on day (D)2, D3, and D6. Evaluation of questionnaire-aided history of metal reactivity patterns and demographics of Fe reactors. RESULTS: Metal reactivity in pre-implant/implant/total group was: to nickel 39%/30%/32%; to cobalt 17%/15%/15%; and to chromium 7%/13%/11%. Co-sensitizations cobalt/nickel (19/58) and cobalt/chromium (11/21) were significant at P < .001; co-sensitizations Fe/nickel (4/10) and chromium/knee arthroplasty (11/73) at P = .03. Ten of 183 (5.5%) reacted to Fe (2 of 41 pre-implant patients, 8 of 142 implant bearers), with 10 reacting only on D6. Fe reactivity was highest in complicated knee arthroplasty (7/73). Further peculiarities of Fe reactors included frequent isolated Fe reactivity (6/10), occupational metal exposure (7/10), previous (par)enteral Fe substitution (6/10). CONCLUSIONS: The 5.5% prevalence of Fe reactions suggests a potentially underestimated role of this metal allergen in general and in implant bearers. The latter also shows a distinct metal sensitization pattern.

Silibinin and related compounds are direct inhibitors of hepatitis C virus RNA-dependent RNA polymerase.

BACKGROUND & AIMS: Silymarin is a mixture of flavonolignans extracted from the milk thistle. Silymarin contains several molecules, including silibinin A, silibinin B, isosilibinin A, isosilibinin B, silicristin, and silidianin. Intravenous infusion of silibinin induces dose-dependent reduction of hepatitis C virus (HCV) RNA levels. The aim of this study was to test the principal isomers contained in silymarin preparations for their ability to inhibit HCV enzymatic functions and replication in different models. METHODS: The inhibitory activity of silymarin components was tested in HCV RNA-dependent RNA polymerase and NS3/4A protease enzyme assays. Their ability to inhibit replication of an HCV genotype 1b replicon model and the JFH1 infectious HCV model in cell culture was also studied. RESULTS: Silibinin A, silibinin B, their water-soluble dihydrogen succinate forms and Legalon SIL, a commercially available intravenous preparation of silibinin, inhibited HCV RNA-dependent RNA polymerase function, with inhibitory concentrations 50% of the order of 75-100 microM. Silibinin A and silibinin B also inhibited HCV genotype 1b replicon replication and HCV genotype 2a strain JFH1 replication in cell culture. None of these compounds inhibited HCV protease function. CONCLUSIONS: Silibinin A and silibinin B, as well as Legalon SIL, inhibit HCV replicon and JFH1 replication in cell culture. This effect is at least partly explained by the ability of these compounds to inhibit HCV RNA-dependent RNA polymerase activity. Our results provide a basis for the optimization and subsequent development of members of the Flavonoid family as specific HCV antivirals.