Cell-Specific and Variant-Linked Alterations in Expression of ERAP1, ERAP2, and LNPEP Aminopeptidases in Psoriasis

ERAP1, ERAP2 and LNPEP are aminopeptidases implicated in autoimmune pathophysiology. Here, we demonstrate that ERAP2 is upregulated and ERAP1 is downregulated in patients with psoriasis who are homozygous for autoimmune-linked variants of ERAP. We also demonstrate that aminopeptidase expression is not uniform in the skin. Specifically, the intracellular antigen-processing aminopeptidases ERAP1 and ERAP2 were strongly expressed in basal and early spinous layer keratinocytes, while granular layer keratinocytes expressed predominantly LNPEP, an aminopeptidase specialized in the processing of extracellular antigens for MHC class I cross-presentation. In psoriasis, basal keratinocytes also expressed the T-cell and monocyte-attracting chemokine, CCL2, and the T-cell supporting cytokine, IL-15. In contrast, TGF-β1 was the major cytokine expressed by healthy control basal keratinocytes. SFRP2-high dermal fibroblasts were also noted to have an ERAP2-high expression phenotype and elevated HLA-C. In psoriasis, the SFRP2-high fibroblast subpopulation also expressed elevated CXCL14. From these results, we postulate that 1) an increased ERAP2/ERAP1 ratio results in altered antigen processing, a potential mechanism by which ERAP risk alleles predispose individuals to autoimmunity; 2) ERAP2-high expressing cells display a unique MHC-bound peptidome, generated from intracellular antigens; and 3) the granular layer peptidome is skewed toward extracellular antigens.