铁蛋白在自身免疫病中的意义Ferritin in autoimmune diseases

Ferritin in autoimmune diseases

Gisele Zandman-Goddard a ,Yehuda Shoenfeld b,?,1

a

Department of Medicine C,Wolfson Medical Center,Israel

b

Department of Medicine B and The Center for Autoimmune Diseases,Sheba Medical Center;Sackler Faculty of Medicine,

Tel-Aviv University,Israel

Received 15January 2007;accepted 31January 2007

Available online 16February 2007

Abstract

Iron,an essential element for many important cellular functions in all living organisms,can catalyze the formation of potentially toxic free radicals.Excessive iron is sequestered by ferritin in a nontoxic and readily available form in a cell.Ferritin is composed of 24subunits of different proportions of two functionally distinct subunits:ferritin H and L.The expression of ferritin is under delicate control and is regulated at both the transcriptional and post-transcriptional levels by iron,cytokines,hormones,and oxidative stress.Mutations in the ferritin gene cause the hereditary hyperferritinemia-cataract syndrome and neuroferritinopathy.Hyperferritinemia is associated with inflammation,infections,and malignancies.While elevated levels of ferritin are characteristic of adult-onset Still's disease and hemophagocytic syndrome,both associated with inflammation,it has scantly been evaluated in other autoimmune diseases.In this review,we describe ferritin structure and function,hyperferritinemia in disease states and in autoimmune diseases.?2007Elsevier B.V .All rights reserved.

Keywords:Ferritin;Rheumatoid arthritis;Systemic lupus erythematosus;Multiple sclerosis;Thyroiditis;Polymyositis;Dermatomyositis

Contents 1.Introduction ..

....................................................4582.Ferritin structure....................................................4583.Ferritin regulation and function ............................................4584.Ferritin and inflammation/infection ..........................................4595.Ferritin and the immune system............................................4596.Altered ferritin levels and disease...........................................4597.Ferritin and malignancies ...............................................4598.

Hyperferritinemia in autoimmune diseases ......................................4608.1.Rheumatoid arthritis (RA).....

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https://www.360docs.net/doc/c913935093.html,/locate/autrev

?Corresponding author.Department of Medicine B and The Center for Autoimmune Diseases,Sheba Medical Center,Tel-Hashomer 52621,Israel.Tel.:+97235302652;fax:+97235352855.

E-mail address:Shoenfel@post.tau.ac.il (Y .Shoenfeld).1

Incumbent of the Laura Schwartz-Kipp Chair for Autoimmune Diseases,Tel-Aviv University,Israel.1568-9972/$-see front matter ?2007Elsevier B.V .All rights reserved.doi:10.1016/j.autrev.2007.01.016

8.2.Systemic lupus erythematosus(SLE) (460)

8.3.Multiple sclerosis(MS) (461)

8.4.Thyroiditis (461)

8.5.Polymyositis/dermatomyositis(PM/DM) (461)

9.Conclusions (461)

Take-home messages (462)

References (462)

1.Introduction

Ferritin is nature's unique and conserved approach to controlled,safe use of iron and oxygen,with protein synthesis in animals adjusted by dual,genetic DNA and mRNA sequences that selectively respond to iron or oxidant signals and link ferritin to proteins of iron, oxygen and antioxidant metabolism[1–3].

It is well established that elevated ferritin levels are found in adult Still's disease,but hyperferritinemia has been scantly investigated in other autoimmune diseases. The rationale for evaluating this protein in autoimmune diseases derives from it being an acute phase reactant (APR),and hence increased during inflammation.APRs have been found to be elevated and conducive of activity of disease,such as C-reactive protein(CRP)in rheumatoid arthritis.In SLE,other than an elevated erythrocyte sedimentation rate(ESR),APRs such as serum amyloid component P(SAP),C-reactive protein (CRP),and mannose binding lectin(MBL)are not raised,indicating a possible mechanism of antibody production that blocks their function.To investigate this hypothesis,we have previously described elevated titers of anti-SAP antibodies in44%of328SLE patients that correlated with disease activity[4].In this review we discuss ferritin and its function,altered states of ferritin leading to disease,and hyperferritinemia reported in various autoimmune diseases.

2.Ferritin structure

Ferritin is the major intracellular iron storage protein in all organisms.Ferritins share a unique protein cage structure that resembling spherical viruses that are preserved throughout species and permit storage of up to4500Fe(III)atoms.Polypeptide subunits of ferritin spontaneously fold into4helix bundles and assemble into hollow spheres with inner cavities,depending on whether there are12(mini-ferritins)or24(maxi-ferritins)subunits.When there are mini-ferritins,such as in bacteria,the catalytic site is created between2 subunits in contrast to maxi-ferritins which are pro-cessed within each subunit.Each apoferritin(iron-free ferritin)shell is assembled from24polypeptide chains of2species,the heavy subunit(H-subunit)and the light subunit(L-subunit).A single functional H gene and L gene have been identified on chromosome11q23and 19q13.3,respectively.H-ferritin plays the major role in rapid detoxification of iron and intracellular iron transport and is found in organs of low iron content including the heart and pancreas.The L-subunit is involved in iron nucleation,mineralization,and long-term storage and predominates in iron storage organs such as the liver and spleen[1,5].

3.Ferritin regulation and function

Controlling iron/oxygen chemistry in biology depends on multiple genes,regulatory messenger RNA(mRNA) structures,signaling pathways and protein catalysts. Ferritin,a protein nanocage around an iron/oxy mineral, centralizes the https://www.360docs.net/doc/c913935093.html,plementary DNA(antioxidant responsive element–/Maf recognition element—ARE/ MARE)and mRNA(iron responsive element—IRE) responses regulate ferritin synthesis rates.Maxi-ferritins concentrate iron for the bio-synthesis of iron/heme proteins,trapping oxygen;bacterial mini-ferritins,DNA protection during starvation proteins,reverse the substrate roles,destroying oxidants,trapping iron and protecting DNA[1].

The ability of cells to induce rapid ferritin synthesis prevents the effects of free radical damages to cellular components.Ferritin synthesis is regulated by intracellu-lar iron at both the transcriptional and translational levels. The translational control of ferritin synthesis is via a unique stem-loop structure,termed IRE,found in the5′untranslated region of ferritin mRNA.The IRE structure is recognized by iron-regulatory proteins(IRP1and2). Targeted deletions of IRPs in mice suggest that IRP2is the primary post-transcriptional regulator of mammalian iron metabolism in response to the iron status.This concordant regulation of transferrin receptors and ferritin is designed so a cell can obtain iron when it is needed,and sequester iron when it is in excess[1,3,5].

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In addition to iron,ferritin synthesis is regulated by cytokines at various levels(transcriptional,post-tran-scriptional,and translational)during development, cellular differentiation,proliferation,and inflammation. The cellular response by cytokines to infection stimu-lates the expression of ferritin genes.Tumor necrosis factor alpha(TNFα)and interleukin-1α(IL-1α)alone or together induce the expression of the H chain of ferritin in mouse adipocytes,human muscle cells and other cell types.Translation of ferritin is induced by IL-1β,IL-6or TNFαin the HepG2hepatic cell line,and iron is required for this regulation[5].Ferritin expression is regulated by oxidative stress that acts either directly on gene expression or indirectly via modifications of IRPs activity.Expression of ferritin is also regulated by hormones,growth factors,second messengers,and hypoxia–ischemia and hyperoxia.Both oxidants and anti-oxidant response inducers regulate H-ferritin gene transcription[5].

Cytokines may also affect ferritin translation indi-rectly through their ability to induce nitric oxide synthase(iNOS)and hence increase NO.NO in turn causes the activation of both IRP1and IRP2(although effects on IRP2appear to exhibit some cell type specificity),effects that may be particularly important in inflammatory conditions.Mechanisms hypothesized to underlie NO-mediated induction of IRP binding activity include cluster disassembly(IRP1),intracellular iron chelation(IRP1and IRP2),or increased de novo synthesis(IRP2)[3].Lipopolysaccharide(LPS;endo-toxin),a component of the outer membrane of gram-negative bacteria,elicits a variety of reactions that involve ferritin[3].

Hormonal pathways are also involved in ferritin regulation.Thyroid hormone may regulate ferritin post-transcriptionally:T3modulates the activity of IRP1, affecting its ability to bind to the ferritin IRE,possibly through induction of signal transduction cascades that result in phosphorylation of IRP1.T3and TRH also induce the phosphorylation of IRP2.In addition to thyroid hormone,insulin and IGF-1have also been implicated in regulation of ferritin at the mRNA level[3].

4.Ferritin and inflammation/infection

Macrophage ferritin accumulates during inflamma-tion,when serum iron decreases and iron in specific cells increases,leading to ferritin with more iron/protein cage. Pathogen ferritins are the mini-ferritins that protect bacterial DNA when exposed to ferrous ions and hydrogen peroxide in vitro and confer cellular resistance to oxidative damage in vivo.During infection or inflammation,it is the relative“iron deficiency”created by the host redistribution of iron,with a deficit in serum and an increase in macrophages(the main stimulus for siderophore production),synthesized in response to environmental iron deficiency and associated with virulence[1].

5.Ferritin and the immune system

Ferritin has been reported to exhibit different immu-nological activities including:binding to T lymphocytes and inhibition of E-rosette formation,a concanavalin A response[6],a source for iron to catalyze oxygen radicals in the Haber–Weiss reaction,suppression of the delayed type of hypersensitivity to induce anergy[7],suppression of antibody production by B lymphocytes[8],decreasing the phagocytosis of granulocytes[9],and regulating granulomonocytopoiesis[9].

6.Altered ferritin levels and disease

Ferritin and iron homeostasis have been implicated in the pathogenesis of many diseases,including diseases involved in iron acquisition,transport and storage (primary hemochromatosis)as well as in atherosclerosis [5],Parkinson's disease[10],Alzheimer disease[11],and pulmonary disease[12].Genetic mutations of the ferritin IRE region as well as coding regions of ferritin cause some hereditary human diseases.Ferritin L IRE mutations cause the hereditary hyperferritinemia-cataract syndrome [13],which is an autosomal dominant disease character-ized by elevated ferritin levels and early-onset bilateral cataracts.Neuroferritinopathy,a dominantly inherited movement disorder characterized by decreased levels of ferritin and abnormal deposition of ferritin and iron in the brain,is caused by a mutation in the C-terminus of the ferritin L gene[14].Recently,a mutation of a hemochro-matosis associated gene(HFE),C282Y,was associated with an increased risk of coronary artery disease and cardiovascular mortality[5,15].

7.Ferritin and malignancies

Early views of the relationship between ferritin and cancer stem from work demonstrating an increase in total ferritin as well as a shift toward acidic(H-rich) ferritins in the serum of patients with various malignan-cies.However,subsequent evaluations of ferritin levels in tumor tissue itself have revealed a complex,perhaps disease-specific picture:for example,in some cases such as colon cancer,testicular seminoma,and breast cancer,

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increases in ferritin in tumor tissue versus comparable normal tissue have been reported;in other cases, including liver cancer,a decrease in ferritin is seen. New forms of ferritin may be involved in certain situations.A novel isoform of ferritin was recently described that is elevated in the serum of patients with neoplastic breast disease as well as during pregnancy and HIV infection[4].Elevated ferritin levels in the CSF indicate meningeal disease such as infection or menin-geal spread in CNS tumor disease,but cannot distin-guish between the two causes.CSF ferritin was measured in patients with benign inflammatory and non-inflammatory neurologic disorders and in patients with malignant disease with and without documented central nervous system(CNS)involvement.CSF ferritin levels were increased in the majority of patients with inflammatory neurologic disease and in patients with malignant involvement of the CNS,but not in patients with non-inflammatory neurologic disorders and in malignant disease without CNS involvement.These findings indicate that although the specificity of CSF ferritin measurement is limited,it is a highly sensitive test that may be useful in the initial evaluation of patients with malignant CNS involvement,and in assessing their response to therapy[16].

8.Hyperferritinemia in autoimmune diseases

Adult onset Still's disease(AOSD)is a systemic inflammatory disorder characterized by fever,arthritis, rash,and hyperferritinemia in89%of cases[17]. Overproduction of IL-18may contribute to the path-ogenic mechanism of AOSD,and serum sIL-2R levels may be used as a marker for monitoring disease activity in AOSD[18].Reactive hemophagocytic syndrome is not uncommon in AOSD and should be sought in a patient with AOSD with extremely elevated serum ferritin and triglyceride levels[19,20].In adult Still's disease,elevated ferritin levels are glycoylated and basic[21].

8.1.Rheumatoid arthritis(RA)

RA is an autoimmune disease involving predomi-nantly the joints,associated with inflammation and elevated cytokine production of TNFαand IL-1α. Serum levels of ferritin do not differ from those of controls,but do fluctuate within the normal range during disease activity.Elevated serum ferritin in RA patients rather reflect total stores of body iron.High concentra-tions of ferritin are found in the synovial fluid and synovial cells of RA patients[22,23].

Hyperferritinemia was reported in patients with systemic juvenile rheumatoid arthritis and correlated with disease activity and reduced steroid dosage[24].In another study,the mean ferritin was higher in the patients with RA compared to controls.There were significant correlations between serum ferritin levels and disease activity based on the disease activity DAS28 score in RA patients[25].

8.2.Systemic lupus erythematosus(SLE)

SLE is a multi-systemic autoimmune disease mani-fested by excessive autoantibody production.While a diffuse inflammatory state is obvious,APRs are not elevated,indicating abnormal function of these proteins. High concentrations of ferritin were reported in certain manifestations of lupus including in the urine of patients with nephritis[26],in the pleural fluid[6],and in the CSF of patients with meningitis[6].Four studies examined the relationship between serum ferritin levels and disease activity in patients with SLE.In one study, the relationship between serum ferritin,disease activity (utilizing the SLEDAI score),and following treatment was sought in128SLE patients compared to RA patients as controls.Serum levels of ferritin during the more active stage of SLE exceeded those of RA patients and patients at less active stages of SLE.There were no significant differences between RA patients and SLE patients with mild disease.Serum ferritin was elevated especially in serositis and hematologic manifestation.In this prospective study,changes in SLEDAI scores before and after treatment correlated significantly with serum ferritin levels and inversely to C3and C4levels [27].In a similar study,serum ferritin levels in72SLE patients were significantly higher than RA patients. There was a significant difference in ferritin levels before and after treatment.The levels of ferritin in SLE were correlated with SLEDAI scores[28].In a third study,the clinical relevance of serum levels of ferritin in SLE patients vs.controls,the correlations between such levels and clinical disease activity,anti-DNA antibody titer,and serum levels of complement were assessed. Thirty-six SLE patients were evaluated for hyperferri-tinemia,including21patients with active disease.The SLE patients exhibited higher serum levels of ferritin and lower serum levels of CRP than the RA patients. Serum levels of ferritin at the active stage of SLE exceeded those at the inactive stage.The levels of se-rum ferritin in SLE were positively correlated with the anti-DNA antibody titer and negatively correlated with CH50values[6].One study found contrasting results.The clinical history,SLEDAI,CRP and ferritin

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concentrations were analysed throughout the disease course of10SLE patients.During a mean follow-up of 4.8years,10exacerbations occurred.Throughout the disease course,CRP and SLEDAI correlated positively in5patients,whereas the correlation between SLEDAI and ferritin was positive in7patients.CRP and ferritin levels remained normal during5exacerbations.From this investigation,it was concluded that despite severe disease activity,ferritin levels can remain well within the normal range,limiting its clinical usefulness as a marker for disease activity[29].

8.3.Multiple sclerosis(MS)

Over the last few years,increased evidence has supported the role of iron dysregulation in the pathogenesis of MS,as iron is essential for myelin formation and oxidative phosphorylation.MS and its animal model,experimental allergic encephalomyelitis (EAE),are autoimmune disorders resulting in demye-lination in the CNS.Data from several biochemical and pharmacological studies indicate that free radicals participate in the pathogenesis of EAE,and iron has been implicated as the catalyst leading to their formation[30].In one study,apoferritin was injected to EAE mice in order to increase plasma ferritin levels and to evaluate disease activity.Additional mice received systemic injections of iron,which induces ferritin synthesis,in order to test the effects of exogenous iron on the disease course.Although plasma levels of ferritin were found to be elevated in both apoferritin and iron-injected EAE mice,only apoferri-tin treatment resulted in a reduction in disease activity. The suppressive effects of apoferritin administration suggest that the increase in endogenous ferritin levels that have been previously observed in the CSF of chronic progressive MS patients with active disease might be functioning to limit the severity and spread of tissue damage[31].Delivery of iron to the brain traditionally has been considered the responsibility of transferring where transferrin receptors are located primarily within gray matter areas.Another report provided evidence of ferritin binding sites primarily in white matter tracts in the brain.In brain tissue from MS patients,the normal pattern of transferrin and ferritin binding distributions is disrupted.Ferritin binding is absent in the lesion itself and in the immediate periplaque region within the white matter but returns to normal as the distance from the lesion becomes greater.These data suggest loss of ferritin binding is invol-ved in or is a consequence of demyelination associated with MS[32].

One study investigated the indices of iron metabo-lism in27MS patients.Ferritin levels were significantly elevated only in chronic progressive active(CP-A) patients.Patients of the CP group had significantly higher ferritin values than the relapsing–remitting(RR) patients.Hence,the increased serum ferritin levels in nonanaemic MS patients with active disease reflect the increased iron turnover[33].In addition,ferritin levels were found to be significantly elevated in the CSF of CP-A MS patients compared to levels in normal individuals.Both ferritin and transferrin levels were elevated in patients that had high CSF IgG values but not in patients with a high IgG index.Since ferritin binds iron,the increase of CSF ferritin levels in CP MS patients could be a defense mechanism to protect against iron induced oxidative injury[34].

8.4.Thyroiditis

Hormonal pathways are involved in ferritin regula-tion.Thyroid hormone induce ferritin expression and hence hyperferritinemia could be expected in inflam-matory thyroid disease.In one study,elevated ferritin levels in patients with subacute thyroiditis correlated with disease activity and decreased following steroid therapy.These levels were higher when compared to patients with Graves'disease and Hashimoto's thyroid-itis.Elevated serum ferritin concentration significantly declined with treatment by either aspirin or prednisolone [35].

8.5.Polymyositis/dermatomyositis(PM/DM)

PM and DM are inflammatory autoimmune myopa-thies characterized by promimal muscle weakness and visceral involvement.Only one study investigated hyperferritinemia in PM/DM patients.Ferritin levels were higher in the elderly patient group compared with the younger group in79consecutive patients'char-acteristics of with polymyositis(PM)and dermatomyo-sitis(DM)[36].

9.Conclusions

Perturbations in ferritin function are not only detri-mental for iron homeostasis,but can lead to disease states by mechanisms of inflammation,infection,injury,and repair.Ferritin has been implicate in various diseases and may be important in autoimmune conditions.Hyperferri-tinemia is present in active SLE,RA,and may play a role in MS.Further investigation into the mechanisms of ferritin in this group of diseases is warranted.

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Take-home messages

?Controlling iron/oxygen chemistry in biology depends on multiple genes,regulatory messenger RNA(mRNA) structures,signaling pathways and protein catalysts.?Ferritin synthesis is regulated by cytokines(TNFαand IL-1α)at various levels(transcriptional,post-transcrip-tional,and translational)during development,cellular differentiation,proliferation,and inflammation.The cellular response by cytokines to infection stimulates the expression of ferritin genes.

?Ferritin has been reported to exhibit different immuno-logical activities including binding to T lymphocytes, suppression of the delayed type of hypersensitivity, suppression of antibody production by B lymphocytes, and decreased phagocytosis of granulocytes.?Ferritin and iron homeostasis have been implicated in the pathogenesis of many diseases,including diseases involved in iron acquisition,transport and storage (primary hemochromatosis)as well as in atheroscle-rosis,Parkinson's disease,Alzheimer disease,and restless leg syndrome.

?Mutations in the ferritin gene cause the heredi-tary hyperferritinemia-cataract syndrome and neuroferritinopathy.

?Hyperferritinemia is associated with inflammation, infections,and malignancies.

?Thyroid hormone,insulin and insulin growth factor-1 have also been implicated in regulation of ferritin at the mRNA level.

?Hyperferritinemia in SLE correlates with disease activity.

?Some evidence points to the importance of hyperfer-ritinemia in RA,MS,and thyroiditis,but further investigations are required including revelation of mechanisms.

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Anti-gp210and anti-centromere antibodies are different risk factors for the progression of primary biliary cirrhosis.

The predictive role of antinuclear antibodies (ANAs)remains elusive in the long-term outcome of primary biliary cirrhosis (PBC).Here,Nakamura M.et.al.(Hepatology 2007;45:118-27)evaluated the progression of PBC in association with ANAs using stepwise Cox proportional hazard regression and an unconditional stepwise logistic regression model based on the data of 276biopsy-proven,definite PBC patients who have been registered to be the National Hospital Organization Study Group for Liver Disease in Japan (NHOSLJ).When death of hepatic failure/liver transplantation (LT)was defined as an end-point,positive anti-gp210antibodies (Hazard ratio (HR)=6.742,95%confidence interval (CI):2.408,18.877),the late stage (Scheuer's stage 3,4)(HR =4.285,95%CI:682,10.913)and male sex (HR =3.266,95%CI:1.321,8.075)were significant risk factors at the time of initial liver biopsy.When clinical progression to death of hepatic failure/LT (i.e.,hepatic failure type progression)or to the development of esophageal varices or hepatocellular carcinoma without developing jaundice (i.e.,portal hypertension type progression)was defined as an end-point in the early stage (Scheuer's stage 1,2)PBC patients,positive anti-gp-210antibodies was significant risk factor for hepatic failure type progression,whereas positive anti-centromere antibodies was a significant risk factor for portal hypertension type progression.Histologically,positive anti-gp-210antibodies were most significantly associated with more severe interface hepatitis and lobular inflammation,whereas positive anti-centromere antibodies were most significantly associated with more severe ductular reaction.These results indicate two different progression types in PBC,hepatic failure type and portal hypertension type progression,which may be represented by positive-anti-gp210and positive-anti-centromere antibodies,respectively.

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