Kern, J. S. | bioRxiv Science

bioRxiv2026

Immunopeptidomics reveals peptide antigens preferentially presented in psoriasis lesional skin of HLA-C*06:02 carriers

BackgroundHuman leukocyte antigen (HLA)-C*06:02 is a major genetic risk factor for psoriasis and understanding the HLA-C*06:02-presented peptide antigen repertoire (immunopeptidome) in the skin of patients is crucial for identifying autoantigens. Yet, no skin immunopeptidome data from patients stratified by their HLA-C*06:02 status exists. ObjectiveWe analysed biopsies from lesional and non-lesional skin of patients with psoriasis vulgaris (n=12), guttate psoriasis (n=8), or from skin of healthy controls (n=16). MethodsHLA class I and class II peptide complexes were isolated by serial immunoprecipitation and HLA-bound peptides identified by liquid chromatography-tandem mass spectrometry. HLA-C*06:02 genotyping was performed by polymerase chain reaction. ResultsOver 99,000 non-redundant peptide ligands were identified across all samples. Substantially more HLA class I and class II peptides were detected in lesional psoriatic skin compared to matched non-lesional and healthy skin. Three peptides predicted to bind HLA-C*06:02, including MRASSFLIV from the known psoriasis marker peptidase inhibitor 3 (PI3), were identified in all lesions of HLA-C*06:02-positive patients but were rarely detected or absent in HLA-C*06:02-negative patient lesional skin and not detected at all in unaffected skin. Keratinocyte differentiation-associated protein (KRTDAP) was a notable source of lesion-specific HLA class II ligands contributing three out of six peptides detected in more than half of the lesional samples. ConclusionActive psoriatic lesions display an altered and expanded immunopeptidome compared to unaffected skin. We have identified numerous unreported, lesion-specific HLA-bound peptides and their source proteins. These findings offer insights into the pathobiology of psoriasis and provide a resource for future functional studies. CAPSULE SUMMARYA selection of immunopeptides is presented exclusively in lesional skin of HLA-C*06:02+ patients with psoriasis that may represent antigenic drivers of disease.

immunology↗

bioRxiv2025

A transgenic mouse allows to capture the HLA-C*06:02 immunopeptidome in a model of psoriasis

Psoriasis vulgaris is a T cell-mediated autoimmune skin condition affecting around one in fifty people worldwide. Whilst advanced immunomodulatory therapeutic options have become available in recent years, ongoing disease suppression is still required with no curative treatment available to date. The human leukocyte antigen class I allele HLA-C*06:02 is the main genetic risk determinant of psoriasis. Its function is to present peptide antigens to CD8+ T cells and natural killer cells which in turn elicit and perpetuate the immune response, yet little is known about ligands presented by HLA-C*06:02. To gain an understanding which HLA-C*06:02-restricted peptides are presented by epidermal cell populations and might be initiators of the autoimmune response in psoriasis, we have conducted an in depth immunopeptidomics analysis of HLA-C*06:02+ keratinocyte and melanocyte cell lines. Furthermore, we introduce a HLA-C*06:02 transgenic mouse which, in conjunction with the imiquimod model of psoriasis, allowed us to assess the ex vivo immunopeptidome of HLA-C*06:02 in psoriasiform skin. Overall, we detected 20,812 high confidence HLA-C*06:02 bound peptide ligands. Thus, we present a comprehensive coverage HLA-C in vitro immunopeptidomics dataset and the first HLA-C*06:02 ex vivo dataset of psoriasis-relevant peptide antigens that may inform the development of antigen-specific, novel curative therapeutic approaches in psoriasis.

immunology↗