Discussion
In this study, we demonstrated that CD14, TLR4 and TLR-9 are involved in
ocular surface inflammatory flare-ups in patients with VKC.
Specifically, tear sCD14 and conjunctival epithelium CD14 expression
were decreased in patients with VKC suggesting that CD14 plays a
potential protective role on the development of inflammatory reaction.
In fact, it has been clearly demonstrated that CD14 modulates immune
response to microbial products via TLRs, and recent evidence
extended its role in the development of the allergic
reaction.15, 26 Although the role of CD14 in the
pathogenesis of allergic diseases has not yet been completely
understood, it has been hypothesized that CD14 is involved in atopy
susceptibility.26 Several studies demonstrated that
CD14 binding with LPS stimulates cytokine release through TLRs’
signalling, and deviates the adaptive immune reaction toward a Th1
response and consequent Th2 suppression.12, 13, 27, 28As a consequence, alterations in the CD14 pathway may influence Th1/Th2
balance and may induce a switch toward atopy.29 In a
paediatric population, an association between circulating sCD14 levels
and low IL-4 response has been reported.30, 31Moreover, sCD14 has been shown to interact with B cells by inhibiting
IL-6 and IgE production.32 It has been also
demonstrated that during acute asthma attacks in children, plasma sCD14
levels were inversely correlated with asthma severity, suggesting that
the expression of circulating sCD14 could have a protective effect in
the development of asthma attacks.33, 34
Accordingly, VKC is characterized by infiltration of Th2 cells,
eosinophils and mast cells and by the release of Th2 cytokines including
IL-4, IL-5, IL10, TNF-alpha and IL-13.35 In vitro
studies showed that IL-4 and IL-13 inhibit sCD14 release in monocyte,
and macrophage cultures.36, 37 Based on this evidence,
we may hypothesize that the decrease of ocular surface CD14 expression
observed in VKC patients may be an epiphenomenon of the inflammatory
reaction during active VKC. This hypothesis may be supported by the
significant correlation between the severity of conjunctival hyperaemia
and the decrease of tear sCD14. However, after seven days of topical
corticosteroid treatment and resolution of the ocular inflammatory
reaction, we did not find significant changes of expression of tear
sCD14 and conjunctival CD14. This result may support the alternative
hypothesis that the lower expression of ocular surface CD14 is
associated with the higher risk to develop recrudescence of VKC
inflammation. On the other hand, ocular surface CD14 expression may
require longer time to normalize after topical corticosteroid
treatments, as suggested by the observation that VKC patients in the
quiescent phase showed CD14 expression levels similar to healthy
subjects.38
Our results also showed that conjunctival epithelium expression of TLR-4
and TLR-9 decreased during active inflammation of VKC, suggesting that
TLRs may contribute to the inhibition of development of the allergic
reaction. This finding is in line with previous studies, which showed
that TLR-4 and TLR-9 were reduced in epithelial and inflammatory cells
in allergic rhinitis.39, 40 The protective role of
TLR-9 against allergic inflammation is supported by several
studies.40, 41 In addition, it has been reported that
TLR-9 expression was decreased in conjunctival biopsies of VKC patients
in the active phase.9, 10 Conversely, the role of
TLR-4 in VKC should be further clarified. Our results showed that
conjunctival epithelium TLR-4 expression was decreased while it has been
reported that immune cells infiltrating the conjunctiva of VKC patients
showed increased expression of TLR-4.10 These findings
suggest a possible different role played by resident cells (conjunctival
epithelium) and the infiltrating immune cells in the development of
allergic reaction in VKC. The active role of conjunctival epithelium in
the development of allergic reaction has been
demonstrated.24 In fact, it is known that
environmental factors, including microbial agents or hormonal influence
may induce changes of conjunctival epithelium expression of TLRs by
which may predispose to atopic conditions. 42-44 On
the other hand, the hypothesis of a protective role of CD14 and TLR-4 in
the development of ocular allergic reaction is supported by the results
of an experimental study showing that that LPS interaction with TLR-4
was able to decrease Th2 response through TLR-4
signalling.18, 44 In addition, Iovieno et al. showed
that administration of topical Lactobacillus was effective in
reducing inflammatory reaction in VKC patients and that the clinical
improvement was associated with decrease of TLR-4 conjunctival
expression. 45 Accordingly, our results demonstrated
that topical steroid treatment in VKC induced significant inhibition of
TLR-4 conjunctival expression.
This study showed that ocular surface decreased expression of CD14 and
its ligands TLR-4 and 9 may foster the development of allergic reaction
in VKC, suggesting tevaluate the potential therapeutic role of agents
targeting these receptors.