ERK/STAT3 activation through CCL17/CCR4 axis-mediated type 2 cytokine-involved signaling pathways in Th2 cells regulates cutaneous drug reactions.

Cutaneous drug reactions (CDRs) are common drug-induced allergic reactions that cause severe consequences in HIV/AIDS patients. The CCL17/CCR4 axis is involved in the immune mechanism of allergic diseases, but its role in the CDRs has not been determined. Here, we aimed to determine the role of the CCL17/CCR4 axis and the underlying mechanism involved in CDRs. In this study, the serum cytokine levels in patients with CDR and healthy controls were measured. The CCL17-triggered allergic profile was screened via a PCR array. Apoptosis of keratinocytes cocultured with CCL17-stimulated Th2 cells was analyzed by flow cytometry. An NVP-induced rat CDR model was established, and dynamic inflammatory factor levels and Th2 cells in the peripheral blood of the rats were measured. Rat skin lesions and signaling pathways in Th2 cells were also analyzed. We showed that the serum CCL17 level was significantly upregulated in CDR patients (P = 0.0077), and the Th2 cell subgroup was also significantly elevated in the CDR rats. The CCL17/CCR4 axis induces Th2 cells to release IL-4 and IL-13 via the ERK/STAT3 pathway. The CCR4 antagonist compound 47 can alleviate rash symptoms resulting from NVP-induced drug eruption, Th2 cell subgroup, IL-4, and IL-13 and inhibit keratinocyte apoptosis. Taken together, these findings indicate that the CCL17/CCR4 axis mediates CDR via the ERK/STAT3 pathway in Th2 cells and type 2 cytokine-induced keratinocyte apoptosis.

HIV infection confers distinct mechanisms in severe drug eruption: Endogenous virus activation with aberrant Th2/Th1 and CD8+ T cells function.

Severe drug eruption (SDE), a common skin disease, becomes dangerous when it occurs in patients with human immunodeficiency virus (HIV). However, the molecular mechanisms are poorly understood. Forty patients including HIV+ SDE+ (n = 15), HIV- SDE+ (n = 15) and HIV+ SDE- (n = 10) subjects were enrolled in our study. All HIV+ patients were at acquired immune deficiency syndrome (AIDS) stage. Serum levels of TNF-α, IFN-γ, IL-4, IL-13, IL-6, CXCL9, and CCL17 were quantified by ELISA. Epstein-Barr virus (EBV) and cytomegalovirus (CMV) loads were quantified by RT-qPCR. CD4, CD8, Th1, Th2, TNF-α-CD8, and IFN-γ-CD8 T cell populations were measured by flow cytometry. Levels of biochemical indexes in HIV+ SDE+ patients were significantly different from in HIV- SDE+ patients (P < .05). EBV and CMV viral loads were significantly higher in HIV+ SDE+ patients, but not in HIV- SDE+ patients (P < .05). Inflammatory cytokines TNF-α and IFN-γ were significantly elevated in HIV+ SDE+ patients (P < .05). Th2/Th1 populations and TNF-α secreting or IFN-γ secreting CD8+ T cells, were significantly up-regulated in HIV+ SDE+ patients compared to HIV- SDE+ patients (P < .05). Conversely, the CD4/CD8 ratio was significantly down-regulated in HIV+ SDE+ patients compared to HIV- SDE+ patients (P < .05). HIV infection confers distinct clinical phenotypes and immune inflammatory mechanisms in SDE. Sustained EBV and CMV activation, unbalanced Th2/Th1 and overactive CD8+ T cells mediating a pro-inflammatory response could act as distinct mechanisms in the aggravation of SDE in HIV+ SDE+ patients.

Effects of CD4 cell count and antiretroviral therapy on mucocutaneous manifestations among HIV/AIDS patients in Yunnan, China.

BACKGROUND: The affecting factors of mucocutaneous manifestations in human immunodeficiency virus (HIV)/acquired immunodeficiency syndrome (AIDS) patients remain unclear in China. METHODS: A retrospective analysis was conducted among HIV/AIDS patients in Yunnan, China. The demographic data, mucocutaneous manifestations, CD4 cell counts, and antiretroviral therapy (ART) regimens were collected. The effects of CD4 cell count and ART on the spectrum of mucocutaneous manifestations were evaluated. RESULTS: Among 508 HIV/AIDS patients, 86.0% of cases showed mucocutaneous manifestations. The average CD4 cell count (176 cells/µl) of the patients with manifestations was significantly lower than those without manifestations (328 cells/µl) (P < 0.001). Diseases such as herpes zoster, oral candidiasis, condyloma acuminatum, genital herpes, oral leukoplakia, talaromycosis, cryptococcosis, and HIV-PPE (pruritic papular eruption) were represented quite frequently in patients with CD4 cell count <200 cells/µl (P < 0.05), but eczema was suffered by those with CD4 cell count ≥200 cells/µl (P < 0.05). ART could decline the incidence of herpes zoster, oral candidiasis, condyloma acuminatum, genital herpes, oral leukoplakia, talaromycosis, and cryptococcosis (P < 0.05). CONCLUSIONS: Mucocutaneous manifestations are closely related to the CD4 cell count and can be used as early predictors of HIV/AIDS and immune status in clinic. ART could reduce the incidence of certain mucocutaneous manifestations.