Research Article Macular Amyloidosis and Epstein-Barr Virusdownloads.hindawi.com/journals/drp/2016/6089102.pdfResearch Article Macular Amyloidosis and Epstein-Barr Virus YaldaNahidi,

Research ArticleMacular Amyloidosis and Epstein-Barr Virus

Yalda Nahidi1 Naser Tayyebi Meibodi1 Zahra Meshkat2 and Narges Nazeri3

1Skin Research Center School of Medicine Mashhad University of Medical Sciences Mashhad 9176699199 Iran2Virology Research Center School of Medicine Mashhad University of Medical Sciences Mashhad 9176699199 Iran3Pathology Department of Mashhad University of Medical Sciences Mashhad 9176699199 Iran

Correspondence should be addressed to Naser Tayyebi Meibodi naser tayyebiyahoocom

Received 3 November 2015 Revised 4 January 2016 Accepted 17 January 2016

Academic Editor Jag Bhawan

Copyright copy 2016 Yalda Nahidi et al This is an open access article distributed under the Creative Commons Attribution Licensewhich permits unrestricted use distribution and reproduction in any medium provided the original work is properly cited

Background Amyloidosis is extracellular precipitation of eosinophilic hyaline material of self-origin with special staining featuresand fibrillar ultrastructure Macular amyloidosis is limited to the skin and several factors have been proposed for its pathogenesisDetection of Epstein-Barr virus (EBV) DNA in this lesion suggests that this virus can play a role in pathogenesis of this diseaseObjective EBV DNA detection was done on 30 skin samples with a diagnosis of macular amyloidosis and 31 healthy skin samplesin the margin of removed melanocytic nevi by using PCR Results In patients positive for beta-globin gene in PCR BLLF1 gene ofEBV virus was positive in 23 patients (8 patients in case and 15 patients in the control group) There was no significant differencein presence of EBV DNA between macular amyloidosis (38) and control (238) groups (119875 = 008) Conclusion The findings ofthis study showed that EBV is not involved in pathogenesis of macular amyloidosis

1 Introduction

Amyloidosis is the extracellular deposition of a group offibrous proteins There is a variety of approaches for classi-fication of amyloidosis but the simplest method is divisioninto systemic and organ-specific (localized) types Skin is aninvolved tissue in both types Cutaneous localized amyloido-sis is of two types (i) keratinic which may be primary orsecondary and (ii) nodular The secondary type is secondaryto other skin lesions such as skin tumors inflammatory skindisorders and phototherapy Two types of keratotic amyloi-dosis have been identified macular and lichen amyloidosisand the latter is more common In keratotic amyloidosiskeratin depositions originating from basal keratinocyte aremainly CK5 positive Keratotic type is mostly observed inSouth-East Asia South America and China It has familial(10) and sporadic forms and the latter is more commonin women [1] The most common sites of involvement areupper back (interscapular area) and extremities (shins andarms) although they have also been described on face trunkand thighs [2] Macular amyloidosis lesions usually appear inthe form of hyperpigmented patches with indefinite margins

composed of grayish brown macules often with a reticulatedor rippled appearance [3] (Figure 1) Itching is a commonsymptom before the onset of amyloidosis [1]

The pathogenesis of this disorder is not fully elucidatedexcept for the fact that the deposited keratin is derivedfrom keratinocytes [1] Two pathogenic mechanisms havebeen proposed including apoptotic (fibrillar) theory andsecretory theory [4] Based on apoptotic theory degenerationof damaged keratinocytes in the basal layer is followed bythe conversion of these colloid bodies by dermal histiocytesand fibroblasts into amyloid in the papillary dermis [5](Figure 2) According to the secretory theory deposits ofamyloid derived fromdegenerated basal keratinocytes spreadinto papillary dermis through the damaged lamina densa [6]There are several etiologic factors implicated in the patho-genesis of macular amyloidosis racial factors [7] geneticpredisposition environmental factors [8] sex (female) [910] female hormones [11] exposure to sunlight [12] fric-tion (long term abrasion) [12ndash14] atopy [15] autoimmunity(based on association with systemic lupus erythematosusdermatomyositis systemic sclerosis sarcoidosis and IgAnephropathy) [16 17] and infection with EBV [18 19] EBV

Hindawi Publishing CorporationDermatology Research and PracticeVolume 2016 Article ID 6089102 5 pageshttpdxdoiorg10115520166089102

2 Dermatology Research and Practice

Figure 1 Hyperpigmented patch composed of small brownmaculesin a rippled or reticulated pattern on the arm

Figure 2 Small globular hyaline materials of amyloid in thepapillary dermis

the presence of which has been reported in epidermis ofmacular amyloidosis is likely to act as a factor contributingto degeneration of keratinocytes [1]

The role of EBV in etiopathogenesis of primary cutaneousamyloidosis has been evaluated in only two prior studiesincluding a single case report [18] and a case series of 27patients from China [19] Considering the shortage of studieson the association between EBV and macular amyloidosiswe set out to perform a study in this regard in Iran Perhapsantiviral agents can be used in the future for treatment of thisdisease in case of association with EBV

2 Materials and Methods

In this case-control study 38 macular amyloidosis samplesand 38 healthy skin samples around excisedmelanocytic nevifrom age- and sex-matched patients without macular amy-loidosis were enrolled in the clinical examination based ona nonrandom objective-oriented sampling Inclusion criteriaincluded paraffin blocks with sufficient tissue in archives of

Pathology Department of Imam Reza Hospital in Mashhaddiagnosed with macular amyloidosis based on pathologyreport and clinical presentation Exclusion criteria includedblockswith imperfect data in records and insufficient samplesfor PCR

In the case group amyloid deposition was confirmed byoptical microscopy and Congo red staining In the next stepsix 5 120583m sections were prepared from each of the blocks incase and control groups in sterile conditions using sterileblade and were placed in sterile Eppendorf tubes

21 Deparaffinization Xylolethanol was used to deparaf-finize the paraffinized tissues One mL xylol was addedto microtubes containing tissue sections and incubated inroom temperature for half an hour with constant shakingIn the next step microtubes were centrifuged in 13000 rpmfor 10 minutes and their supernatant was discarded Thesetwo steps were repeated once Five hundred 120583L of 100ethanol was added to the precipitate and centrifuged for10m in 13000 rpm after several inversions of microtube andthe supernatant was then removed This step was repeatedagain Finally the resulting precipitate was placed in roomtemperature to completely evaporate ethanol but not theprecipitate

22 DNA Extraction DNA extraction was done using BIOBASIC INC (Canada) kit with lot number 8401-140116 Lysisbuffer-T was used for extraction In the next step 100 120583Lextraction buffer and 10 120583L proteinase K were added to eachmicrotube and were mixed Tissue samples were added to themixture and incubated at room temperature for 10 minutesThen the samples were incubated at 95∘C for 3 minutes toinactivate proteinase K One hundred 120583L Universal BufferNST was added to the tubes and inverted 10 times Theobtained mixture was used for PCR

23 PCR In this study PCR was used to detect the pres-ence of EBV genome in macular amyloidosis After DNAextraction from paraffinized blocks the quality of DNAextracted from paraffin-embedded tissues was determinedusing beta-globin gene primers GH20 and PC04 beta-globingene primers used in this study amplified a 260 bp fragmentThe sequence of these primers was as follows

GH20 51015840 GAA GAG CCA AGG ACA GGT AC 31015840PC04 51015840 CAA CTT CAT CCA CGT TCA CC 31015840

The samples producing the 260 bp fragment using the desiredprimers were considered favorable for amplification of EBVvirus BLLF1 gene

Presence of EBV sequence in the extracted DNA sampleswas tested using Cinna Gen kit with lot number 935701(Sina Clon Iran) This kit has been designed to determinethe quality of EBV DNA in infected samples using PCROptimized 1x PCR as a mixture of recombinant Taq DNApolymerase PCR buffer MgCl

2 dNTPs and primers was the

reagent used for mixing The highly specific and repetitiveregion of BLLF1 gene encoding gp 350220 is amplified byprimers They can detect at least 30 copies of EBV The

Dermatology Research and Practice 3

Figure 3 PCR results of beta-globin gene in terms of amplificationsamples 1 2 and 3 are part of positive beta-globin gene (260 bpband)and samples 4 5 and 6 are negative C+ andCminus indicate positive andnegative controls respectively and M represents the DNA marker

presence of 239 bp or 256 bp fragments indicates a positivetest result

Data analysis was performed using SPSS 115 softwareGraphs and statistical tables were used to describe data andChi-square and independent 119905-tests were used to compareEBV in healthy and patientsrsquo samples In all tests thesignificance level of 005 was considered

3 Results

Fifty percent of the patients were male (1938) and 50 werefemale (1938)Three patients were in the age group under 20years (79) 5 patients 20ndash30 years (132) 10 patients 30ndash40 years (263) 13 patients 40ndash50 years (342) 4 patients50ndash60 years (105) and 3 patients over 60 years (79)The minimum and maximum ages were 19 and 76 yearsrespectively There were 27 cases of infection in the trunk(711) and 11 cases in the extremities (289)The study andcontrol group were matched for age (119875 = 0535) and sex(119875 = 0646)

PCR was conducted for beta-globin gene in 76 samples(38 cases and 38 controls) which was positive in 61 samples(30 samples in case group and 31 in the control group) andwas negative in 15 samples (8 samples in case and 7 in controlgroup) (Figure 3)

In 61 samples positive for beta-globin gene in PCR BLLF1gene fromEBVwas positive in 23 cases (8 cases in study groupand 15 cases in control group) andwas negative in 38 cases (22cases in the study group and 16 cases in the control group)(Figure 4)

PCR of BLLF1 gene from EBV was 267 positive instudy group and 484 positive in control group Chi-squaretest results showed no correlation between EBV and macularamyloidosis (119875 = 008) (Table 1)

4 Discussion

Amyloidosis is known as extracellular deposition ofeosinophilic hyaline material of self-origin with specificstaining and ultrastructural characteristics This disordercan occur in the background of systemic diseases or may belimited to the skin Macular amyloidosis is limited to the skin

Figure 4 PCR results of BLLF1 gene of EBV samples 2 4 and 5 arepositive (239 bp or 256 bp bands) and samples 1 and 3 are negativeC+ and Cminus indicate positive and negative controls respectively andM represents the DNA marker

Table 1 Percentage distribution of PCR results from BLLF1 geneof EBV in 30 patients with macular amyloidosis and 31 melanocyticnevus samples among samples positive for beta-globin gene

EBV DNAPCR

Study groupsChi-square test

resultsCases ControlsNumber Percent Number Percent

Positive 8 267 15 484119875 = 008

Negative 22 917 16 762Total 30 31 61

[1] EBV may stimulate the secretion of amyloid materialby keratinocytes or may be a stimulus for degeneration ofkeratinocytes and conversion of degenerated keratinocytefilaments into amyloid [1 18] Recent studies have indicatedthe role of epithelial cells in continued reproduction ofEBV EBV cell surface receptors found in less differentiatedsquamous epithelium suggest the direct infection ofepidermal keratinocytes Infection may occur in germinativelayers however virus replication is only feasible throughmaturation and differentiation of cells The expression ofcytokeratin in human keratinocytes is changed in vitroafter infection with EBV resulting in their conversion tofibroblasts [18 19] Fibroblasts can phagocytize keratinaggregates and convert them to amyloid [18]

Drago et al showed this correlation in Italy in 1996Theirpatient was a 30-year-old female with a ten-year history ofitchy brown papules and macules on the chest and back withsymptoms of chronic fatigue syndrome They could showEBV genome in epidermal lesions using in situ hybridizationtechnique EBV genome was principally shown in basalepidermal cells as well as higher layer cells especially in thecytoplasm Serological tests for EBV were also positive in thepatient Antiviral therapy with acyclovir and interferon alphaimproved skin lesions and general symptoms in the patient[18] Another study was conducted by Chang et al on skintissue of 27 patients with a diagnosis of lichen and macularamyloidosis in Taiwan in 1997 In situ hybridization methodindicated EBV DNA in lesions of 11 patients (407) while


the control group (including three patients with secondarycutaneous amyloidosis two patients with primary systemicamyloidosis and four patients with chronic simplex lichen)lacked EBV DNA [19]

According to this study there was no correlation betweenEBV and macular amyloidosis (119875 = 008) EBV DNA waspresent in 8 patientswithmacular amyloidosis and 15 controlsin our study The difference in rate of detection of EBV DNAbetween macular amyloidosis patients and controls in thisstudy with the mentioned studies can be due to the followingreasons

(1) Lack of association between macular amyloidosisand EBV infection there are a few studies present-ing insufficient evidence for a definitive correlationbetween EBV and macular amyloidosis so basedon the results of our study we could make thisconclusion

(2) Methodology (PCR versus in situ hybridization)we used a sensitive method for detection of EBVDNA with positive and negative controls Basedon the previous studies PCR is as sensitive as insitu hybridization [20 21] However as we did notuse in situ hybridization we could not localize theexact infected cell with EBV in our controls whichmight be the circulating B cells of the skin insteadof keratinocytes As we used positive and negativecontrols in our PCR kit for EBV the positive cases inour control group could not be false positive

(3) Controls the controls in our study were the healthyskin around melanocytic nevi but the controls inChang study were other cutaneous disorders

(4) Type of cutaneous amyloidosis in our study all thepatients had macular amyloidosis but in both theprevious studies [18 19] most of the patients were oflichen amyloidosis

5 Conclusion

According to the results of this study there was no correlationbetween EBV and macular amyloidosis We recommend theuse of fresh tissue or quickly frozen biopsy punch as wellas simultaneous serological study of patients for anti-EBVantibody to achieve more accurate results for comparativestudy of EBV DNA in macular amyloidosis In situ PCR canalso be used to localize the EBV DNA positive cells in thesamples Other genes can be used to detect EBV in the tissuesince some EBV samples are mutated for BLLF1 gene used inthis study [22]

Also we recommend performing a comparative study ondetection of EBV in both involved and uninvolved skin of thepatients with macular amyloidosis

Conflict of Interests

The authors declare no conflict of interests

Acknowledgments

The authors express their profound gratitude for researchdeputy of MUMS for financial support and approval of theresearch proposal (no 911283) related to thesis of NargesNazeri Financial support by research deputy of MashhadUniversity of Medical Sciences is acknowledged

References

[1] A Fernandez-Flores ldquoCutaneous amyloidosis a conceptreviewrdquoTheAmerican Journal of Dermatopathology vol 34 no1 pp 1ndash14 2012

[2] J T Al-Ratrout and M B Satti ldquoPrimary localized cutaneousamyloidosis a clinicopathologic study from Saudi ArabiardquoInternational Journal ofDermatology vol 36 no 6 pp 428ndash4341997

[3] A Bandhlish A Aggarwal and R Koranne ldquoA clinico-epidemiological study of macular amyloidosis from NorthIndiardquo Indian Journal of Dermatology vol 57 no 4 pp 269ndash274 2012

[4] Y Horiguchi J-D Fine I M Leigh T Yoshiki M Ueda andS Imamura ldquoLamina densa malformation involved in histoge-nesis of primary localized cutaneous amyloidosisrdquo Journal ofInvestigative Dermatology vol 99 no 1 pp 12ndash18 1992

[5] H Kobayashi and K Hashimoto ldquoAmyloidogenesis in organ-limited cutaneous amyloidosis an antigenic identity betweenepidermal keratin and skin amyloidrdquo Journal of InvestigativeDermatology vol 80 no 1 pp 66ndash72 1983

[6] D M Touart and P Sau ldquoCutaneous deposition diseases partIrdquo Journal of the American Academy of Dermatology vol 39 no2 pp 149ndash171 1998

[7] W-J Wang C-Y Huang Y-T Chang and C-K WongldquoAnosacral cutaneous amyloidosis a study of 10 Chinese casesrdquoBritish Journal of Dermatology vol 143 no 6 pp 1266ndash12692000

[8] V Eswaramoorthy I Kaur A Das and B Kumar ldquoMacularamyloidosis etiological factorsrdquo The Journal of Dermatologyvol 26 no 5 pp 305ndash310 1999

[9] A-G Kibbi N G Rubeiz S T Zaynoun and A K KurbanldquoPrimary localized cutaneous amyloidosisrdquo International Jour-nal of Dermatology vol 31 no 2 pp 95ndash98 1992

[10] Y T Chang C K Wong K C Chow and C H TsaildquoApoptosis in primary cutaneous amyloidosisrdquo British Journalof Dermatology vol 140 no 2 pp 210ndash215 1999

[11] A Rasi A Khatami and S M Javaheri ldquoMacular amyloidosisan assessment of prevalence sex and agerdquo International Journalof Dermatology vol 43 no 12 pp 898ndash899 2004

[12] V K Somani H Shailaja V N V L Sita and F Razvi ldquoNylonfriction dermatitis a distinct subset of macular amyloidosisrdquoIndian Journal of Dermatology Venereology and Leprology vol61 no 3 pp 145ndash147 1995

[13] L Onuma M Vega R Arenas and L Dominguez ldquoFrictionamyloidosisrdquo International Journal of Dermatology vol 33 no1 p 74 1994

[14] M Siragusa R Ferri V Cavallari and C Schepis ldquoFrictionmelanosis friction amyloidosis macular amyloidosis towelmelanosis many names for the same clinical entityrdquo EuropeanJournal of Dermatology vol 11 no 6 pp 545ndash548 2001


[15] D D Lee C K Huang P C Ko Y T Chang W Z Sunand Y J Oyang ldquoAssociation of primary cutaneous amyloidosiswith atopic dermatitis a nationwide population-based study inTaiwanrdquo British Journal of Dermatology vol 164 no 1 pp 148ndash153 2011

[16] A Tanaka K Arita J E Lai-Cheong F Palisson M Hideand J A McGrath ldquoNew insight into mechanisms of pruritusfrommolecular studies on familial primary localized cutaneousamyloidosisrdquo British Journal of Dermatology vol 161 no 6 pp1217ndash1224 2009

[17] M J Dahdah M Kurban A-G Kibbi and S Ghosn ldquoPrimarylocalized cutaneous amyloidosis a sign of immune dysregula-tionrdquo International Journal of Dermatology vol 48 no 4 pp419ndash421 2009

[18] F Drago E Ranieri A Pasturino S Casazza F Crovato andA Rebora ldquoEpstein-Barr virus-related primary cutaneous amy-loidosis Successful treatment with acyclovir and interferon-alphardquo British Journal of Dermatology vol 134 no 1 pp 170ndash174 1996

[19] Y T Chang H N Liu C K Wong K C Chow and K YChen ldquoDetection of Epstein-Barr virus in primary cutaneousamyloidosisrdquo British Journal of Dermatology vol 136 no 6 pp823ndash826 1997

[20] N Suh H Liapis J Misdraji E M Brunt and H LWang ldquoEpstein-Barr virus hepatitis diagnostic value of in situhybridization polymerase chain reaction and immunohisto-chemistry on liver biopsy from immunocompetent patientsrdquoAmerican Journal of Surgical Pathology vol 31 no 9 pp 1403ndash1409 2007

[21] Z-L Qi X-Q Han J Hu et al ldquoComparison of three methodsfor the detection of Epstein-Barr virus in Hodgkinrsquos lymphomain paraffin-embedded tissuesrdquoMolecular Medicine Reports vol7 no 1 pp 89ndash92 2013

[22] A Janz M Oezel C Kurzeder et al ldquoInfectious Epstein-Barrvirus lacking major glycoprotein BLLF1 (gp350220) demon-strates the existence of additional viral ligandsrdquo Journal ofVirology vol 74 no 21 pp 10142ndash10152 2000

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Parkinsonrsquos Disease

Evidence-Based Complementary and Alternative Medicine

Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom


Figure 1 Hyperpigmented patch composed of small brownmaculesin a rippled or reticulated pattern on the arm

Figure 2 Small globular hyaline materials of amyloid in thepapillary dermis

the presence of which has been reported in epidermis ofmacular amyloidosis is likely to act as a factor contributingto degeneration of keratinocytes [1]

The role of EBV in etiopathogenesis of primary cutaneousamyloidosis has been evaluated in only two prior studiesincluding a single case report [18] and a case series of 27patients from China [19] Considering the shortage of studieson the association between EBV and macular amyloidosiswe set out to perform a study in this regard in Iran Perhapsantiviral agents can be used in the future for treatment of thisdisease in case of association with EBV

2 Materials and Methods

In this case-control study 38 macular amyloidosis samplesand 38 healthy skin samples around excisedmelanocytic nevifrom age- and sex-matched patients without macular amy-loidosis were enrolled in the clinical examination based ona nonrandom objective-oriented sampling Inclusion criteriaincluded paraffin blocks with sufficient tissue in archives of

Pathology Department of Imam Reza Hospital in Mashhaddiagnosed with macular amyloidosis based on pathologyreport and clinical presentation Exclusion criteria includedblockswith imperfect data in records and insufficient samplesfor PCR

In the case group amyloid deposition was confirmed byoptical microscopy and Congo red staining In the next stepsix 5 120583m sections were prepared from each of the blocks incase and control groups in sterile conditions using sterileblade and were placed in sterile Eppendorf tubes

21 Deparaffinization Xylolethanol was used to deparaf-finize the paraffinized tissues One mL xylol was addedto microtubes containing tissue sections and incubated inroom temperature for half an hour with constant shakingIn the next step microtubes were centrifuged in 13000 rpmfor 10 minutes and their supernatant was discarded Thesetwo steps were repeated once Five hundred 120583L of 100ethanol was added to the precipitate and centrifuged for10m in 13000 rpm after several inversions of microtube andthe supernatant was then removed This step was repeatedagain Finally the resulting precipitate was placed in roomtemperature to completely evaporate ethanol but not theprecipitate

22 DNA Extraction DNA extraction was done using BIOBASIC INC (Canada) kit with lot number 8401-140116 Lysisbuffer-T was used for extraction In the next step 100 120583Lextraction buffer and 10 120583L proteinase K were added to eachmicrotube and were mixed Tissue samples were added to themixture and incubated at room temperature for 10 minutesThen the samples were incubated at 95∘C for 3 minutes toinactivate proteinase K One hundred 120583L Universal BufferNST was added to the tubes and inverted 10 times Theobtained mixture was used for PCR

23 PCR In this study PCR was used to detect the pres-ence of EBV genome in macular amyloidosis After DNAextraction from paraffinized blocks the quality of DNAextracted from paraffin-embedded tissues was determinedusing beta-globin gene primers GH20 and PC04 beta-globingene primers used in this study amplified a 260 bp fragmentThe sequence of these primers was as follows

GH20 51015840 GAA GAG CCA AGG ACA GGT AC 31015840PC04 51015840 CAA CTT CAT CCA CGT TCA CC 31015840

The samples producing the 260 bp fragment using the desiredprimers were considered favorable for amplification of EBVvirus BLLF1 gene

Presence of EBV sequence in the extracted DNA sampleswas tested using Cinna Gen kit with lot number 935701(Sina Clon Iran) This kit has been designed to determinethe quality of EBV DNA in infected samples using PCROptimized 1x PCR as a mixture of recombinant Taq DNApolymerase PCR buffer MgCl

2 dNTPs and primers was the

reagent used for mixing The highly specific and repetitiveregion of BLLF1 gene encoding gp 350220 is amplified byprimers They can detect at least 30 copies of EBV The





3 Results





4 Discussion




EBV DNAPCR



Positive 8 267 15 484119875 = 008

Negative 22 917 16 762Total 30 31 61










5 Conclusion





Acknowledgments


References





























of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of




















3 Results





4 Discussion




EBV DNAPCR



Positive 8 267 15 484119875 = 008

Negative 22 917 16 762Total 30 31 61










5 Conclusion





Acknowledgments


References





























of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of























5 Conclusion





Acknowledgments


References





























of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of






























of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of





















of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of
















Documents

Research Article Macular Amyloidosis and Epstein-Barr Virusdownloads.hindawi.com/journals/drp/2016/6089102.pdfResearch Article Macular Amyloidosis and Epstein-Barr Virus YaldaNahidi,