Pathomechanisms Inducing and Perpetuating an Autoimmune Response in Psoriasis vulgaris

• Applicant: Professor Dr. Jörg Christoph Prinz
• Subject Area: Dermatology ; Rheumatology
• Term: from 2016 to 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 317045689

• Final Report Year: 2022

Final Report Abstract

Psoriasis is due to an immune response caused by CD8+ T cells in lesional epidermis. HLA- C*06:02 mediates the actual psoriasis-specific risk in epistasis with variants of the endoplasmic reticulum aminopeptidase 1 (ERAP1) gene. Both interact in antigen presentation. Using a pathogenic Vα3S1/Vβ13S1 T-cell receptor (TZR) from a lesional psoriatic CD8+ T-cell clone, we had uncovered that HLA-C*06:02 mediates an autoimmune response against melanocytes by presenting an autoantigenic peptide from ADAMTS-like protein 5. These results were the basis of the grant proposal. In the funded project, we now reveal that the immunogenicity of melanocytes in psoriasis and the generation of the autoantigenic ADAMTSL5 epitope from precursor peptides is ERAP1- dependent. ERAP1-knock out in melanoma cell lines completely abolished the ability to stimulate the Vα3S1/Vβ13S1 TCR. Risk haplotypes of ERAP1 enhanced melanocyte immunogenicity through increased production of the HLA-C*06:02-presented ADAMTSL5 epitope. Interestingly, HLA-C*06:02 protects from malignant melanoma. As a side aspect of the psoriatic autoimmune response against melanocytes we followed TCR diversity during checkpoint inhibition for the treatment of advanced malignant melanoma. Here we find that the extent of clonal T cell expansion prior to checkpoint inhibition is a prognostic marker for response to therapy. Psoriasis is triggered by environmental factors throughout life. Fine characterization of the peptide recognition motif of the ADAMTSL5-specific Vα3S1/Vβ13S1 T-cell receptor allowed us to identify various environmental antigens from microbiota, pathogens, tobacco, yeast and wheat as environmental triggers of psoriasis that stimulate the Vα3S1/Vβ13S1-TCR and CD8+ T cells of psoriasis patients. Through developing peptide-loaded HLA-C*06:02 tetramers, we could demonstrate that ADAMTSL5-specific CD8+ T cells are increased in the blood of psoriasis patients and may also react against wheat peptides. A wheat-free diet improved psoriasis in several patients. This opens up the possibility to establish a diseasespecific biomarker and indicates how psoriasis patients may ameliorate the disease by lifestyle changes. Generalized pustular psoriasis (GPP) is the most severe manifestation in the psoriasis spectrum. During the research period, we demonstrate that unopposed IL-36 activity mediates dominant activation of CD4+ T cells as the main source of IL-17 in GPP. This distinguishes GPP from chronic plaque psoriasis. Psoriasis has a similar genetic architecture to ankylosing spondylitis and Behçet's disease, where HLA-B*27 and HLA-B*51 mediate disease risk in epistasis with ERAP1 variants. In both psoriasis and Behçet's disease, we find a strong lesional infiltration of CD8+ T cells producing IL-17, indicating similar pathogenic pathways. We further searched the evolutionary origin of these HLA-class I risk alleles. We find that HLA-C*06:02, HLA-B*27 and HLA-B*51 as well as several pathogenic ERAP1 haplotypes introgressed from Denisovan and Neanderthal genomes. Our findings suggest that the protective property of the three HLA- alleles against viral infections is associated with an increased risk of autoimmune reactions. The HLA-C*06:02-restricted autoimmune response against melanocytes which can be triggered by environmental antigens is thus a central pathogenetic momentum in the development of psoriasis which may have its origin in archaic hominins.

Publications

• 2016. 'Therapeutic Efficacy of Interleukin 12/Interleukin 23 Blockade in Generalized Pustular Psoriasis Regardless of IL36RN Mutation Status', JAMA Dermatol, 152: 825-8
  Arakawa, A., T. Ruzicka, and J. C. Prinz
  
• 2017. 'Autoimmune aspects of psoriasis: Heritability and autoantigens', Autoimmun Rev, 16: 970-79
  Prinz, J. C.
  
• 2017. 'Melanocytes: Target Cells of an HLA-C*06:02-Restricted Autoimmune Response in Psoriasis', J Invest Dermatol, 137: 2053-58
  Prinz, J. C.
  
• 2018. 'Human Leukocyte Antigen-Class I Alleles and the Autoreactive T Cell Response in Psoriasis Pathogenesis', Front Immunol, 9: 954
  Prinz, J. C.
  
• 2018. 'Unopposed IL-36 Activity Promotes Clonal CD4(+) T-Cell Responses with IL-17A Production in Generalized Pustular Psoriasis', J Invest Dermatol, 138: 1338-47
  Arakawa, A., S. Vollmer, P. Besgen, A. Galinski, B. Summer, Y. Kawakami, A. Wollenberg, K. Dornmair, M. Spannagl, T. Ruzicka, P. Thomas, and J. C. Prinz
  
• 2019. 'Clonality of CD4(+) Blood T Cells Predicts Longer Survival With CTLA4 or PD-1 Checkpoint Inhibition in Advanced Melanoma', Front Immunol, 10: 1336
  Arakawa, A., S. Vollmer, J. Tietze, A. Galinski, M. V. Heppt, M. Burdek, C. Berking, and J. C. Prinz
  
• 2020. 'Myeloperoxidase Modulates Inflammation in Generalized Pustular Psoriasis and Additional Rare Pustular Skin Diseases', Am J Hum Genet, 107: 527-38
  Haskamp, S., H. Bruns, M. Hahn, M. Hoffmann, A. Gregor, S. Lohr, J. Hahn, C. Schauer, M. Ringer, C. Flamann, B. Frey, A. Lesner, C. T. Thiel, A. B. Ekici, S. von Horsten, G. Assmann, C. Riepe, M. Euler, K. Schakel, S. Philipp, J. C. Prinz, R. Mossner, F. Kersting, M. Sticherling, A. Sefiani, J. Lyahyai, W. Sondermann, V. Oji, P. Schulz, D. Wilsmann-Theis, H. Sticht, G. Schett, A. Reis, S. Uebe, S. Frey, and U. Huffmeier
  
• 2020. 'Rare Loss-of-Function Mutation in SERPINA3 in Generalized Pustular Psoriasis', J Invest Dermatol, 140: 1451-55 e13
  Frey, S., H. Sticht, D. Wilsmann-Theis, A. Gerschutz, K. Wolf, S. Lohr, S. Haskamp, B. Frey, M. Hahn, A. B. Ekici, S. Uebe, C. Thiel, A. Reis, H. Burkhardt, F. Behrens, M. Kohm, J. Rech, G. Schett, G. Assmann, K. Kingo, S. Koks, R. Mossner, J. C. Prinz, V. Oji, P. Schulz, L. E. Munoz, A. E. Kremer, J. Wenzel, and U. Huffmeier
  
• 2020. 'The Woronoff Ring in Psoriasis and the Mechanisms of Postinflammatory Hypopigmentation', Acta Derm Venereol, 100: adv00031
  Prinz, J. C.
  
• 2021. 'ERAP1 Controls the Autoimmune Response against Melanocytes in Psoriasis by Generating the Melanocyte Autoantigen and Regulating Its Amount for HLA-C*06:02 Presentation', J Immunol, 207: 2235-44
  Arakawa, A., E. Reeves, S. Vollmer, Y. Arakawa, M. He, A. Galinski, J. Stohr, K. Dornmair, E. James, and J. C. Prinz
  
• 2021. 'Genetic Analysis of MPO Variants in Four Psoriasis Subtypes in Patients from Germany', J Invest Dermatol, 141: 2079-83
  Haskamp, S., J. S. Horowitz, V. Oji, S. Philipp, M. Sticherling, K. Schakel, S. Schuhmann, J. C. Prinz, H. Burkhardt, F. Behrens, B. Bohm, M. Kohm, J. Rech, D. Simon, G. Schett, K. Morrison, S. Gerdes, G. Assmann, A. Nimeh, V. Schuster, A. Jacobi, A. Weyergraf, A. Reis, S. Uebe, D. Wilsmann-Theis, R. Mossner, and U. Huffmeier
  
• 2021., Br J Dermatol., 185:1209-1220
  Vural, S., K. Kerl, P. Ertop Dogan, S. Vollmer, U. Puchta, M. He, Y. Arakawa, A. O. Heper, A. Karal-Oktem, D. Hartmann, A. Boyvat, J. C. Prinz, and A. Arakawa
  
• 2022. 'Antigen Processing, Presentation, and Tolerance: Role in Autoimmune Skin Diseases', J Invest Dermatol, 142: 750-59
  Prinz, J. C.