Role of B-cell antigenicity in the psoriatic autoimmune response against melanocytes

He, Mengwen (2024): Role of B-cell antigenicity in the psoriatic autoimmune response against melanocytes. Dissertation, LMU München: Medizinische Fakultät

Abstract

Psoriasis is an inflammatory skin disease caused by a T-cell-mediated autoimmune response, clinically characterized by distinct reddish plaques covered with a thick layer of silvery scales resulting from excessive proliferation of keratinocytes. Psoriasis arises from a complex genetic predisposition, with the human leukocyte antigen (HLA) class I-allele HLA-C*06:02 representing the actual psoriasis risk gene. HLA-class I molecules on the cell surface present endogenous peptides originating from cytoplasmic proteins to CD8+ T cells, thereby guiding the T-cell reaction against specific target cells that express the parental protein containing the antigenic epitope. Using a pathogenic Vα3S1/Vβ13S1 T-cell receptor (TCR) from a lesional psoriatic CD8+ T-cell clone, our research group demonstrated that HLA-C*06:02, as the underlying pathomechanism of the HLA association, facilitates an autoimmune reaction against melanocytes in psoriasis by presenting an autoantigenic peptide from ADAMTS-like protein 5 (ADAMTSL5). Psoriasis is not a congenital condition but rather develops at some point during the life course. The T-cell receptor (TCR) repertoire is largely fixed at birth, and both the autoantigen and potentially autoreactive T cells are present prior to the onset of the disease but remain immunologically quiescent. Consequently, environmental factors, lifestyle, and infections are thought to induce psoriasis by priming potentially autoreactive T cells. The precise mechanisms of the gene-environment interaction in the development of psoriasis, however, are still not clear. Streptococcal angina is the most common trigger for psoriasis onset and relapses. Identical T-cell clones in tonsils and skin lesions identified in patients with streptococcal-driven psoriasis, improvement of psoriasis by therapeutic blockade of T cell emigration from secondary lymphoid organs by an S1P1-receptor agonist ponesimod, and resolution of psoriasis following tonsillectomy collectively indicate that induction and maintenance of the pathogenic T-cell response in lesion rely on continuous recruitment of pathogenic T cells from secondary lymphoid organs into the skin. The primary objective of my thesis was to identify how streptococcal angina induces the autoimmune psoriatic T-cell response. For this, I used a reporter mouse T-hybridoma cell line, in which the psoriatic Vα3S1/Vβ13S1 TCR was reconstituted to identify potential target cells and antigens in the tonsils. I first co-cultured the Vα3S1/Vβ13S1-TCR hybridoma with primary human cells obtained from the tonsils and blood of HLA-C*06:02+psoriasis patients and with cell lines of various origins. This way, I showed that besides melanocytes, B cells specifically activate both the Vα3S1/Vβ13S1 TCR and CD8+ T cells of psoriasis patients. The difficulty of the identification of T-cell antigens lies in the complexity of TCR antigen recognition. TCRs are polyspecific and can recognize up to a million different antigenic peptides associated with the cognate HLA molecule if the peptides correspond to the peptide recognition motif of that TCR. I further precisely characterized the peptide recognition pattern ligating the Vα3S1/Vβ13S1 TCR. With this motif, I searched the transcriptome and the HLA-C*06:02 immunopeptidome of B cells for possible B cell antigens of the Vα3S1/Vβ13S1 TCR. Employing various experimental approaches, I finally identified several self-peptides in the HLA-C*06:02 immunopeptidome of B cells that stimulate the Vα3S1/Vβ13S1 TCR and are distinct from the melanocyte autoantigen. My results suggest that the strong inflammatory reaction during streptococcal angina triggers activation of self-reactive CD8+ T cells against B cells in the tonsils, which then cross-react against melanocytes in the skin and cause psoriasis. The B-cell-directed immune activation of CD8+ T cells in secondary lymphoid organs may thus activate and expand the effector T cells that mediate the pathogenic autoimmune response against melanocytes in the skin of psoriasis patients. These data clarify an essential step in the induction and perpetuation of the psoriatic autoimmune response and they identify a formerly unknown pathomechanism by which streptococcal infections may initiate autoimmunity.

• Dokumententyp: Dissertationen (Dissertation, LMU München)
• Keywords: Psoriasis, Autoimmunity, B cells, CD8+ T cells, Streptococcal angina, Autoantigen
• Themengebiete: 600 Technik, Medizin, angewandte Wissenschaften ; 600 Technik, Medizin, angewandte Wissenschaften > 610 Medizin und Gesundheit
• Fakultäten: Medizinische Fakultät
• Sprache der Hochschulschrift: Englisch
• Datum der mündlichen Prüfung: 18. September 2024
• 1. Bericht­erstatter:in: Prinz, Jörg Christoph