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

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

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

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

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)

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

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

Multiple sclerosis: overactive Th1/Th17 cytokine response,

immune attack against myelin base protein

• Inverse latitude gradientthe further from the Equator, the higher the risk

18 degrees south ________________________________________12 per 100,000

43 degrees south _________________________________________76 per 100,000

Prevalence of multiple sclerosis

Hammond et al. 1988

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

How is UVR protective in MS?

• Through the immunoregulatory activity of vitamin D

• Through the immunosuppression that follows UVR

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

???

Squamous cell carcinoma Basal cell carcinoma

Non-melanoma skin cancers:

Cutaneous malignantmelanoma

UVR

Cumulative lifetimesun exposure

Intermittent sun exposureand sunburning in childhood

Intermittent sun exposure andsunburning in childhoodand adulthood

SCC

BCC

CMM

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

20 rodent models of UVR + infection: immunosuppression in almost all cases, increased microbial load and increased severity of symptoms

Cold sores: herpes simplex virus

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

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

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

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