EFFECTS OF CHRONIC UV RADIATION ON IMMUNE …EFFECTS OF CHRONIC UV RADIATION ON IMMUNE RESPONSES •...
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EFFECTS OF CHRONIC UV RADIATION ON IMMUNE
RESPONSES• Mary Norval• University of
Edinburgh• Scotland
THE CHALLENGES OF UV-INDUCED IMMUNOMODULATION
FOR CHILDREN’S HEALTH
Emeritus Professor Mary Norval
University of Edinburgh
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UVB
~ 30 weeks UV-inducedprimar y tumour immunosuppress ed tolerance
mouse
normal syngenei c mouse re jection
UVB-irradiat ed mouse tolerance (~10 wee ks)
Kripke and Fisher 1976, 1977
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Chromophores DNA photoproducts cis-urocanic acid membrane lipid peroxidation
Immune mediators: platelet activating factor, neuropeptidescytokines, histamine, prostaglandins, complement
Cell migration to/from epidermis/dermis:Langerhans cell from
Dermal dendritic cells fromMast cells to and from
Monocytes/macrophages to
Loss of IL-12, IL-23 and Th1 cytokinesGeneration of T and B regulatory cells
EPIDERMIS
LOCAL LYMPH NODE
UV RADIATION
LOCAL SUPPRESSION OF IMMUNITY
Change in antigen presentation
SYSTEMIC SUPPRESSIONOF IMMUNITY
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7-dehydrocholesterol
previtamin D
vitamin D
25-hydroxyvitamin D
1,25-dihydroxyvitamin D
solar UV-B radiation
skin
blood
active form
Binds to vitamin D receptor and activates >500 genes
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Effects of 1,25(OH)2D on immune responses
Suppresses Th1 and Th17 responses ? Effects on Th2 responses Enhances innate responses
Skin + UVR: repairs damaged DNAsuppresses immune responses(dendritic cells)
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UV-INDUCED IMMUNOSUPPRESSION
• GOODStops chronic inflammatory
response to neoantigens:polymorphic light eruption
Prevents induction of autoimmune reactions:
multiple sclerosis
Prevents asthma?
• BADLack of control of skin tumours
Lack of control of infectious diseases/vaccination
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Polymorphic light eruption (PLE)5-20% population Europe/America:25% younger than 15 years20% younger than 10 years
UVR
Cutaneous neoantigens
Lack of immunosuppression
Hypersensitivity response
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Multiple sclerosis: overactive Th1/Th17 cytokine response,
immune attack against myelin base protein
• Inverse latitude gradientthe further from the Equator, the higher the risk
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18 degrees south ________________________________________12 per 100,000
43 degrees south _________________________________________76 per 100,000
Prevalence of multiple sclerosis
Hammond et al. 1988
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Multiple sclerosis: association with UVR
• Inverse latitude gradient• Higher solar UV exposure before age 15 reduces risk of
MS• Migration after age 15 gives MS risk of original residence• More sun exposure during childhood decreases risk of MS
in monozygotic twins• Highest risk of MS if born in spring/summer, lowest risk if
born in autumn/winter• Higher UVR in first trimester, most protective against MS• Incidence lowest in subjects with highest 25(OH)D3
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How is UVR protective in MS?
• Through the immunoregulatory activity of vitamin D
• Through the immunosuppression that follows UVR
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Asthma: Th1/Th2/TregsUV-inducedimmunosuppression:No association with past solar
UVRNo latitude gradientNegative correlation with
monthly hours of sunshine(hospital admissions)
Mouse models: Th1 and Th2
Vitamin D:Prenatal vit D in diet wheezingVit D level in pregnancy asthmaVit D supplements childhood asthmaCord-blood 25(OH)D wheezing,
not asthma
???
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Squamous cell carcinoma Basal cell carcinoma
Non-melanoma skin cancers:
Cutaneous malignantmelanoma
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UVR
Cumulative lifetimesun exposure
Intermittent sun exposureand sunburning in childhood
Intermittent sun exposure andsunburning in childhoodand adulthood
SCC
BCC
CMM
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UV-induced immunosuppression and skin tumours:Human evidence• Immunosuppressed subjects: SCCx65-250, BCCx10-16, MMx7
on UV-exposed body sites
• Local suppression of immunity - UV susceptibleHealthy subjects 35%NMSC subjects 92%MM subjects 100% Yoshikawa et al. 1990
• People with fair skin/inability to tan more susceptible to local suppression of immunity than people with darker skin/tan for a given dose of solar UVR
Kelly et al. 2000
• High dermal mast cell prevalence associated with BCC and MMGrimbaldeston et al. 2003, 2004
• UVR at early age results in generation of specific T regulatory cellsMuller et al. 2008
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20 rodent models of UVR + infection: immunosuppression in almost all cases, increased microbial load and increased severity of symptoms
Cold sores: herpes simplex virus
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Microbial infections affected by UVR
?+Leishmania donovani: post-kala-azar
?+Mycobacterium leprae: leprosy
?+Polyomavirus: Merkel cell carcinoma
++Human papillomavirus: squamous cell carcinoma
?+Varicella zoster virus: shingles
++Herpes simplex virus: cold sores
Local immune effects
Lesions on sun-exposed body sites
Organism and disease
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A role for vitamin D in protection against infectious diseases?
• Low 25(OH)D - increased upper respiratory tract infections
• Vitamin D supplements - reduced influenza A infections
• Vitamin D supplements - no effect on symptoms, mortality, immunity in tuberculosis
• 1,25(OH)2D in mice - no effect on most infections
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UVR and vaccination - hints• Polio/influenza/hepatitis B/rubella:
lower Ab in tropics vs temperatelower Ab in summer vs winter
• Hepatitis B:lower Ab and T cell responses in
some irradiated subgroups• BCG: vaccine more protective against
infection with increasing distancefrom the Equator
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UV-induced immunosuppression and/or vitamin D
Positive:
Allergic responses
Autoimmunediseases
Asthma
Negative:
Skin cancers
Infectiousdiseases
Vaccination
Avoid sunburn, take sensible precautions when sun is intense
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