Autoantibody mediated deficiency of IL-36-receptor antagonist in a subset of patients with psoriasis and psoriatic arthritis

• Published in: Immunology letters Vol. 270; p. 106926
• Main Authors: Hoffmann, Marie-Christin, Fadle, Natalie, Regitz, Evi, Kos, Igor Age, Cetin, Onur, Lesan, Vadim, Preuss, Klaus-Dieter, Zaks, Marina, Stöger, Elisabeth, Zimmer, Vincent, Klemm, Philipp, Assmann, Gunter, Pfeifer, Jochen, Bittenbring, Joerg Thomas, Bewarder, Moritz, Vogt, Thomas, Pföhler, Claudia, Thurner, Bernhard, Kessel, Christoph, Thurner, Lorenz
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.12.2024
• Subjects: Autoantibodies targeting the IL-36 receptor antagonist (IL-36Ra) occur in subgroups of patients with PsA and Pso; IL-36Ra-autoantibodies deplete IL-36Ra serum/plasma level, result in immunecomplex formation, and promote unrestricted IL-36 signal; Autoantibodies targeting the IL-36 receptor antagonist (IL-36Ra) occur in subgroups of patients with PsA and Pso; IL-36Ra-autoantibodies deplete IL-36Ra serum/plasma level, result in immunecomplex formation, and promote unrestricted IL-36 signal
• ISSN: 0165-2478; 1879-0542; 1879-0542
• DOI: 10.1016/j.imlet.2024.106926

•Autoantibodies targeting the IL-36 receptor antagonist (IL-36Ra) occured in subgroups of patients with PsA and Pso.•IL-36Ra-autoantibodies depleted IL-36Ra serum/plasma level, resulted in immune-complex formation, and promoted unrestricted IL-36 signaling.•Autoimmunity-mediated depletion of IL-36Ra (autoimmune-DITRA) is a new pathomechanism relevant in subgroups of both Pso and PsA. Psoriatic arthritis (PsA) is known as a seronegative form of spondylarthropathy. The interleukin-36 cytokine family may have a major role in disease pathogenesis and particularly the related cutaneous manifestations. In light of our recent observations on (transient) autoantibody phenotypes neutralizing endogenous anti-inflammatory receptor antagonists (progranulin, IL-1Ra) in different inflammatory conditions, we set out to investigate the potential role of such antibodies targeting IL-36 cytokine family members in PsA and psoriasis without arthritic manifestations (Pso). In the present study we screened for hypothetic autoantibodies against the anti-inflammatory mediators IL-36 receptor antagonist (IL-36Ra) and anti-inflammatory IL-38 in PsA, Pso and inflammatory and healthy controls. Serum samples of patients with PsA (n = 254), Pso (n = 100), systemic lupus erythematosus (SLE, n = 50), rheumatoid arthritis (RA, n = 100), ulcerative colitis (UC, n = 50), Crohn´s disease (CD, n = 50), and healthy controls (n = 237) were screened for autoantibodies against IL-36Ra and IL-38 as well as IL-36Ra levels by ELISA. Biochemical analysis for immune complexes and atypic protein isoforms as well as IL-36 signaling reporter assays were performed. Anti-IL-36Ra antibodies were detected in five out of 100 (5.0 %) patients with Pso, in 12 of 254 (4.72 %) patients with PsA and in one of 50 (2 %) patients with CD, but in none of the other investigated inflammatory or healthy controls. The IL-36Ra autoantibodies belonged to the IgG1 subclass and their titers ranged between 1:200 to 1:1600. They resulted in immune-complex formation, depletion of serum IL-36Ra levels and were functional in terms of facilitating unrestricted IL-36 signaling. IL-36Ra autoantibodies were found in subgroups of patients with Pso and PsA and may drive respective pathology.