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To determine the role of CD4 molecules in the generation and regulation of contact hypersensitivity (CHS), we treated mice lacking the CD4 gene as a result of targeted disruption with dinitrofluorobenzene to induce CHS. The mutant mice lacking CD4 (CD4(-) mice) showed marked hyporesponsiveness in CHS compared with normal syngeneic C57BL/6 mice (38.3 +/-9.0% of normal at 24 h after the challenge assessed by net ear swelling; p < 0.025). CD4(-) mice had a larger CD4-8- double negative T-cell receptor alpha beta+ cell population in the lymph nodes than did normal mice, and the increase of this cell population was observed in CD4(-) mice after sensitization. Draining lymph node cells from sensitized normal mice restored the responsiveness in CD4(-) mice, but those from sensitized CD4(-) mice were less effective in restoring the CHS response in normal mice. Langerhans cell numbers were normal, and function, as assessed by the ability to present soluble hapten, was not impaired in CD4(-) mice. Skin cytokine profiles demonstrated an increase in interferon-gamma, interleukin-2, and interleukin-4 mRNA levels after challenge in normal mice, whereas this response was blunted in CD4(-) mice. CD4(-) mice also showed hyporesponsiveness in inflammatory reaction to irritant chemicals. These results suggest that the CD4 molecule is required for optimal induction of CHS as well as irritant contact dermatitis and may influence the development of CHS by modulating the cytokine profiles in the skin.

Many single nucleotide polymorphisms (SNPs) have been described as putative risk factors for melanoma. The aim of our study was to validate the most prominent genetic risk loci in an independent Greek melanoma case-control dataset and to assess their cumulative effect solely or combined with established phenotypic risk factors on individualized risk prediction. We genotyped 59 SNPs in 800 patients and 800 controls and tested their association with melanoma using logistic regression analyses. We constructed a weighted genetic risk score (GRSGWS) based on SNPs that showed genome-wide significant (GWS) association with melanoma in previous studies and assessed their impact on risk prediction. Fifteen independent SNPs from 12 loci were significantly associated with melanoma (P < 0.05). Risk score analysis yielded an odds ratio of 1.36 per standard deviation increase of the GRSGWS (P = 1.1 × 10(-7)). Individuals in the highest 20% of the GRSGWS had a 1.88-fold increase in melanoma risk compared with those in the middle quintile. By adding the GRSGWS to a phenotypic risk model, the C-statistic increased from 0.764 to 0.775 (P = 0.007). In summary, the GRSGWS is associated with melanoma risk and achieves a modest improvement in risk prediction when added to a phenotypic risk model.