Biomarkers of the epithelial barrier
Environmental factors, microbiome, epithelial cells and immune cells
show a dynamic crosstalk at the skin and mucosal barriers in the
development of AD, AR, CRS, eosinophilic esophagitis and
asthma.162,289-294 Studies on the pathogenesis of
these diseases have clearly demonstrated a barrier defect in the skin
and involved mucosas and a systemic
inflammation.293-296 Defects in the epithelial
barriers, caused by both environmental risk factors and a genetic
predisposition, may represent the starting point of a chronic
inflammation and allergen sensitization.293-296 A
significant number of studies have reported that environmental factors
directly affect the barrier function of
epithelium.150,297,298 In addition, T helper 2 cells,
ILC2s and their cytokine IL-13 damage skin and lung
barriers.293 299 In addition mast
cells and their enzyme chymase damage the epithelial
barrier.300 290 The effects of
environmental factors may, at least in part, be mediated by epigenetic
mechanisms. Histone deacetylase activation by type 2 immune response has
a major effect on leaky barriers and blocking of histone deacetylase
activity corrects the defective barrier in human air-liquid interface
cultures and mouse models of allergic asthma with
rhinitis.95,293,301 The assessment of the barrier
function of the skin and mucosas in vivo has an extremely high
value in the clinics to identify barrier leakiness for an individual
patient and requires the discovery of biomarkers.
To date, there were a few noninvasive methods to assess the skin
epidermal barrier function in vivo . The quantification of
transepidermal water loss (TEWL) in the skin across the stratum corneum
had received some interest for early prediction of atopy prone children
and detection of skin barrier.302 Although TEWL
increases in proportion to the level of damage, it is also affected by
environmental factors such as humidity, temperature, season and moisture
content of the skin.303 The noninvasive and rapid
measurement of natural moisturizing factor by Raman Spectroscopy
provides a method suitable for use in children. The association of
natural moisturizing factor, filaggrin null mutations and AD suggest
Raman Spectroscopy as a promising approach for stratification of
endotypes in AD in the clinics. Other noninvasive methods currently used
include assessment of the stratum corneum hydration, colorimetry, skin
surface pH and sebometry, but they only provide information on different
characteristics and/or the condition of the skin and do not directly
measure the barrier function.304
Recently, electrical impedance spectroscopy (EIS) has been identified as
an effective and stable tool for the detection of epidermal
barrier.163 This method works by transmitting a
harmless electrical signal through the skin at several depths and
frequencies and measuring the electrical resistance and impedance
response of the tissue. EIS reflects particularly the tissue barrier
status by collecting the electric impedance information from
extracellular and intracellular tissue.305 Recently,
our group has studied the impairment of the epidermal barrier in mice by
the epicutaneous administration of barrier damaging proteases, such as
papain, trypsin, Vibrio cholera toxin or by tape stripping. We were able
to show the barrier damaging effects of these substances which
correlates with the electric conductivity of the skin, causing a
decrease of electrical impedance. According to these results, EIS shows
a broad range of possible clinical applications in AD and atopic march,
including early prediction of atopy prone children, early diagnosis of
the disease, stratification and endotyping of patients, evaluation of
the overall therapy response as well as single lesions and assessment of
disease severity.
A critical feature of the gastrointestinal epithelium is intestinal
barrier permeability as it must allow an efficient passage of nutrients
while restricting the entry of larger molecules to avoid food allergy
development. Multiple autoimmune diseases have been identified to arise
or be exacerbated by a leaky gut, such as in inflammatory bowel disease,
celiac disease, type 1 diabetes, systemic lupus erythematosus, multiple
sclerosis.306-309 Recent studies point to a leaky gut
as the initiator of type 1 diabetes because a subclinical intestinal
barrier dysfunction was already detected before clinical onset of type 1
diabetes.310 Zonulin is a prehaptoglobulin protein and
a biomarker for gut barrier leakiness that downregulates TJ function and
it has been proposed to play a role in several autoimmune
diseases.311
Translocation of bacterial endotoxin (lipopolysaccharide, LPS) from the
gut microbiota to blood circulation stimulates systemic inflammatory
responses.312 Measurement of intestinal permeability
is often used in the examination of inflammatory gastrointestinal
disorders. It can be assessed by measurement of urinary recovery of
ingested non-metabolizable lactulose and mannitol. Urine L/M ratio
measured by 1H NMR spectroscopy showed high
correlation with the standard measurement of the urinary recoveries by
enzymatic assays. In conclusion, NMR metabolomics enables simultaneous
intestinal permeability testing and discovery of biomarkers associated
with an impaired intestinal permeability.313 In
conclusion, identification of clinically reliable biomarkers for skin,
respiratory and intestinal barrier measurements represent an important
future research area.