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Objectives Cutaneous Lupus erythematosus (CLE) presents with different subtypes including chronic LE forms namely chronic discoid (CDLE), subacute cutaneous (SCLE), and acute LE. The underlying cause for different clinical presentations is not well understood. We were interested in understanding the expression of IFN signature and LE-associated parameters in different body compartments in LE subtypes.Methods Peripheral blood mononuclear cells (PBMC), plucked hair follicles and oral mucosa swabs were investigated for expression of IFN stimulated genes (ISG; BST2, IFI27, IFIH1, MX1) by qPCR in CDLE, SCLE, SLE patients (n=40) and healthy individuals(n=8). 3-5 hair follicles were plucked from healthy looking, uninvolved scalp (occipital area), and oral swabs were taken from non involved buccal area.Results All LE subtypes showed an increased IFN signature compared to healthy controls. PBMC from SLE patients showed a 20-fold and those from CLE patients a 10-fold increase in expression of the ISG when compared to healthy controls.By contrast, the expression of ISG in hair follicles was 5-fold higher in individuals suffering from CDLE and 2-fold higher in SLE patients, when compared to healthy controls. CDLE with scarring outcome is believed to start at the hair follicle. We also observed a significantly higher expression of the MHC class I related molecule beta 2-microglobulin in LE samples with high ‘hair follicle ISG’ expression compared to healthy individuals. This may suggest a collapse of the immune privilege at the hair follicle site.The oral mucosa swab analysis further confirmed higher ISG expression in CDLE (20-fold increase) than in SLE (10-fold increase), when compared to healthy controls.Conclusions Our results show that the tissue is differentially ‘poised’ for a lupus response. There are two conclusions from these results: (1) plucked hair are a suitable source to determine increased IFN response in all LE patients and (2) high IFN hair follicle signatures is associated with and may facilitate the establishment of CDLE and could serve as an ‘early’ marker allowing treatment prior to irreversible scarring damage.