Pigmentation is an important process in skin physiology and skin diseases and presumably also plays a role in Parkinson’s disease (PD). In PD, alpha-Synuclein (aSyn) has been shown to be involved in the pigmentation of neurons. The presynaptic protein is intensively investigated for its pathological role in PD, but its physiological function remains unknown. We hypothesized that aSyn is both involved in melanocytic differentiation and melanosome trafficking processes. We detected a strong expression of aSyn in human epidermal melanocytes (NHEMs) and observed its regulation in melanocytic differentiation via the microphthalmia-associated transcription factor (MITF), a central regulator of differentiation. Moreover, we investigated its role in pigmentation by performing siRNA experiments but found no effect on the total melanin content. We discovered a localization of aSyn to melanosomes, and further analysis of aSyn knockdown revealed an important role in melanocytic morphology and a reduction in melanosome release. Additionally, we found a reduction of transferred melanosomes in co-culture experiments of melanocytes and keratinocytes but no complete inhibition of melanosome transmission. In summary, this study highlights a novel physiological role of aSyn in melanocytic morphology and its so far unknown function in the pigment secretion in melanocytes.

Background/Objectives: Cutaneous side effects are the most common immune-related adverse events (irAEs) caused by immune checkpoint inhibitors (ICIs) and affect 70–90% of patients. Besides diverse types of exanthema, rare skin toxicity includes bullous dermatoses in 0.3% of cases. Systemic steroids are the first-line treatment for immune-related bullous pemphigoid (irBP); however, some cases are corticosteroid-resistant. IrBP is one of the irAEs most frequently chronic and associated with long-term steroid use. However, steroids may interfere with tumor response. Therefore, alternative treatment strategies for irBP are desperately needed. Dupilumab, a monoclonal antibody blocking the receptor binding of interleukin-4 (IL-4) and interleukin-13 (IL-13), has been successfully used to treat spontaneous forms of bullous pemphigoid (BP). In this study, we analyzed the gene expression profiles of BP and irBP. Patients and Methods: A retrospective multicenter study evaluated the gene expression profiles of irBP and BP in comparison to healthy controls. Gene expression analyses of skin biopsies were performed using NanoString technology from patients with BP (n = 17), irBP (n = 19), and healthy skin (n = 24) after the patients had consented to participate in this study, and differentially expressed genes (DEGs) were determined using Rosalind software. Results: Compared to healthy skin, BP showed 167 DEGs, and irBP revealed 99 DEGs. Some of the DEGs from irBP and BP vs. healthy skin overlapped. Specifically, IL-4- and IL-13-associated genes were upregulated in both irBP and BP compared to healthy skin. Interestingly, expression profiles of BP vs. irBP also showed 13 DEGs. Conclusions: These findings suggest a possibility for therapeutic efficacy of IL-4 and IL-13 inhibitors in the treatment of irBP.

Although initially assumed to be similar, immune checkpoint inhibitor (ICI)–induced autoimmunity can differ from spontaneous autoimmune disease in regard to clinical presentation, pathogenesis, and therapy. Despite limited pathogenetic understanding, ICI-induced colitis (irColitis), a common adverse event during ICI therapy, is treated analogously to its autoimmune counterpart, ulcerative colitis (UC). Thus, there is a tremendous need to characterize immunophenotypes in both forms of colonic inflammation to ultimately identify specific therapeutic strategies. In a multicenter study, local and systemic immunophenotypes of patients with irColitis were compared with those of patients with UC. Colonic mucosa, patient serum, and peripheral blood mononuclear cells (PBMC) of 20 patients with irColitis, 15 patients with UC, and 25 patients receiving ICI without toxicity were investigated. Immunophenotyping was performed using gene expression analyses of mucosal samples and PBMC, serum proteomics, and flow cytometry–based PBMC analysis. Mucosal gene expression analysis revealed higher expression of B cell– and TNF signaling–related genes in UC, whereas irColitis mucosa showed an upregulation of genes associated with effector T-cell responses and IFN signaling. Immunophenotyping of PBMC demonstrated increased activation and differentiation of T cells and higher expression of exhaustion markers in irColitis compared with UC. In contrast, dendritic cells and B cells demonstrated increased markers of activation in patients with UC. Taken together, irColitis is characterized by T cell–associated immunity, whereas B cell– and dendritic cell–mediated immune responses and TNF signaling are more important for UC immunopathogenesis. These observations could help identify more specific and efficient treatment strategies for irColitis.

Supplementary Figure 7: DC subset distribution in irColitis and ulcerative colitis patients