Lennart M. Roesner

IL-33 impacts on the skin barrier by downregulating the expression of filaggrin

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Cytokine Effects Induced by the Human Autoallergen α-NAC

Autoallergy is a phenomenon found in a subgroup of patients with atopic dermatitis (AD). These patients exhibit serum IgE reactivity toward autoantigens like the alpha-chain of the nascent polypeptide-associated complex (α-NAC; Hom s 2). α-NAC has been shown before to induce T-cell proliferation and secretion of IFN-γ. To elucidate the immune modulating functions α-NAC may exert, we analyzed its effects on cytokine transcription and secretion in peripheral blood mononuclear cells (PBMCs), monocytes, and CD4+ T cells. Transcription and secretion of IFN-γ, IL-17, and IL-22 were increased in α-NAC-stimulated PBMCs. As IL-17 was significantly upregulated by α-NAC, we assessed signal transduction in PBMCs and found signal transducer and activator of transcription 3 phosphorylation in α-NAC-stimulated cells. Furthermore, we could show the importance of monocyte activation by α-NAC, as isolated T cells reacted only weakly toward the stimulation. Inhibition of IL-23 p19 led to lower amounts of IL-17 in the PBMC supernatants after α-NAC stimulation. α-NAC stimulation of PBMCs from non-allergic donors resulted in secretion of IL-10, which was greatly reduced in PBMCs from α-NAC-sensitized AD patients. Our findings provide insights into the mechanisms of autoallergy, investigating the interplay of immune cells, signaling events, and cytokines, which are known to be relevant in atopic skin inflammation.

α-NAC–Specific Autoreactive CD8+ T Cells in Atopic Dermatitis Are of an Effector Memory Type and Secrete IL-4 and IFN-γ

Autoreactivity may play a critical role in the chronification of atopic dermatitis (AD). Several studies showed that AD patients produce IgE Abs specific for autoantigens, and we described Th as well as CD8+ T cells specific for the autoallergen Hom s 2, the α-chain of the nascent polypeptide-associated complex (α-NAC). This study aimed to investigate the frequency and inflammatory phenotype of autoallergen-specific CD8+ T cells. CD8+ T cell immunodominant epitopes of α-NAC were mapped by applying prediction softwares, and binding affinity was confirmed by stabilization of empty MHC complexes. MHC class I tetramers were assembled and binding cells were analyzed directly ex vivo by flow cytometry and in terms of single-cell assessment by ChipCytometry. We report significantly elevated numbers of α-NAC–specific peripheral T cells in sensitized patients compared with nonatopic controls. These cells secrete IL-4 and IFN-γ, and surface markers revealed significantly elevated frequencies of circulating terminally differentiated α-NAC–specific CD8+ T cells in patients with AD compared with nonatopic donors. The observed phenotype of α-NAC–specific CD8+ T cells indicates a role in the pathogenesis of AD.

The adaptive immune system in atopic dermatitis and implications on therapy

ABSTRACT In atopic dermatitis (AD), the skin inflammation is believed to occur due to a misdirected immune reaction against harmless antigens on the one hand, and to a disturbed skin barrier on the other. In recent years, vast efforts have been made to investigate the relevance and details of the immune response to allergens. Clinically, it was demonstrated for the first time that aeroallergen exposure leads to worsening of AD symptoms. An overexpression of Th2 cytokines has been observed in acute and subacute lesions of AD. The clinical impact of the key Th2 cytokines IL-4 and IL-13 on atopic dermatitis has recently been shown in clinical studies with dupilumab, a monoclonal antibody which blocks the IL-4/IL-13 receptor. In vitro data indicate, however, that the T cell response is not solely Th2-polarized but may lead to heterogeneous cytokine production involving IFN-γ and IL-17 in an allergen-dependent manner. Classical thymus-derived Foxp3 T cells have interestingly been detected in elevated numbers in the circulation of AD patients. Therapeutic approaches with allergen specific immunotherapy aim to induce regulatory T cells of the Tr1 type. The strikingly altered microbiome of AD skin with diminished diversity of bacteria on lesional skin but increases of S. aureus colonization and the sensitization against microbial allergens and homologue self-proteins deserve special attention. For the treatment of itch symptoms, which still represent a challenge in daily practice, promising data have been published on the relevance of the H(histamine)4-receptor and on mediators such as IL-31, TSLP.