8 research outputs found
Modulation of immune responses by UV irradiation
Atopic dermatitis (AD) is a common, chronic relapsing inflammatory skin disease associated
with cutaneous hyper-reactivity to environmental triggers that are innocuous to normal nonatopic
individuals. AD affects 10% to 15% of children and 2% to 10% of adults in
industrialized countries. There has been increasing interest in this disease triggered by its
increasing prevalence in western societies and its contribution to the increasing health care
costs. Yet, the underlying pathophysiologic and genetic mechanisms leading to the
manifestation of AD are not clear. AD results from a complex interplay between
environmental triggers, susceptibility genes including mutations in the keratinocyte protein
filaggrin and altered immune responses resulting in allergic CD4+ T cell (Th2) immunity to
epidermally encountered antigens. Regulatory T cells (Tregs) play an important role in
controlling responsiveness to self-antigens and preventing autoimmune diseases, as well as in
limiting inflammatory responses during inflammation and infection. Currently, studies
investigating the number and function of Tregs in patients with AD have shown controversial
results.
It has been long established that symptoms of AD improve on exposure to sunlight.
Narrowband UVB (NB-UVB) phototherapy is a common treatment modality for a variety of
skin diseases. Considering the adverse effects for systemic treatment for severe adult AD,
phototherapy, especially NB-UVB phototherapy may be a more practical long-term treatment.
However, approximately 50% of patients over an 8-week treatment course do not improve
after NB-UVB phototherapy. Therefore, it is important to identify characteristics of AD
patients to determine whether they will respond to phototherapy and to avoid adverse effects
for unresponsive patients. UVB exposure has also been associated with induction of Tregs in mice and increasing their
numbers and/or functional capacity may offer benefit to patients with chronic AD. Active
vitamin D (1,25(OH)2D3), one of the factors induced by UV-B radiation induces Tregs and is
suggested to contribute to the suppressive effect of NB-UVB phototherapy. However, UV
radiation could also have beneficial effects through other pathways known to affect
immunoregulation. UVB exposure upregulates production of nitric oxide (NO) in the skin
which also affects immune cell function. The protein filaggrin is broken down in
differentiating keratinocytes to form the natural moisturizer of the skin. The gene encoding
filaggrin (FLG) has been shown to be a major predisposing factor for AD. A key breakdown
product is urocanic acid (UCA) which also acts as a natural sunscreen and undergoes trans-cis
isomerisation on exposure to UV-B. Cis-UCA is known to modulate immune responses,
however, the mechanisms of its action remain elusive. The production of all three compounds,
vitamin D, cis-UCA and NO might all increase in the circulation of patients undergoing UVB
phototherapy. While the immunomodulatory effect of Vitamin D is well described, cis-UCA
and NO may also affect the behaviour of T lymphocytes systemically. Therefore, I
investigated the effect of NO and cis-UCA on the phenotype and function of CD4+T cells and
monocyte-derived dendritic cells (Mo-DCs) derived from peripheral blood mononuclear cells
(PBMCs) from healthy volunteers. I also investigated the correlation between plasma
concentration of 25(OH) vitamin D and nitrate, FLG genotype, circulating Tregs and clinical
efficacy of NB-UVB phototherapy.
My results showed that NO did not affect the phenotype of human mo-DCs and directly
affected peripheral CD4+ T cells by inducing functional CD25+Foxp3+CD127-Tregs from
CD4+CD25lo/- effector T cells. Moreover, NO increased expression of the of skin homing
marker CLA on these Tregs, suggesting an increased ability of NO-induced Tregs to migrate
to the skin. These NO-induced CD25+Foxp3+CD127-Tregs had immunosuppressive
functions and inhibited autologous CD4+ T cell proliferation. Cytokines, at least IL-10,
secreted by NO-treated CD4+ T cells were not sufficient for the suppressive function of NOinduced
Foxp3+Tregs. The immune regulatory function of NO-induced Fopx3+Tregs
required cell-cell contact and was mediated by membrane bound TGFÎČ and PD-1/PD-L1 but
not CTLA-4. Results also showed that cis-UCA might have both pro- and anti-inflammatory effects. Cis-
UCA significantly decreased the proportion of CD25hi Foxp3+ cells from activated CD4+ T
cells. It also decreased the expression of vitamin D receptor in CD4+ T cells which may
interfere with the immune regulatory function of vitamin D. These results suggested that there
might be a fine balance between UV-induced anti-inflammatory moleculesâ effect on CD4+ T
cells. However, Cis-UCA also modulated CD4+ T cell directly by decreasing CD4+ T cell
proliferation, decreasing phosphorylation of ERK after TCR activation, enhancing immune
suppressive cytokines secretion, and inhibiting the percentage of CLA+CD4+T cells
suggesting a decreased ability to migrate to the skin, . Cis-UCA also affected the phenotype
and function of antigen presenting cells by decreasing the expression of HLA-DR, CD86 and
CD40 on immature mo-DCs, which led to increased proportion of CD25+Foxp3+CD127- T
cells when co-cultured with allogenic CD4+ T cells.
Results generated from the clinical study in which all 29 patients got better after phototherapy
suggested although circulating 25 (OH) vitamin D concentration was significantly increased
after NB-UVB phototherapy, the change of circulating 25 (OH) vitamin D concentration did
not correlate with disease improvement. This suggests that vitamin D is not the only pathway
involved and that other molecules contribute to UVB-induced immune-regulation. The data
also show that of the levels of circulating nitrate and the FLG genotype did not correlate with
improvement / change with phototherapy. However, the expression of CD69 and CLA on
circulating CD4+ T cells was decreased after treatment suggesting that UVB affected T cell
activation and migration to the skin, and their importance in determining clinical responses
requires further investigation.
Taken together, the results from my study provide evidence that vitamin D is not the only
molecule responsible for the beneficial effect of NB-UVB phototherapy. NO and cis-UCA
may down-regulate immune responses by affecting human peripheral CD4+ T cells and mo-
DCs phenotype and function. A further understanding of the effect of NO and cis-UCA on
skin resident immune cells will provide more insights for narrowing NB-UVB phototherapy
which will help to select patients that most likely to benefit from a mechanism-based
treatment
Filaggrin-null mutations are associated with increased maturation markers on Langerhans cells
Nitric oxide induces functional human CLA+CD25+Foxp3+ regulatory T cells with skin homing potential
International audienc
Prostaglandin E<sub>2</sub> constrains systemic inflammation through an innate lymphoid cell-IL-22 axis
Systemic inflammation, which results from the massive release of proinflammatory molecules into the circulatory system, is a major risk factor for severe illness, but the precise mechanisms underlying its control are not fully understood. We observed that prostaglandin E2 (PGE2), through its receptor EP4, is down-regulated in human systemic inflammatory disease. Mice with reduced PGE2 synthesis develop systemic inflammation, associated with translocation of gut bacteria, which can be prevented by treatment with EP4 agonists. Mechanistically, we demonstrate that PGE2-EP4 signaling acts directly on type 3 innate lymphoid cells (ILCs), promoting their homeostasis and driving them to produce interleukin-22 (IL-22). Disruption of the ILCâIL-22 axis impairs PGE2-mediated inhibition of systemic inflammation. Hence, the ILCâIL-22 axis is essential in protecting against gut barrier dysfunction, enabling PGE2-EP4 signaling to impede systemic inflammation