M. Küpper

The main function of sebocytes is considered to be the production of lipids to moisturize the skin. However, it recently became apparent that sebocytes release chemokines and cytokines and respond to proinflammatory stimuli as well as the presence of bacteria. To analyse the functional communication between human sebocytes and T cells. Immunofluorescence stainings for CD4 and interleukin (IL)‐17 were performed on acne sections and healthy skin. Migration assays and T‐cell‐stimulation cultures were performed with supernatants derived from unstimulated or prestimulated SZ95 sebocytes. Dendritic cells were generated in the presence of SZ95 supernatant and subsequently used in mixed leucocyte reactions. We showed that CD4+ IL‐17+ T cells accumulate around the pilosebaceous unit and are in close contact with sebocytes in acne lesions. By using SZ95 sebocyte supernatant, we demonstrate a chemotactic effect of sebocytes on neutrophils, monocytes and T cells in a CXCL8‐dependent manner. Furthermore, sebocyte supernatant induces the differentiation of CD4+ CD45RA+ naive T cells into T helper (Th)17 cells via the secretion of IL‐6, transforming growth factor‐β and, most importantly, IL‐1β. No direct effects of sebocytes on the function of CD4+ CD45RO+ memory T cells were detected. Moreover, sebocytes functionally interact with Propionibacterium acnes in the maturation of dendritic cells, leading to antigen‐presenting cells that preferentially prime Th17 cells. Our study provides evidence that human sebocytes actively participate in inflammatory processes in the skin by recruiting and communicating with immune cells. This interaction leads to the generation of Th17 cells, which might contribute to the pathogenesis not only of acne vulgaris, but also of several inflammatory skin diseases.

Imbalances of T-cell subsets are hallmarks of disease-specific inflammation in psoriasis. However, the relevance of B cells for psoriasis remains poorly investigated.To analyse the role of B cells and immunoglobulins for the disease-specific immunology of psoriasis.We characterized B-cell subsets and immunoglobulin levels in untreated psoriasis patients (n = 37) and compared them to healthy controls (n = 20) as well as to psoriasis patients under disease-controlling systemic treatment (n = 28). B-cell subsets were analysed following the flow cytometric gating strategy based on the surface markers CD24, CD38 and CD138. Moreover, immunofluorescence stainings were used to detect IgA in psoriatic skin.We found significantly increased levels of IgA in the serum of treatment-naïve psoriasis patients correlating with disease score. However, IgA was only observed in dermal vessels of skin sections. Concerning B-cell subsets, we only found a moderately positive correlation of CD138+ plasma cells with IgA levels and disease score in treatment-naïve psoriasis patients. Confirming our hypothesis that psoriasis can develop in the absence of functional humoral immunity, we investigated a patient who suffered concomitantly from both psoriasis and a hereditary common variable immune defect (CVID) characterized by a lack of B cells and immunoglobulins. We detected variants in three of the 13 described genes of CVID and a so far undescribed variant in the ligand of the TNFRSF13B receptor leading to disturbed B-cell maturation and antibody production. However, this patient showed typical psoriasis regarding clinical presentation, histology or T-cell infiltrate. Finally, in a group of psoriasis patients under systemic treatment, neither did IgA levels drop nor did plasma cells correlate with IgA levels and disease score.B-cell alterations might rather be an epiphenomenal finding in psoriasis with a clear dominance of T cells over shifts in B-cell subsets.

Imbalances of T cell subsets have been demonstrated as hallmarks of disease-specific inflammation in psoriasis. However, the role of B cells as important counterparts of T cell function remains poorly investigated. Here, we analysed a broad set of B cell subsets and immunoglobulins in psoriasis patients and correlated their distribution in peripheral blood with disease severity. Surface staining and flow cytometry was performed on leucocytes from whole blood of 100 psoriasis patients and 20 individuals without history of skin disease. The severity of psoriasis was determined by Psoriasis Area and Severity Index (PASI) and patients were classified as PASI low (< 5) or PASI high (> 10). Five developmentally different B cell subsets defined by their CD24 and CD38 expression were characterized as well as the distribution of CD138 and CD27. The humoral immunologic profile was complemented by serum parameters including immunoglobulins. We found a significant increase of plasma cells (CD19+, CD38highCD24-) accompanied by increased IgA serum levels in patients with higher severity scores (PASI high) as compared to patients of the PASI low group and healthy volunteers. Moreover, frequencies of regulatory B cells, defined as CD19+CD24highCD38high, were upregulated in psoriasis patients and showed positive correlation with PASI. These data suggest a contribution of B cell subsets to the severity of psoriasis with increased frequencies of regulatory B cells representing a possible compensatory mechanism to increased frequencies of plasma cells and IgA serum levels observed in psoriasis patients.

In this thesis the role of B cells and humoral components in the immune pathogenesis of psoriasis was investigated. It could be shown that in psoriasis patients absolute values of immunoglobulin (Ig) A, complement factors C3 and C4 were increased as well as disease severity was positively correlated with expression of IgA, IgA positive plasma cells and Cluster of differentiation (CD) 138. Whether these are epiphenomena or whether these differences have a modifying effect on the pathogenesis of psoriasis goes beyond the scope of this thesis.

Authorship correction on Is the humoral immunity dispensable for the pathogenesis of psoriasis? Thomas J, Küpper M, Batra R, Jargosch M, Atenhan A, Baghin V, Krause L, Lauffer F, Biedermann T, Theis FJ, Eyerich K, Eyerich S, Garzorz-Stark N. J Eur Acad Dermatol Venereol. 2019 Jan; 33(1): 115–122. https://doi.org/10.1111/jdv.15101. Epub 2018 Jul 2. This corrigendum is to note that the name of Prof. Carsten Schmidt-Weber was inadvertently omitted as an author in the initial version of the paper. Schmidt-Weber CB has been added for his participation and contributions in this project.