Bucharest Vitamin D Cutolo.pdf

8/11/2019 Bucharest Vitamin D Cutolo.pdf

http://slidepdf.com/reader/full/bucharest-vitamin-d-cutolopdf 1/30

VITAMIN D AND AUTOIMMUNE RHEUMATIC

DISEASES

Maurizio CUTOLO, MDResearch Laboratory and Accademic Unit of Clinical Rheumatology

Department of Internal Medicine

University of Genova - Italy [email protected]



SUN LIGHT

Skin

Thermal

isomerization

Liver+Kidney

1,25(OH)2D3

Blood

Skin

INTESTINES

Increased absorption

Calcium, Phosphorus

IMMUNE SYSTEM

DOWREGULATIONS

Immature to mature dendritic cells

Maturation of monocytes to macrophages

Release of cytokines from macrophages

B cells antibody production and secretion

IL-2 and IFN-γ secretion by CD4 T cells

Th1 cells proliferation and cytokine production

Inhibiton of IL6 production and consequentTh17 down regulation

PROD3

PRED3

25(OH)D3

70-80%



Exp Dermatol. 2009 Feb;18(2):97-108. Links

Role of the vitamin D3 pathway in healthy and diseased skin--facts, contradictions and

hypotheses.Lehmann B.

This local pathway of vitamin D(3) is unique, but its relevance for healthy and diseased skin is widely

unknown, yet.

We know today that the skin has a unique role in the human body's vitamin D endocrine system. It is the

only site of vitamin D photosynthesis, and has therefore a central role in obtaining a sufficient vitamin D

status.

Irradiation of human keratinocytes with UVB (280-320 nm) in vitro and in vivo activates the metabolism of

7-dehydrocholesterol to hormonally active calcitriol (1alpha,25-dihydroxyvitamin D(3).

The production of calcitriol in the skin strongly depends on the photosynthesis of vitamin D(3) which is

biologically inactive in the first instance.

Vitamin D(3) serves as the starting substrate for two subsequent enzymatic hydroxylation steps in

epidermal keratinocytes. Both the amount of vitamin D(3) and the activity of anabolic and catabolic vitamin

D hydroxylases determine the cutaneous level of calcitriol.

The hormonally active metabolite of vitamin D(3) regulates a huge number of genes in keratinocytes, and

thus acts in an autocrine and/or paracrine manner.



When atmospheric conditions are ideal and skies are clear, 30

minutes of whole-body exposure of pale skin to sunlight without

clothing or sunscreen can result in the synthesis of between

10,000 and 20,000 IU of vitamin D. These quantities of vitamin D

are large, and therefore capable of supplying the body's full

needs.

The availability of UV-B rays, however, depends on the angle atwhich sunshine strikes the earth, making vitamin D synthesis

impossible for most people at most latitudes during parts of the

year called the "vitamin D winter."

At the same time, the body has two mechanisms to prevent an

excess of vitamin D from developing: first, further irradiation

converts excess vitamin D in the skin to a variety of inactive

metabolites; second, the pigment melanin begins to accumulate

in skin tissues after the first exposure of the season, which

decreases the production of vitamin D.

In order to consume vitamin D as food,

we must eat the cholesterol-rich animal

foods we are so often told to avoid.

Sources of Vitamin D: Foods High in

Vitamin D Are High in Cholesterol

If you skip the cholesterol and take

vitamin D supplements, make sure

they are vitamin D3 and not vitamin D2



Nature Clinical Practice Rheumatology 2008;4:404-12

Control of autoimmune diseases by the vitamin D endocrine system.

Adorini A, Penna G

antibacterial

inhibition

IL12-p40



Dtsch Med Wochenschr. 2009 Jan;134(1-2):35-8.

Cathelicidins: multifunctional defense molecules of the skinPeric M, Koglin S, Ruzicka T, Schauber J.

Current studies have unexpectedly identified vitamin D3 as a major factor for the regulation of cathelicidin

expression.

This finding may provide new strategies in the management of infectious and inflammatory diseases of the

skin by targeting control of the expression and function of cathelicidin and other AMPs

The human skin is constantly exposed to microbial pathogens but infections only rarely occur. Innate

cutaneous immunity is a primary system for protection against infection, and antimicrobial peptides (AMPs)

expressed in skin are essential defence molecules.

The AMPs include molecules such as the defensins that were first characterized for their antimicrobial

properties as well as other peptides and proteins first known for their activity as chemokines, enzymes,

enzyme inhibitors and neuropeptides.

Cathelicidins are unique AMPs that act as defensive and signalling molecules. Two different pathways are

involved in this function: cathelicidins have direct antimicrobial activity and they also initiate a host of cellular

responses in cytokine release, inflammation and angiogenesis.

In psoriasis cathelicidin peptide converts self-DNA to a potent stimulus in an autoinflammatory cascade.



BACKGROUND: Antimicrobial peptides (AMPs) such as cathelicidins contribute to initial defense of the airway

against inhaled pathogens.

Recent studies have shown that the hormonally active form of vitamin D(3), 1,25-dihydroxyvitamin D(3)

(1,25(OH)(2)D(3)) up-regulates AMP gene expression in several established cell lines.

METHODS: We investigated the effect of 1,25(OH)(2)D(3) on AMP mRNA levels in primary cultures of normalhuman bronchial epithelial (NHBE) cells by real-time PCR, and protein levels by Western blot. Antimicrobial

activity of airway surface fluid from these cells was measured by in vitro assay against laboratory strains of

bacteria.

RESULTS: Treatment of NHBE cells with 1,25(OH)(2)D(3) (10(-8)M), resulted in a 10-fold up-regulation of

cathelicidin mRNA levels after 12 h, which was augmented 2-fold with co-incubation of 1 mM Calcium.

Moreover, 1,25(OH)(2)D(3) induced antimicrobial activity against the airway pathogens Bordetella

bronchiseptica and Pseudomonas aeruginosa. 1,25(OH)(2)D(3) induced cathelicidin mRNA expression

equally in both normal and CF bronchial epithelial cells.

CONCLUSIONS: Elucidation of the effect of 1,25(OH)(2)D(3) on cathelicidin expression in NHBE cells and CF

bronchial epithelial cells will aid in the development of novel therapeutic agents for treatment of airway

infections in CF

J Cyst Fibros. 2007 Nov 30;6(6):403-10

Induction of cathelicidin in normal and CF bronchial epithelial cells by 1,25-

dihydroxyvitamin D(3).Yim S, Dhawan P, Ragunath C, Christakos S, Diamond G.



J Steroid Biochem Mol Biol. 2005 Oct;97(1-2):93-101

Immunoregulation by 1,25-dihydroxyvitamin D3: basic concepts.van Etten E, Mathieu C.

1,25-Dihydroxyvitamin D(3) (1,25(OH)(2)D(3)), the biologically active metabolite of Vitamin D(3),

not only regulates bone and calcium metabolism but also exerts other biological activities,including immunomodulation via the nuclear Vitamin D receptor expressed in antigen-presenting

cells and activated T cells.

This regulation is mediated through interference with nuclear transcription factors such as NF-

AT and NF-kappaB or by direct interaction with Vitamin D responsive elements in the promoter

regions of cytokine genes.

Vitamin D

receptor

Vitamin D



Bcell

Th0

Th1

Th2

Th3

Treg

Th1

7NKT

CD4+

APC-DC

Monocytes

Marcophages

Expression of Vitamin D

receptors on cells involved

in the immune response

Cutol o M. Rheum atolog y 2009 Mar;48(3):210-2



Th0

Th1

IFN-g

IL-12

IL12-p40

Th2IL-4

IL-10

Th3

Treg

IL-2

IL-10

Th1

7

IL-6

IL-23

IL-2

IL-1

TNF

IL-4

IL-5

IL-10

TGF-b1

IL-10

IL-17

Vitamin D = inhibition

Vitamin D = enhancement

NKT

CD4+

IFN-g

IL-4

IL-13

Bcell Differentiation

Proliferation

Antibodies

APC-DC

Monocytes

Marcophages

Activation

Differentiation

Cutolo M. Rheumato logy 2009 Mar;48(3):210-2



GENETICS

INFECTIONS

CHRONIC

STRESS

ESTROGENS

MAJOR RISK FACTORS IN AUTOIMMUNITY

D-Hormone

deficiency



Dendritic cells (DCs as ) are primary targets for the immunomodulatory activityof 1,25(OH)2D3, as indicated by inhibited DC differentiation and maturation,

leading to down-regulated expression of MHC-II, costimulatory molecules

(CD40, CD80, and CD86) and decreased production of interleukin (IL)-12.

Moreover, 1,25(OH)2D3 enhances IL-10 production and promotes DC

apoptosis. Together, these effects of 1,25(OH)2D3 inhibit DC-dependent T cell

activation.

Rheumatology (Oxford). 2008 (in press)

Vitamin D and autoimmune rheumatic diseases

Cutolo M

Immune responseInflammation

Autoimmunity

Vitamin D

insufficient



Nature Clinical Practice Rheumatology 2008;4:404-12

Control of autoimmune diseases by the vitamin D endocrine system.

Adorini L, Penna G

Epidemiological evidence indicates a significant association between vitamin D

deficiency and an increased incidence of several autoimmune diseases, and

clarification of the physiological role of endogenous VDR agonists in the regulation

of autoimmune responses will guide the development of pharmacological VDR

agonists for use in the clinic.

The antiproliferative, prodifferentiative, antibacterial, immunomodulatory andantiinflammatory properties of synthetic VDR agonists could be exploited to treat a

variety of autoimmune diseases, from rheumatoid arthritis to systemic lupus

erythematosus, and possibly also multiple sclerosis, type 1 diabetes, inflammatory

bowel diseases, and autoimmune prostatitis.



Th0

Th1

Th2

Th3

Treg

Th1

7

Bcell

NKT

CD4+

IL-4

IL-10

IL-2

IL-10

IL-6

IL-23

IL-2

IL-1

TNF

IL-4

IL-5

IL-10

TGF-b1

IL-10

IL-17



IFN-g

IL-4

IL-13

Differentiation

Proliferation

Antibodies

APC-DC

Monocytes

Marcophages

Activation

Differentiation

Cutolo M. Rheumatolog y 2009 Mar;48(3):210-2

IFN-g

IL-12

IL12-p40



Th0

Th2

Th3

Treg

NKT

CD4+

IL-4

IL-10

IL-2

IL-10

Th1

IFN-g

IL-12

IL-2

IL-1

TNF

IL-4

IL-5

IL-10

TGF-b1

IL-10IL-6

IL-23

Th1

7

IL-17

IFN-g

IL-4

IL-13


Proliferation

Antibodies

APC-DC

Monocytes

Marcophages

Activation

Differentiation

Vitamin D insufficiency in

Rheumatoid arthritis

Cuto lo M. Rheum atolog y 2009 Mar;48(3):210-2



Arthritis Rheum. 2004;50:72-7

Vitamin D intake is inversely associated with rheumatoid arthritis: results

from the Iowa Women's Health Study.Merlino LA, Curtis J, Mikuls TR, Cerhan JR, Saag KG; Iowa Women's Health Study.

Greater intake (highest versus lowest tertile) of vitamin D was inversely

associated with risk of RA (RR 0.67, 95% CI 0.44-1.00, P for trend =

0.05).

Inverse associations were apparent for both dietary (RR 0.72, 95% CI

0.46-1.14, P for trend = 0.16) and supplemental (RR 0.66, 95% CI 0.43-

1.00, P for trend = 0.03) vitamin D.

CONCLUSION:

Greater intake of vitamin D may be associated with a lower risk of RA in

older women

We analyzed data from a prospective cohort study of 29,368 women of ages

55-69 years without a history of RA at study baseline in 1986.



Clin Exp Rheumatol. 1999;17(4):453-6.

Andjelkovic Z et al.

An older study in 19 RA patients, evaluated the effects of oral alphacalcidiol 2

micrograms/day added to regular drug regimen.

After 3 months, high dose oral alphacalcidiol therapy showed a positive effect

on disease activity in 89% of the patients (45% or 9 pts. with completeremission and 44% or 8 pts. with a satisfactory effect). Only two patients

(11%) showed no improvement, but no new symptoms occurred.

No side effects were observed. These results suggest that alphacalcidiol is a

powerful immunomodulatory agent with fairly low hypercalcemic activity.

CONCLUSION:

Alphacalcidiol could therefore possibly be used as an adjunct therapy

with DMARDs in patients with active RA .



Th0

Th1

Th2

Th3

Treg

Th1

7

Bcell

NKT

CD4+

IL-4

IL-10

IL-2

IL-10

IL-6

IL-23

IL-2

IL-1

TNF

IL-4

IL-5

IL-10

TGF-b1

IL-10

IL-17



IFN-g

IL-4

IL-13

Differentiation

Proliferation

Antibodies

APC-DC

Monocytes

Marcophages

Activation

Differentiation

Cuto lo M. Rheum atolog y 2009 Mar;48(3):210-2

IFN-g

IL-12

IL12-p40



SYSTEMIC LUPUS ERYTHEMATOSUS



Th0

Th2

Th3

Treg

NKT

CD4+

IL-4

IL-10

IL-2

IL-10

Th1 IL-2

IL-1

TNF

IL-4

IL-5

IL-10

TGF-b1

IL-10IL-6

IL-23

Th1

7

IL-17

IFN-g

IL-4

IL-13


Proliferation

Antibodies

APC-DC

Monocytes

Marcophages

Activation

Differentiation


Systemic lupus erythematosus

Cuto lo M, Otsa K .Lupu s. 2008;17(1):6-10

IFN-g

IL-2

IL12-p40



Data from a population-based cohort of 123 recently diagnosed SLE patients and

240 controls were used.

A trend toward lower 25(OH)D levels in SLE cases compared to controls, which was

statistically significant in Caucasians (p=0.04), controlling for age, sex, season, and

smoking was detected.

Overall, 67% of the subjects were vitamin D deficient, with mean levels significantly

lower among African Americans (15.9 ng/ml) compared to Caucasians (31.3 ng/ml).

Autoimmun Rev. 2006;5:114-7

Vitamin D deficiency in systemic lupus erythematosus.

Kamen DL, Cooper GS, Bouali H, Shaftman SR, Hollis BW, Gilkeson GS.

Critically low vitamin D levels (<10 ng/ml) were found in 22 of the SLE cases, with

presence of renal disease being the strongest predictor (OR 13.3, p<0.01) followedby photosensitivity (OR 12.9, p<0.01).

These results further suggest vitamin D deficiency as a possible risk factor for SLE

and provide guidance for future investigations looking at a potential role of vitamin D

in the prevention and/or treatment of SLE .



Approximately 65% of the SLE patients had values less than 80 nmol, which

is accepted as the lower limit of vitamin D adequacy.

In addition, 20% of the patients had levels of 25-hydroxyvitamin D that were

lower than the normal range for the assay (<47.7 nmol/L).

The group of SLE patients with these lowest levels showed disease

activity measures, including global assessment scores, that were higher

in the than in those with levels considered normal in the assay (P < or =

0.003).

Am J Med Sci. 2008;335:99-104

Vitamin D levels and disease status in Texas patients with systemic lupus

erythematosus.Thudi A, Yin S, Wandstrat AE, Li QZ, Olsen NJ.

CONCLUSION:

The increased disease symptoms present in SLE patients with very low levels

of vitamin D suggests a role for supplementation with exogenous vitamin D to

optimize therapeutic outcomes.



This recent study further showed that vitamin D insufficiency and deficiency

are common in patients with SLE and are associated with sun avoidance.

92 SLE patients (90% women, 98% white) sixty-nine (75%) and 14 (15%)

patients presented with vitamin D insufficiency and deficiency, respectively.

Female sex, treatment with HCQ and treatment with calcium and vitamin D

predicted higher levels of 25(OH)D.

Photosensitivity [odds ratio (OR) 3.5] and photoprotection (OR 5.7) predicted

vitamin D insufficiency and deficiency, respectively.

Patients with vitamin D deficiency had a higher degree of fatigue as quantified

by a 0-10 VAS (mean 5.32 vs 4.03, P = 0.08).

Rheumatology (Oxford). 2008;47:920-3

Vitamin D deficiency in systemic lupus erythematosus: prevalence,

predictors and clinical consequences.

Ruiz-Irastorza G, Egurbide MV, Olivares N, Martinez-Berriotxoa A, Aguirre C.



Treatment of vitamin D deficiency could be particularly important in SLE

patients due to concomitant insults on their tissues such as bone, and in view

of the possible immunomodulatory effects exerted by vitamin D.

Lupus. 2008;17(1):6-10.

Review: vitamin D, immunity and lupus.Cutolo M, Otsa K.

Patients with autoimmune diseases such as multiple sclerosis, rheumatoid

arthritis and systemic lupus erythematosus (SLE) show low 25-OH vitamin D

serum levels.

In particular, SLE patients have multiple risk factors for vitamin D deficiency

and disease severity seems correlated with lower 25-OH vitamin D serum

levels.



In addition, vitamin D may play an important role in the maintenance of B

cell homeostasis and the correction of vitamin D deficiency may be useful

in the treatment of B cell-mediated autoimmune rheumatic disorders such

as SLE.

The vitamin D endocrine system is recognized as an important immune

modulatory factor involved in autoimmune rheumatic diseases as well asin protection fro infections

VDR agonists seem primarily to inhibit DC differentiation, pathogenic

proinflammatory T cells such as Th1 and Th17 cells and, under

appropriate conditions, they seem to favor a deviation to the Th2 pathway.

These immunomodulatory and antiinflammatory activities might be

particularly efficient in RA patients and support a therapeutical role of

1,25(OH)2D3 in such disease.

CONCLUSIONS



Th0

Th1

Th2

Th3

Treg

Th1

7

Bcell

NKT

CD4+

IFN-g

IL-12

IL-4

IL-10

IL-2

IL-10

IL-6

IL-23

IL-2

IL-1

TNF

IL-4

IL-5

IL-10

TGF-b1

IL-10

IL-17



IFN-g

IL-4

IL-13

DifferentiationProliferation

Antibodies

APC-DC

Monocytes

Marcophages

Activation

Differentiation

Cutol o M. Rheum atolog y 2009 Mar;48(3):210-2



Th0

Th2

Th3

Treg

NKT

CD4+

IL-4

IL-10

IL-2

IL-10

Th1

IFN-g

IL-12

IL-2

IL-1

TNF

IL-4

IL-5

IL-10

TGF-b1

IL-10IL-6

IL-23

Th1

7

IL-17

IFN-g

IL-4

IL-13

Bcell DifferentiationProliferation

Antibodies

APC-DC

Monocytes

Marcophages

Activation

Differentiation


Rheumatoid arthritis

Cutol o M Rheum atolog y 2009 Mar;48(3):210 2

Bucharest Vitamin D Cutolo.pdf

Documents

Transcript of Bucharest Vitamin D Cutolo.pdf