Autoimmunity Reviews 11 (2011) 84–87

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Autoimmunity Reviews

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Review

Vitamin D endocrine system involvement in autoimmune rheumatic diseases

Maurizio Cutolo ⁎, Carmen Pizzorni, Alberto SulliResearch Laboratories and Academic Unit of Clinical Rheumatology, Department of Internal Medicine, University of Genova, Italy

⁎ Corresponding author at: Research Laboratories aRheumatology, Department of Internal Medicine, UniverXV,6 16136 GNOVA, Italy. Tel.: +39 010 353 7994; fax:

E-mail address: mcutolo@unige.it (M. Cutolo).

1568-9972/$ – see front matter © 2011 Elsevier B.V. Adoi:10.1016/j.autrev.2011.08.003

a b s t r a c t

a r t i c l e i n f o

Article history:Received 1 August 2011Accepted 5 August 2011Available online 16 August 2011

Keywords:Vitamin DD hormoneInnate and adaptive immunityRheumatoid arthritisSystemic lupus erythematosus

Vitamin D is synthesized from cholesterol in the skin (80–90%) under the sunlight and then metabolized intoan active D hormone in liver, kidney and peripheral immune/inflammatory cells. These endocrine-immuneeffects include also the coordinated activities of the vitamin D-activating enzyme, 1alpha-hydroxylase(CYP27B1), and the vitamin D receptor (VDR) on cells of the immune system in mediating intracrine andparacrine actions. Vitamin D is implicated in prevention and protection from chronic infections (i.e.tubercolosis), cancer (i.e. breast cancer) and autoimmune rheumatic diseases since regulates both innate andadaptive immunity potentiating the innate response (monocytes/macrophages with antimicrobial activityand antigen presentation), but suppressing the adaptive immunity (T and B lymphocyte functions). Vitamin Dhas modulatory effects on B lymphocytes and Ig production and recent reports have demonstrated that 1,25(OH)2D3 does indeed exert direct effects on B cell homeostasis. A circannual rhythm of trough vitamin Dlevels in winter and peaks in summer time showed negative correlation with clinical status at least inrheumatoid arthritis and systemic lupus erythematosus.Recently, the onset of symptoms of early arthritis during winter or spring have been associated with greaterradiographic evidence of disease progression at 12 months possibly are also related to seasonal lower vitaminD serum levels.

nd Academic Unit of Clinicalsity of Genova, Viale Benedetto+39 010 353 8885.

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© 2011 Elsevier B.V. All rights reserved.

Contents

1. Vitamin D is a steroid hormone . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 842. Vitamin D, innate immunity and seasonality of rheumatoid arthritis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 853. Vitamin D, adaptive immunity and rheumatoid arthritis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 854. Vitamin D, B cells and systemic lupus erythematosus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 865. Possible inhibition of cell growth via aromatase inhibition by 1,25(OH)2D3 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 866. Take-home messages . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 86References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 86

1. Vitamin D is a steroid hormone

Both genetic and environmental factors affect prevalence ofautoimmune disturbances and are involved in the altered neuroendo-crine immune response that characterize several autoimmune rheu-matic diseases [1]. Therefore, the fact that vitamin D (1,25(OH)2D3 ) as

a true steroid hormone (common structure with glucocorticoids, sinceboth synthesized from cholesterol) has been implicated in thepathogenesis of different autoimmune diseases, suggests that vitaminD endocrine system might be one of the environmental/hormonalfactors that normally participate in the control of self-tolerance [2].These endocrine-immune effects include also the coordinated activitiesof the vitamin D-activating enzyme, 1alpha-hydroxylase (CYP27B1),and the vitamin D receptor (VDR) on cells of the immune system inmediating intracrine and paracrine actions of 1,25(OH)2D3 [3].

Indeed, major immune system-mediated rheumatic diseases such asrheumatoid arthritis (RA) and systemic lupus erythematosus (SLE),systemic sclerosis or overlap syndromes like undifferentiated connective

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tissue disease (UCTD) and others are characterized by low-serum levelsof vitamin D that often correlated to the severity of the disease [4–10].

2. Vitamin D, innate immunity and seasonality of rheumatoidarthritis

Vitamin D, via its active hormonal metabolite 1,25(OH)2D3,regulates both innate and adaptive immunity potentiating the innateresponse (monocytes/macrophages with antimicrobial activity andantigen presentation), but suppressing the adaptive immunity (T andB lymphocyte functions) (Fig. 1)[11].

Potentiation of the innate immune response at surfaces exposed tothe environment provides a first line of defense against pathogens,and so would be expected to enhance resistance to acute infections inthe skin, lungs, gastrointestinal tract, bladder, and other epithelialsurfaces [12]. However, the suppressive effects of 1,25(OH)2D3 havebeen mainly linked to the modulation of functional activities ofantigen presenting cells (APC) [13].

The synthesis of precursors of vitamin D is 80–90% sunlight-dependent and obtained at the level of the skin with furtherhydroxylation and activation in liver and kidney, however, activevitamin D is also produced starting from the serum precursors at anincreased rate inside monocytes/macrophages/keratinocytes (intra-crine hydroxylation) in the presence of bacterial and viral infections[14]. Very recent findings support an important role for macrophageautophagy during HIV-1 infection induced by the hormonally active1,25(OH)2D3 and provide new insights into novel approaches toprevent and treat viral (HIV-1) infections and related opportunisticinfections [15].

Inside macrophages the intracrine produced vitamin D (due to thepresence of the 1alpha-hydroxylase (CYP27B1), stimulates thesynthesis of antimicrobial peptides such as cathelicidins, whichcontribute to bacterial killing and initial defense against pathogens(such as Mycobacterium tuberculosis) (Fig. 1)[16].

These mechanisms underlie the beneficial effects exerted bygraded sun exposure, which was used to treat chronic tuberculosisin sanatoriums from the middle of the nineteenth century.

Fig. 1. Effects of normal serum concentrations of vitamin D (1,25(OH)2D3) on innate and adaD – white=upregulation by vitamin D.

Therefore, if chronic infections represent one of the risk factors fordeveloping of several autoimmune rheumatic diseases, the seasonal-ity of the onset and severity of RA might be due to the seasonality ofinfections [17]. Interestingly, in a recent study significantly lower(P=0.01) serum levels of 1,25(OH)2D3 were observed in patientswith RA from the north versus the south of Europe [18].

At the same time, a circannual rhythm of trough levels in winterand peaks in summer time showed, notably, significant (Pb0.0001)negative correlation between 1,25(OH)2D3 and clinical RA status, asassessed using the 28-joint disease activity score (DAS28) [18].

In addition, a very recent study added further evidence to theseasonality of RA and role of the connection with sun/vitamin Dproduction [19,20]. Clinicians in this large multicenter investigation,enrolled adult patients with symptoms of early arthritis, and theinvestigators used multivariate analysis to identify predictors ofradiographic progression among the study population. Besides theusual initial biomarkers that have been associated with the progres-sion of early RA (i.e. biomarkers), the study found that the season ofsymptom onset (winter or spring) acts as an independent predictivefactor of the progression of joint structural damage at 6 months [19].

Furthermore, the onset of symptoms of arthritis during winter orspring was also associated with greater radiographic evidence ofdisease progression at 12 months. Adding weight to these findings,univariate analysis produced the same results at two adjoiningseasons (winter and spring, summer and autumn), and at both 6and 12 months [19].

Interestingly, vitamin D intake has been found to be inverselyassociated with the risk of RA among patients and in anothermulticenter large study, RA disease activity and disability scoreswere found inversely related to 25(OH)D serum level deficiency[21,22].

3. Vitamin D, adaptive immunity and rheumatoid arthritis

By considering in a more detailed manner the effects on theadaptive immune response, vitamin D mainly downregulates Th1-dependent responses such as in RA (Fig. 1)[23].

ptive immunity (for details read the test). Arrows: yellow=down regulation by vitamin

86 M. Cutolo et al. / Autoimmunity Reviews 11 (2011) 84–87

Although T cell polarization can indirectly be affected by 1,25(OH)2D3 induced altered APC cytokine expression, it is becoming clear thatT cells including Th17 cells are direct 1,25(OH)2D3 targets (Fig. 1)[24,25]. In human T cells, vitamin D suppresses IL-17A and IFN-γproduction and stimulates IL-4 and IL-10 production [26]. Moreover,1,25(OH)2D3 directly reduced the production of the Th17 cytokines IL-17A, IL-17 F and IL-22 by memory T cells of patients with early RA [27].

The pro-inflammatory cytokine TNF-α is a commonly used targetfor RA treatment, however, 1,25(OH)2D3 had no effect on TNF-αproduction by stimulated PBMCs and only limited inhibitory effectson TNF-α production by memory T cells [27].

Recently, a significant (Pb0.05), downregulation of Toll-likereceptor 4 mediated production of IL 1β, IL 6, TN F, IFN γ and IL 10by peripheral blood mononuclear cells was observed in summer,compared with winter in healthy individuals, once again clearlyrelated to the seasonality of vitamin D status [28].

4. Vitamin D, B cells and systemic lupus erythematosus

Vitamin D has modulatory effects also on B lymphocytes and Igproduction (Fig. 1). Recent reports have demonstrated that 1,25(OH)2D3 does indeed exert direct effects on B cell homeostasis [29]. Inaddition, to confirming direct VDR-mediated effects on B cellproliferation and Ig production, a recent study also highlighted theability of 1,25(OH)2D3 to inhibit the differentiation of plasma cellsand class switched memory cells, suggesting a potential role forvitamin D in B cell-related disorders such as SLE. Notably, expressionof CYP27b1 (1alpha-hydroxylase) was also detected in B-cells,indicating that also B-cells may be capable of autocrine/intracrinesynthesis/ response to vitamin D [30,31].

As matter of fact, 1,25(OH)2D3, modulates NF-kB mediatedactivation of human naïve B cells. Naïve B cells were predominantlytargeted by 1,25(OH)2D3 in comparison with memory B cells asshown by pronounced induction of the VDR target gene cyp24a1 [31].

Vitamin D receptor activation resulted in a strongly reduced p105/p50 protein and mRNA expression in human naïve B cells. This effectis mediated by impaired nuclear translocation of p65 and conse-quently reduced binding of p65 to its binding site in the p105promoter [31].

From the clinical point of view, serum concentrations of 25-OHD inpatients with SLE have been found inversely related to disease activity[32–34].

The observation that ANA-positive healthy controls are signifi-cantly more likely to be deficient in vitamin D than ANA-negativehealthy controls, together with the finding that 1,25(OH)2D3deficiency is associated with certain immune abnormalities in SLE,further suggests that vitamin D plays an important role in autoanti-body production and SLE pathogenesis. Interestingly, SLE patientswith vitamin D deficiency also had higher mean (SD) serum IFNαactivity than patients without 1,25(OH)2D3 deficiency [35]. Of course,vitamin D deficiency is probably not sufficient to cause B cellhyperactivation and autoantibody production, but rather is acontributing factor along with other genetic and environmentalrisks as already mentioned.

5. Possible inhibition of cell growth via aromatase inhibition by1,25(OH)2D3

Aromatase, is the enzyme that catalyzes estrogen synthesis fromandrogenic precursors and its expression in the breast is critical forthe progression of ER-positive breast cancer (BCa) in postmenopausalwomen [36].

Interestingly, 1,25(OH)2D3 regulates the expression of aromatasein a tissue-selective manner and a recent study revealed that 1,25(OH)2D3 significantly decreases aromatase expression by a directtranscriptional repression of promoter II/I.3 in human BCa cells and a

cell culture model of preadipocytes [37]. Furthermore, by reducingestrogen synthesis and downregulating estrogen-receptor (ERα)levels, 1,25(OH)2D3 attenuates the mitogenic stimulus of estrogenon BCa cells, causing significant inhibition of BCa cell proliferation.

Therefore, aromatase inhibitors which inhibit the enzymaticactivity of aromatase, have become the major therapeutic agents totreat ER-positive BCa and inhibit BCa progression or recurrence inpostmenopausal women after primary surgical and/or radiationtherapy [38].

Since aromatase activity is increased together with the estrogen/androgen ratio in the synovial tissue/fluids of both male and femaleRA patients, the effects of 1,25(OH)2D3 on aromatase expression havebeen evaluated in cultures of human macrophages, in order toevaluate the relationship between 1,25(OH)2D3 and inflammatorycytokine production/cell growth, by considering that macrophagesare fully involved in RA synovitis and generally in immune/inflammatory response [39,40]. Interestingly, 1,25(OH)2D3 decreasedsignificantly the aromatase expression at the level of human RAmacrophages and a significant downregulation of proinflammatorycytokine production was also observed at the same time.

These observations further support the immune-endocrine in-volvement of 1,25(OH)2D3 in the pathophysiology of RA (and otherautoimmune rheumatic diseases, i.e. SLE) and further support atherapeutical role of 1,25(OH)2D3 also as selective aromatasemodulator in clinical practice [41–43].

6. Take-home messages

• Vitamin D is a true steroid hormone having a common structurewith glucocorticoids, since both are synthesized from cholesterol,and being metabolized into active D hormone in liver, kidney andperipheral cells.

• Vitamin D, via its active hormonal metabolite 1,25(OH)2D3,regulates both innate and adaptive immunity potentiating theinnate response (monocytes/macrophages with antimicrobial ac-tivity and antigen presentation), but suppressing the adaptiveimmunity (T and B lymphocyte functions).

• Major immune system-mediated rheumatic diseases such asrheumatoid arthritis (RA), systemic lupus erythematosus (SLE)and overlap syndromes like undifferentiated connective tissuedisease (UCTD) are characterized by low-serum levels of vitaminD that often correlated to the severity of the disease.

• A circannual rhythm of trough vitamin D levels in winter and peaksin summer time showed negative correlation with clinical status inrheumatoid arthritis and systemic lupus erythematosus.

• The onset of symptoms of arthritis during winter or spring havebeen associated with greater radiographic evidence of diseaseprogression at 12 months possibly also related to seasonal lowervitamin D serum levels.

• Vitamin D is implicated in prevention and protection from chronicinfections (i.e. tubercolosis), and cancer (i.e. breast cancer).

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ve transfer of immunoglobulin G serum from patients

the beneficial effect of intravenous immunoglobulin suggests an

investigate whether the transfer of IgG antibodies from patientsisease. Serum IgG from 12 patients and 12 controls was injectedc open field, stimulus evoked pain and motor coordination, andsignificant depression of rearing behaviour (number of times the

was evident in three CRPS-IgG injected mice.hypothesis of an immune- mediated pathogenesis of CRPS.