Eosinophilic dermatosis implications of skin-commensal bacteria and antimicrobial peptides and proteins at birth

Sammanfattning: At birth, the newborn infant is transferred from a sterile life in utero to an earthly life in coexistence with microbes. This transition includes the potential danger of a microbial invasion through the epithelial linings, and the infant must find a balance between elimination of harmful pathogens and cooperation with microorganisms that are of benefit. The neonatal skin immune system plays an important role in this regard; however its interactions with the commensal flora are still poorly understood. The common rash erythema toxicum (ET) affects healthy newborn infants and is characterized by local eosinophil accumulation. In Paper I, evidence is provided that the rash reflects the penetration of a rapidly colonizing microflora through the hair follicles. Electron-microscopic (EM) analysis of skin biopsies obtained from ET lesions showed cocci-like bacteria located near or in the hair follicle epithelium, and skin cultures obtained from healthy infants showed that 84% were colonized with coagulase-negative staphylococci already at one day of age. Bacterial penetration might induce an activation of a local innate immune response which most probably also contributes to a postnatal systemic acute-phase response, including a significant increase in body temperature found in infants with ET. As shown in Papers III and IV the local response in ET also includes mast cells and high mobility group box protein 1 (HMGB1). Mast cells are well known for their role in allergic diseases and in the protection against parasitic infections, but the cells are also important parts of host defense against bacteria. HMGB1 is an important cytokine, but also has potential to function as an antimicrobial peptide in skin. In the second study we found that S. epidermidis isolated from newborn infants commonly expressed two kinds of pilus-like structure, as visualised with negativestaining transmission EM. Pili may be involved in functions such as attachment and bacterial virulence, but their role in S. epidermidis is unknown. Cathelicidin antimicrobial peptide LL37, constitutively expressed in the skin barrier of the newborn infant, significantly inhibited growth of S. epidermidis, indicating its importance for the homeostasis of the colonizing flora. In the fifth study we focused on incontinentia pigmenti (IP), a rare neurodermatosis caused by mutations leading to loss of nuclear factor-kappa B activation. In neonatal skin lesions, showing a predominant eosinophil infiltration, we found an upregulation and activation of LL37, psoriasin and HMGB1. These findings, combined with relevant inhibition of local microbial growth, indicate that the inflammatory process naturally occurring in IP contributes to effective local defense and that it may be relevant in the context of commensal homeostasis. In summary, these studies show that the skin innate immune system in the newborn infant is highly activated, and we suggest that local commensal flora may have a part in this reactivity.