IgG from Adult Atopic Dermatitis (AD) Patients Induces Thymic IL-22 Production and CLA Expression on CD4+ T Cells: Possible Epigenetic Implications Mediated by miRNA

Abstract

Atopic dermatitis (AD) is a common relapsing inflammatory skin disorder characterized by immune-mediated inflammation and epidermal barrier dysfunction. The pathogenesis of AD is multifactorial and has not been fully elucidated to date. This study aimed to evaluate whether serum IgG from adult AD patients could modulate the thymic maturation of IL-22-producing T cells and CLA+ T cells of non-atopic infants. Given that miRNAs regulate immune response genes, we evaluated whether miRNA expression is also altered in cultured thymocytes. Thymocytes were cultured with purified IgG from AD patients or control conditions (mock, Intravenous-IgG (IVIg), non-atopic IgG, or atopic non-AD IgG). Using flow cytometry analysis, we assessed the expression of CLA and intracellular levels of IL-4, IFN-γ, and IL-22 on double-positive T cells (DP T), CD4 T cells, or CD8 T cells. We also investigated the frequency of IgG isotypes and their direct interaction with the thymic T cells membrane. The miRNA profiles were evaluated by the Illumina small RNA-seq approach. MiRNA target gene prediction and enrichment analyses were performed using bioinformatics. Increased frequencies of IL-22 and CLA+ producing CD4+ T cells cultured with IgG of AD patients was seen in non-atopic infant thymocytes compared to all control conditions. No alterations were observed in the frequency of IgG isotypes among evaluated IgG pools. Evidence for a direct interaction between IgG and thymic DP T, CD4 T, and CD8 T cells is presented. The small RNA-seq analysis identified ten mature miRNAs that were modulated by AD IgG compared to mock condition (miR-181b-5p, hsa-miR-130b-3p, hsa-miR-26a-5p, hsa-miR-4497, has-miR-146a, hsa-let-7i-5p, hsa-miR-342-3p, has-miR-148a-3p, has-miR-92a and has-miR-4492). The prediction of the targetome of the seven dysregulated miRNAs between AD and mock control revealed 122 putative targets, and functional and pathway enrichment analyses were performed. Our results enhance our understanding of the mechanism by which IgG can collaborate in thymic T cells in the setting of infant AD.

Immune modulation and possible pathological implications mediated by naturally produced immunoglobulin G idiotypes: from historical to recent experimental and clinical studies focused on atopic dermatitis

“…More recently, it was demonstrated that purified IgG from AD individuals could induce overexpression of cutaneous lymphocyte-associated antigen (CLA) on thymic CD4+ T cells since its immature DP stage in vitro , an effect that was not observed on CD8+ T cells, where an opposite effect was revealed [ 28 ]. This observation was relevant because CLA-expressing CD4+ T cells can be considered a peripheral biomarker of AD [ 29 ].…”

Mechanism underlying polyvalent IgG-induced regulatory T cell activation and its clinical application: Anti-idiotypic regulatory T cell theory for immune tolerance

“…In this theory, direct binding of idiotype of polyvalent IgG to the TCRs or unidentified antigens on the surface of CD4 + cells can induce differentiation of Treg cells from naive T cells or activate pre-existing Treg cells to secrete IL-10 ( Figure 1C ). The direct interaction between polyvalent IgG and antigens on the cell membrane of CD4 + thymic T cells induced cytokine production from CD4 + thymic T cells ( 53 ). However, this study did not evaluate the activation of Treg cells by direct binding of polyvalent IgG to antigens on the cell membrane of T cells.…”

The Interaction between the Host Genome, Epigenome, and the Gut–Skin Axis Microbiome in Atopic Dermatitis

“…According to some authors, the natural history of AD suggests that males predominate in childhood and females after puberty [ 6 ]. Studies in Europe have suggested an increase in the incidence and prevalence of AD in the 21st century compared to the 20th century [ 7 , 8 ], possibly due to various factors such as genetic and epigenetic factors, impaired skin barrier integrity, autoimmunity, viral infections, gut microbiome composition, dietary habits, and lifestyle factors [ 7 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 ]. Recent research has shown functional links between genetic variants in the IL-17 promoter, the gut microbiome, and AD [ 17 ].…”