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Selenium Status and Over-Expression of Interleukin-15 in Celiac Disease

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Selenium Status and Over-Expression of Interleukin-15 in Celiac Disease ANN IST SUPER SANITÀ 2010 | VOL. 46, NO. 4: 389-399 389 DOI: 10.4415/ANN_10_04_06 ES Selenium status and over-expression I OLOG of interleukin-15 in celiac disease D and autoimmune thyroid diseases ETHO M (a) (b) Anna Velia Stazi and Biagino Trinti D N (a) A Dipartimento di Ambiente e Connessa Prevenzione Primaria, Istituto Superiore di Sanità, Rome, Italy (b)Istituto di Ingegneria Biomedica di Roma, Consiglio Nazionale delle Ricerche, Rome, Italy RCH A ESE R Summary. In celiac disease (CD), for its multifactorial nature, the target organs are not limited to the gut, but include thyroid, liver, skin and reproductive and nervous systems. Between the extraintestinal symptoms associated with CD, autoimmune thyroid diseases (AITDs) are more evident, underlin- ing as CD-related autoimmune alterations can be modulated not only by gluten but also by various concurrent endogenous (genetic affinity, over-expression of cytokines) and exogenous (environment, nutritional deficiency) factors. In their pathogenesis a central role for over-expression of interleukin-15 (IL-15) is shown, by inhibiting apoptosis, leading to the perpetuation of inflammation and tissue de- struction. Thyroid is particularly sensitive to selenium deficiency because selenoproteins are significant in biosynthesis and activity of thyroid hormones; besides, some selenoproteins as glutathione peroxi- dase are involved in inhibiting apoptosis. Thus, selenium malabsorption in CD can be thought as a key factor directly leading to thyroid and intestinal damage. Considering the complexity of this interaction and on the basis of available evidence, the aim of this review is to assess as preventive and therapeutic target the role of IL-15 and selenium in the pathogeneses of both CD and AITD. Key words: celiac disease, autoimmune thyroid diseases, selenium, interleukin-15. Riassunto (Stato del selenio e sovra-espressione dell’interleuchina-15 nella malattia celiaca e nelle malattie autoimmuni tiroidee). Nella malattia celiaca (MC), per la sua natura multifattoriale, gli organi target non sono solo limitati all’intestino, ma includono la tiroide, il fegato, la pelle ed i sistemi riproduttivo e nervoso. Tra i sintomi extraintestinali associati alla MC, le malattie autoim- muni tiroidee (AITD) sono le più evidenti, sottolineando come le alterazioni autoimmuni associate alla MC possano essere modulate non solo dal glutine ma anche dalla coesistenza di vari fattori endogeni (ad esempio l’affinità genetica, la sovra-espressione di citochine) ed esogeni (ad esempio l’ambiente, le carenze nutrizionali). Nella loro patogenesi, viene mostrato un ruolo centrale della so- vra-espressione della interleuchina-15 (IL-15) che, determinando l’inibizione dell’apoptosi, conduce alla perpetuazione dell’infiammazione e del danno tissutale. La tiroide è particolarmente sensibile alla carenza di selenio, poiché le selenoproteine (SeP) sono importanti nella biosintesi e attività degli ormoni tiroidei; inoltre, alcune SeP, come il glutatione perossidasi, sono coinvolte nella inibizione dell’apoptosi. Perciò, il malassorbimento del selenio nella MC può essere considerato un fattore chiave che conduce direttamente al danno tiroideo e intestinale. Considerando la complessità di que- sta interazione e sulla base delle evidenze disponibili, lo scopo di questo lavoro è di valutare, come target preventivo e terapeutico, il ruolo della IL-15 nella patogenesi della MC e AITD. Parole chiave: malattia celiaca, malattie autoimmuni della tiroide, selenio, interleuchina-15. INTRODUCTION Sometimes the association does not reflect a clini- Celiac disease (CD) has increasingly become con- cal status of overt diseases, thus it must be carefully sidered as a multi-organ disorder, and it has been evaluated by further research. Therefore, pathologi- linked to a number of diseases including autoim- cal manifestations can be also modulated by various mune disorders. Besides for both diseases’ multifac- concurrent endogenous (e.g. genetic affinity, over- torial nature, the gene-environment interaction seems expression of cytokines, signaling mechanisms) and a fundamental process for their occurrence. Several exogenous (e.g. environment, nutritional deficiency, studies have shown that CD is associated with an in- gluten presence) factors. creased prevalence of autoimmune thyroid disease In CD and AITD both HLA DQ2 and DQ8 and (AITD) and vice versa [1]. the gene coding for cytotoxic T-lymphocyte-associ- Address for correspondence: Anna Velia Stazi, Dipartimento di Ambiente e Connessa Prevenzione Primaria, Istituto Superiore di Sanità, Viale Regina Elena 299, 00161 Rome, Italy. E-mail: [email protected]. 390 Anna Velia Stazi and Biagino Trinti ated to antigen-4 (CTLA-4) are over-expressed. CD the mucosa, while the submucosa and muscularis ES I induces malabsorption, with consequent micronu- mucosae of the small intestine are not involved. trients deficiency as selenium, important element of Because it leads to malabsorption, CD causes de- OLOG D selenoproteins. These enzymes as glutathione per- ficiencies of micronutrients such as iron, folic acid oxidase act by mechanisms that include effects on and vitamin K, which are essential for organogen- ETHO gene expression, DNA damage and repair, signaling esis, of fat-soluble vitamins that are important for pathways, regulation of cell cycle and apoptosis. spermatogenesis, of vitamin D and calcium, nec- M D Some intestinal glutathione peroxidases by modu- essary for normal maintenance of bone structure, N A lating apoptosis defend the tissue from reactive oxy- and of selenium, an important element for many gen species (ROS) by removing the cells affected by systems such as nervous [4], cardiovascular [5] and RCH A oxidative damage. Association factor in the patho- endocrine [6]. Besides selenium, in endocrine system genesis of active CD and AITD is over-expression of the thyroid, other micronutrients (e.g. vitamins ESE R of interleukin-15 (IL-15) that, by inhibiting apopto- A, B1, B2, magnesium, manganese, potassium, cop- sis, is a survival factor of intraepithelial lymphocytes per, zinc, iron and mainly iodine) are required for (IELs), leading to progressive damage to enterocytes thyroid hormone synthesis and function [7]. and thyrocytes. The association is confirmed by se- These deficiencies may in part explain the patho- lenoproteins that are also involved in inhibiting ap- genesis of complex extraintestinal symptoms associ- optosis; thyroid is particularly sensitive to selenium ated with CD on account of their relationship with deficiency because selenoproteins are significant in both a subclinical malabsorption of these nutrients functions of RNA in biosynthesis and activity of and a common basis of immune and/or endocrine thyroid hormones; thus, selenium malabsorption in imbalances linked to the direct interference of glu- CD can be thought as a key factor directly leading ten with these systems [8]. This important charac- to thyroid and intestinal damage. teristic becomes evident when it is considered that In light of the available evidence, the review aims CD is also associated with other disorders such as: to investigate the mechanisms whereby the lack of osteoporosis [9], type 1 insulin-dependent diabetes selenium due to CD-associated malabsorption may mellitus [10], neuropathy [11], increased risk of in- affect the health of the thyroid, by over-expression of testinal lymphoma [12] and of autoimmune diseases inflammatory IL-15. Since, uncontrolled expression of the liver [13], biliary system [14] and thyroid [15]. of IL-15 is critical in the pathogenesis and mainte- Studies on the incidence and prevalence of autoim- nance of refractory CD and AITD [2], it could be mune diseases have demonstrated the protective effect considered an attractive and sensitive target for de- of GFD in both adult and pediatric celiac individu- velopment of early diagnosis and new therapies. als. Incidence is 5.4 per thousand patients/year who follow the GFD, compared with 11.3 per thousand patients/year who do not follow the GFD (p = 0.002). CELiac DISEASE AND autoiMMUNE Besides, the patients most at risk are those with a fa- THYroid DISEASES miliar history of autoimmune diseases [16]. CD and AITD are autoimmune diseases that, de- The assessment on the prevalence reports as these spite the different origin of their antigens, the gluten disorders increase in parallel with the process of age- in CD as exogenous environmental factor, and self- ing. For subjects diagnosed in the first two years of thyroid antigens in AITD as endogenous factors, life and who therefore eliminate gluten from their diet are caused by abnormal immune response to these at an early age the risk of developing autoimmune antigens; they are the outcome of a complex gene- diseases is 5.1%, while for those diagnosed between 2 environment interaction. In addition, it is important and 10 years and after 10 years the risk rises to 17% to stress that they are among the diseases frequently and 23.6% respectively [17]. These data emphasize observed in association [3]; common autoimmune how celiac patients with early diagnosis and treatment disorders tend to coexist in the same subjects and to can reduce the risk of developing other autoimmune cluster in families. diseases, and show how the mechanisms underlying Celiac disease. CD in genetically predisposed indi- this association, such as environmental factors, im- viduals is a permanent intolerance to gluten, a protein munological mechanisms and genetic predisposition,
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