T‐cell activation and bacterial infection in skin wounds of recessive dystrophic epidermolysis bullosa patients

Abstract

Recessive dystrophic epidermolysis bullosa (RDEB) patients develop poorly healing skin wounds that are frequently colonized with microbiota. Because T cells play an important role in clearing such pathogens, we aimed to define the status of adaptive T cell-mediated immunity in RDEB wounds. Using a non-invasive approach for sampling of wound-associated constituents, we evaluated microbial contaminants in cellular fraction and exudates obtained from RDED wounds. Infectivity and intracellular trafficking of inactivated Staphylococcus aureus was accessed in RDEB keratinocytes. S. aureus and microbial antigen-specific activation of RDEB wound-derived T cells were investigated by fluorescence-activated cell sorting-based immune-phenotyping and T-cell functional assays. We found that RDEB wounds and epithelial cells are most frequently infected with Staphylococcus sp. and Pseudomonas sp. and that S. aureus essentially infects more RDEB keratinocytes and RDEB-derived squamous cell carcinoma cells than keratinocytes from healthy donors. The RDEB wound-associated T cells contain populations of CD4 + and CD8 + peripheral memory T cells that respond to soluble microbial antigens by proliferating and secreting interferon gamma (IFNγ). Moreover, CD8 + cytotoxic T lymphocytes recognize S. aureus-infected RDEB keratinocytes and respond by producing interleukin-2 (IL-2) and IFNγ and degranulating and cytotoxically killing infected cells. Prolonged exposure of RDEB-derived T cells to microbial antigens in vitro does not trigger PD-1-mediated T-cell exhaustion but induces differentiation of the CD4 high population into CD4 high CD25 + FoxP3 + regulatory T cells. Our data demonstrated that adaptive T cell-mediated immunity could clear infected cells from wound sites, but these effects might be inhibited by PD-1/ Treg-mediated immuno-suppression in RDEB.

Epidermolysis-Bullosa-Associated Squamous Cell Carcinomas Support an Immunosuppressive Tumor Microenvironment: Prospects for Immunotherapy

“…The mechanisms of inflammation in EB are multi-layered, involving tissue repair and bacterial colonization, both contributing to carcinogenesis [33]. Recent in vitro data suggest that adaptive T-cell-mediated immunity might be inhibited by PD-1/Treg-mediated immunosuppression in DEB [34]. Nevertheless, little is known about the immunological microenvironment of EB-SCC.…”

Temporal Changes in the Skin Microbiome of Epidermolysis Bullosa Patients following the Application of Wound Dressings

“…The wounds can easily become infected with pathogens such as Staphylococcus spp. Furthermore, the frequent use of antibiotics in these patients, sometimes in combination, and for longer duration, may select for antibiotic-resistant strains [2]. Moreover, the incidence of resistant skin bacteria, such as methicillin-resistant S. aureus (MRSA) is rising globally and their role in skin infections is becoming more prominent, thus impacting the management of skin disorders.…”