Immunological mechanisms underlying progression of chronic wounds in recessive dystrophic epidermolysis bullosa

Abstract

Hereditary epidermolysis bullosa (EB) is a mechanobullous skin fragility disorder characterized by defective epithelial adhesion, leading to mechanical stress-induced skin blistering. Based on the level of tissue separation within the dermal-epidermal junction, EB is categorized into simplex (EBS), junctional (JEB), dystrophic (DEB) and Kindler syndrome. There is no cure for EB, and painful chronic cutaneous wounds are one of the major complications in recessive (RDEB) patients. Although RDEB is considered a cutaneous disease, recent data support the underlying systemic immunological defects. Furthermore, chronic wounds are often colonized with pathogenic microbiota, leading to excessive inflammation and altered wound healing. Consequently, patients with RDEB suffer from a painful sensation of chronic, cutaneous itching/burning and an endless battle with bacterial infections. To improve their quality of life and life expectancy, it is important to prevent cutaneous infections, dampen chronic inflammation and stimulate wound healing. A clear scientific understanding of the immunological events underlying the maintenance of chronic poorly healing wounds in RDEB patients is necessary to improve disease management and better understand other wound healing disorders. In this review, we summarize current knowledge of the role of professional phagocytes, such as neutrophils, macrophages and dendritic cells, the role of T-cell-mediated immunity in lymphoid organs, and the association of microbiota with poor wound healing in RDEB. We conclude that RDEB patients have an underlying immunity defect that seems to affect antibacterial immunity.

Keywords: cutaneous disease; epidermolysis bullosa; immunity; inflammation; microbiota; wound healing.

FIGURE 1

Schematic view of T‐cell activation in a draining lymph node after cutaneous infection. Migrating DC take up microbial antigens at the wound site and route via a lymphatic vessel to a local draining lymph node. A draining lymph node consists of micro‐domains containing paracortical T‐cell areas and follicular B‐cell areas. Lymph fluid (less than 70 kDa) enters the conduit system, which forms a tube system within T‐cell and B‐cell areas. The conduit system consists of organized collagen fibres with FRC wrapped around it. Resident DC within T‐cell areas are able to pick up antigens that flow through the conduit system. Resident mature DC present antigen to local naïve T cells, resulting in T‐cell priming and activation

FIGURE 2

Central T‐cell education in the thymus. The thymic microenvironment directs T‐cell differentiation. T cells that enter the outer cortex undergo positive selection (cTEC, cortical thymic epithelial cells). Next, T cells migrate to the inner medullary area where they undergo negative selection (mTEC, medullary thymic epithelial cells). T cells that survive all educational steps become naïve T cells and migrate to peripheral organs, such as the draining lymph nodes, mucosal barrier sites and exocrine glands

FIGURE 3

Expression of common EB‐causing gene variants in thymus and draining lymph node (cTEC, cortical thymic epithelial cell and mTEC, medullary thymic epithelial cells). (A) Thymus. (B) Draining lymph node