Cutaneous lupus erythematosus (CLE) is an autoimmune skin disorder that is characterized by an anti-epidermal lymphocytic infiltrate invading the dermo-epidermal junction, causing an interface
dermatitis (ID). Pathogenesis of CLE has been linked to activation of innate immunity. NKG2D is an innate immune receptor on NK cells and distinct T-cell populations. The NKG2D
ligands MHC class I
polypeptide-related sequence A and B (
MICA, MICB) have been associated to CLE susceptibility. Our gene microarray analyses of chronic
discoid lupus erythematosus (CDLE) skin lesions, separated in epidermal, junctional and dermal skin areas via
laser microdissection, revealed a high expression of NKG2D in the lymphocytic infiltrate and led us to further investigate the role of NKG2D in CLE. Pathway analyses showed a strong "
interferon (IFN) signature" and vast activation of innate immune response pathways (TLR, RIG-I, cytosolic
DNA sensing, JAK/STAT) in CDLE, that expressed the high NKG2D signal. Immunohistochemistry (IHC) confirmed the presence of NKG2D and its
ligand MICB in CDLE and subacute
cutaneous lupus erythematosus (SCLE) lesions. Finally, HaCaT cells were stimulated with
nucleic acids and extracted
RNA was sequenced with Illumina HiSeq and showed that stressed keratinocytes express typical NKG2D
ligands MICA/B and ULBP2. This study provides first evidence that NKG2D is present in CDLE and SCLE skin lesions and could be relevant for cytotoxicity in IFN-driven skin lesions with upregulated innate immune response pathways present in CLE. It could furthermore play a role in CLE
inflammation promoted by keratinocytes under cell stress.