Thyroid Fetal Male Microchimerisms in Mothers with Thyroid Disorders: Presence of Y-Chromosomal Immunofluorescence in Thyroid-Infiltrating Lymphocytes Is More Prevalent in Hashimoto's Thyroiditis and Graves' Disease Than in Folli

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Thyroid Fetal Male Microchimerisms in Mothers with Thyroid Disorders: Presence of Y-Chromosomal Immunofluorescence in Thyroid-Infiltrating Lymphocytes Is More Prevalent in Hashimoto's Thyroiditis and Graves' Disease Than in Follicular
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  Thyroid Fetal Male Microchimerisms in Motherswith Thyroid Disorders: Presence of  Y-Chromosomal Immunofluorescence inThyroid-Infiltrating Lymphocytes Is MorePrevalent in Hashimoto’s Thyroiditis and Graves’Disease Than in Follicular Adenomas CHRISTOPH RENNE´, ELIZABETH RAMOS LOPEZ, SUSANNE A. STEIMLE-GRAUER,PIOTR ZIOLKOWSKI, MICHAEL A. PANI, CHRISTINA LUTHER, KATHARINA HOLZER, ALBRECHT ENCKE, ROBERT A. WAHL, WOLF O. BECHSTEIN, KLAUS H. USADEL,MARTIN-LEO HANSMANN,  AND  KLAUS BADENHOOP  Institute of Pathology (C.R., S.A.S.-G., M.-L.H.), Department of Internal Medicine I, Division of Endocrinology (E.R.L., M.A.P., K.H.U., K.B.), Department of Surgery (C.L., K.H., A.E., W.O.B.), University Hospital Frankfurt, D-60596 Frankfurtam Main, Germany; Department of Surgery, Bu¨rgerhospital (R.A.W.), D-60596 Frankfurt am Main, Germany; and Department of Pathology, Wroclaw Medical University (P.Z.), 50-368 Wroclaw, Poland Thepresenceoffetalcellsinamaternalcompartmentisdefinedas fetal-maternal microchimerism, which has been detected inthyroidsofmotherssufferingfromautoimmunity.Weanalyzedthe immunohistology of paraffin-embedded thyroid specimentaken at surgery from 49 women with Hashimoto’s thyroiditis(n  25),Graves’disease(n  15),ornodularordiffusefollicularadenomas(n  9),whosechildbirthhistorywaspositiveforsons.By fluorescence  in situ  hybridization we screened for X-chro-mosome-andY-chromosome-specificstainingandcomparedthefinding with human leukocyte antigen (HLA) DQ types of themothersand,whereavailable,theiroffspring.In23thyroidswefound Y-chromosome-specific staining, which was more fre-quentinthyroidautoimmunedisease(60%Hashimoto’sthyroid-itisand40%Graves’disease)thaninfollicularadenomas(22.2%).There was no significant difference for HLA DQ alleles among women whose thyroids showed Y-chromosome staining andthose without. However, a subgroup of all investigated micro-chimerism-positive mother-child pairs and women with Hashi-moto’s thyroiditis and Graves’ disease more often had the sus-ceptibilityallelesHLADQA1*0501-DQB1*0201orDQB1*0301.Inconclusion, fetal microchimerism is observed in thyroids of motherswithsons,andthisisfoundmorefrequentlyinthyroidautoimmune diseases. (  J Clin Endocrinol Metab  89: 5810–5814,2004) T HYROID DISORDERS ARE more common in womenthan in men, an observation that extends from auto-immunity to nodular thyroid disease and even congenitalhypothyroidism (1). Whereas pregnancy leads to an amelio-ration of autoimmunity, the postpartal period is associatedwithanexacerbationofGraves’diseaseandwithpostpartumthyroiditis (2). These alterations of a pregnant woman’s im-mune system have been explained by a switch to Th2-typeimmuneresponseandareboundtoTh1-typeimmunityafterchildbirth(3).Theimmunologicalchangesduringpregnancypromote a more successful fetal development, because themother must tolerate a semiidentical implant.Mother and fetus are in cellular contact through the syn-cytiotrophoblast layer, the maternal-fetal synapse. This celllayer expresses human leukocyte antigen (HLA) G, a mem- ber of the major histocompatibility complex that is thoughtto play an important role in the tolerance of the mothertoward the implant, because HLA G1-expressing cells ap-peartobedirectlyinvolvedinthesuppressionofanimmuneresponse (4). This immunoinhibitory function is exertedthrough the receptors ILT2/CD85j, ILT4/CD85d, andKIR2DL4/CD158d (5–7). These molecules may induce thedifferentiation of CD4  T lymphocytes into regulatory/sup-pressive cells.Previous reports about the findings of microchimerism inthyroid disease have been based on PCR employing Y-chro-mosome-specific primers in thyroid tissue of autoimmuneand nonautoimmune disorders (8, 9). We designed a retro-spective study to elucidate the possible role of fetal-maternalmicrochimerism in thyroids of women who had undergonethyroid surgery. We selected for the study those who hadgiven birth to at least one son before thyroid surgery. Thepresence of fetal microchimers within the thyroid was as-sessed by fluorescence  in situ  hybridization (FISH) on 49paraffin-embedded sections and was correlated with thepathological and clinical diagnoses. Furthermore, we ana-lyzed the immunogenetic background by HLA DQ typing of the mothers and offspring, where available, because persis-tent fetal microchimerism in mothers with scleroderma has Abbreviations:FISH,Fluorescence in situ hybridization;HLA,humanleukocyte antigen.  JCEM is published monthly by The Endocrine Society (http://www.endo-society.org), the foremost professional society serving the en-docrine community. 0021-972X/04/$15.00/0 The Journal of Clinical Endocrinology & Metabolism 89(11):5810–5814  Printed in U.S.A.  Copyright © 2004 by The Endocrine Societydoi: 10.1210/jc.2004-1049 5810   been found to be associated with HLA DQA1*0501 andDQB1*0301 (10). We present evidence of fetal microchimer-ism in thyroids of mothers with sons by FISH. This phe-nomenon appears to be more prevalent in thyroids affected by the autoimmune disorders Hashimoto’s thyroiditis andGraves’ disease. Subjects and Methods We studied retrospectively 49 female patients after thyroid surgeryfrom the endocrine and surgical departments of University Hospital aswell as from Bu¨rgerhospital (Frankfurt am Main, Germany). The studywas confined to those women whose pathohistological diagnosis wasHashimoto’s thyroiditis, Graves’ disease, or follicular adenoma. A letterwas sent to request permission for questions about childbirth beforethyroidoperationsandforabloodsample.Of58respondentswithason,we could study 49 by FISH analyses of thyroid sections. Of the total of 49 women, 16 provided a blood sample for additional HLA DQ typing.The age of the women at thyroid surgery ranged from 28–77 yr. Thehistory of childbirth included women with one son (n  12), two sons(n  12), three or more sons (n  1), and a son and a daughter (n  24).The time span between the nearest son’s birth and thyroid surgeryranged from 2–51 yr (mean, 27.2 and 20.75 yr) in mothers withmicrochimerism.  Patient material Paraffin-embedded tissue samples of the thyroid gland from 49women who underwent thyroid surgery were analyzed for diagnosticpurposes. The pathological diagnoses for histological paraffin-embed-ded sections stained with hematoxylin-eosin were as follows: in 25patients Hashimoto’s thyroiditis was found, 15 cases had Graves’ dis-ease, and nine had follicular adenomas.To study immunogenetic compatibility between maternal and fetalcells by DNA typing for HLA DQ, we obtained blood samples from 16patients and seven offspring, which allowed us to investigate sevenmother-child pairs. The study protocol was approved by the ethicscommittee of University Frankfurt am Main, and written consent wasobtained from all participants.  Immunohistochemistry Serial sections of paraffin-embedded material were used. Antibodiesdirected against CD3, CD20, and CD45 (leukocyte common antigen;Dako,Hamburg,Germany)werevisualizedwiththeavidin-biotincom-plex technique with alkaline phosphatase using Fast Red (Dako) aschromogen. All cases were analyzed for the number of CD45-positivecells.Inaddition,10patientswithHashimoto’sthyroiditis(fivewithandfive without microchimerism) were analyzed for the ratio of CD20/CD3-positive cells.  FISH  Serial sections of the immunohistochemically analyzed, paraffin-embedded, human tissue samples (4   m) were dewaxed and gentlydehydratedthroughanethanolseriesofincreasinggrade(79%,85%,and96%). Then the samples were pressure-cooked in 1 m m EDTA (pH 8.0)for 2 min and fixed for each 10 min in ice-cold Carnoy’s solution andice-cold 1% paraformaldehyde. The samples were dehydrated by eth-anol treatment with increasing concentrations. Both X- and Y-centro-meric probes were obtained from Vysis (Downers Grove, IL). FISH wasperformed following the manufacturer’s instructions.Slides were analyzed using an Axioskop-2 fluorescence microscope(Zeiss,Gottingen,Germany)equippedwithappropriatefiltersets(AHF,Tubingen, Germany), and findings were documented using the ISISimaging system (MetaSystems, Altlussheim, Germany). For each tissuesample, two slides resulting from separate hybridization experimentswere analyzed.  HLA DQ typing TypingforthecommonHLADQA1andDQB1alleleswasperformedasdescribedpreviouslybysequence-specificprimersandPCR(11).Thiswas accomplished in 16 women and seven mother-child pairs, six of them mother-son. Results Y-chromosome-positive cells in thyroid sections WedetectedY-chromosomalcellsin23of49(47%)thyroidtissues. The number of Y-chromosome-positive cells rangedfrom one to six per section. Lymphatic cells stained for Y-chromosome were lying sporadically between infiltrates of maternal lymphocytes and scattered in connective tissue ad- jacent to follicular epithelium cells (Fig. 1). No Y-chromo-some-positive thyrocytes were found. The proportion of Y-chromosome-positive thyroid sections was highest inHashimoto’s thyroiditis (15 of 25, 60%), lower in Graves’disease(sixof15,40%),andinfrequentinfollicularadenomas(two of nine, 20%; Table 1). The difference between autoim-mune thyroid disorders (21 of 45, 53%) and follicular ade-nomas did not reach significance due to the low number of  F IG . 1. Fetal male microchimerisms in lymphocytes infiltrating thyroid glands of mothers with thyroid disorders. A, Hybridization of X- and Y-chromosomalcentromersinathyroidglandofapatientsufferingfromHashimoto’sthyroiditis.The arrow pointstoafetallymphocyteshowing hybridization of the X-chromosome centromeric probe ( red ) and the Y-chromosome centromeric probe (  green ), which lies in a field of maternallymphocytes(positivityfortwo red  X-chromosomalcentromericFISHprobes).B,X-/Y-Chromosomalcentromerichybridizationinathyroidglandwith Graves’ disease. The  arrow  points to a fetal lymphocyte (presence for each one X- and Y-chromosome) that lies in the connective tissuebehind the maternal follicle epithelial cells ( arrowheads ). Autofluorescence of erythrocytes appears as bright  yellow  spots. Renne´  et al.  • Thyroid Fetal Male Microchimerisms J Clin Endocrinol Metab, November 2004, 89(11):5810–5814  5811  follicular adenomas (by Fisher’s exact test, one-sided, P  0.1).  Leukocytes per section, CD20/CD3 ratio Between 631 and 56,800 CD45-positive cells (leukocytes)/section were observed. The highest number was found inthyroids with Hashimoto’s thyroiditis (mean, 35,540),whereas patients with Graves’ disease had a mean of 2,058CD45 cells/section and 1,980 follicular adenomas thyroids/section.The number of Y-chromosomal cells/CD45-positive cellsranged from one in 200 up to one in 56,800/section. Thedensity of Y-chromosomal cells/CD45-positive cells variedand was lowest in thyroids of women with Hashimoto’sthyroiditis (mean of one per 13,369/section).Because tissues from patients with Hashimoto’s thyroid-itis showed the highest number of infiltrating lymphocytes,we analyzed five cases each with or without presence of microchimerism.CD20/CD3ratiosrangedbetween0.94and3.40, and no significant difference was found between sam-ples with or without fetal lymphocytes (data not shown).  HLA DQ types in women of subgroups Typing for HLA DQA1 and DQB1 alleles was performedin16patientswhosethyroidsectionshadundergoneanalysisfor microchimerism. The major HLA DQ alleles known toconfersusceptibilitytothyroidautoimmunediseaseareHLADQA1*0501, *0301, DQB1*0201, and DQB1*0301 (12). Eitherof these alleles was found in nine patients of 12 (75%) withHashimoto’s thyroiditis, six of them with microchimerism, both (100%) patients with Graves’ disease, and one patient(50%) with follicular adenomas (Table 2), all of the latterwithout microchimerism. Because not all women were avail-able for HLA DQ typing, we could not distinguish whetherthyroids with microchimerism carried more often the sus-ceptibility alleles than thyroids without microchimerism.However, seven mother-child pairs could be investigatedfor HLA DQ haplotypes, of whom four mothers had Y-chromosome-positive cells in their thyroids; in all mothersor children at least one HLA DQ haplotype was observedthat had previously been found to be associated with thy-roid autoimmunity (12): HLA DQA1*0301-DQB1*0301,DQA1*0501-DQB1*0201, DQA1*0102-DQB1*0602/DQB1*0604,or DQA1*0103-DQB1*0603. Y-Chromosome-positive thyroids compared with thyroidtissues without microchimerism Patients with microchimerism were multiparous in 19 of 23 cases; four patients each had one son. In one of the latterpatients the highest cell number of microchimers (six) wasobserved(Table3).Patientswithoutdetectablemicrochimer-ism were multiparous in 18 of 26, seven of them had twosons, and 11 had a son and a daughter (data no shown). Discussion To examine the possible influence of male fetal microchi-merismonautoimmunethyroiddisease,weassessedthyroidtissue samples obtained at surgery in female patients withHashimoto’s thyroiditis, Graves’ disease, and follicular ad-enoma; all had previously given birth to a son. This seriesrepresents the largest cohort of female thyroid tissues ex-aminedforthepresenceofmalemicrochimerismtodate.Thepresence of a Y-chromosome in thyroid tissues was taken asevidence for persistent fetal-maternal microchimerism, aphenomenonthatwasdescribedinsmallerstudiesin2001(8,13) and in Graves’ disease in 2002 (9). We confirm thoseearlier findings of a higher prevalence of microchimerism inthyroid autoimmune disease, but we also observed it infollicular adenoma. Furthermore, we extended our analysesto the immunogenetic background in patients as well as theobstetrichistory.Thepresenceofmicrochimerismwasfound TABLE 2.  Distribution of the HLA-DQ risk alleles in 16 patients with thyroid disease Diagnosis DQ2/DQ2 DQ8/X X/DQ8 DQ2/X X/DQ2 0201 0501 X/X  Hashimoto’s thyroiditis (n  12) 1 (8.33) 1 (8.33) 1 (8.33) 3 (25) 3 (25) 3 (25)Graves’ disease (n  2) 1 (50) 1 (50)Follicular adenoma (n  2) 1 (50) 1 (50) Values are the number of subjects (percentage). TABLE 3.  Distribution of the Y-chromosome-positive cells inthyroid tissues according to number of children, their gender, andbirth order Cells positive X, Y No. of childrenS SS SD DS DSS 1 1 2 22 1 2 33 1 3 1 2 14 1 15 16 1S, Son; SS, two sons; SD, son and daughter; DS, daughter and son;DSS, daughter and two sons. TABLE 1.  Number of Y-chromosome-positive cells in mothers with Graves’ disease, Hashimoto’s thyroiditis, and follicular adenoma DiagnosisNo. (%) of Y-chromosomal cells positive1 2 3 4 5 6 Hashimoto’s thyroiditis (n  15) 1 (6.6) 5 (33.3) 5 (33.3) 2 (13.3) 1 (6.6) 1 (6.6)Graves’ disease (n  6) 3 (50) 3 (50)Follicular adenoma (n  2) 1 (50) 1 (50) 5812  J Clin Endocrinol Metab, November 2004, 89(11):5810–5814 Renne´  et al.  • Thyroid Fetal Male Microchimerisms  in all mother-child pairs where at least one susceptible HLADQ haplotype was present. It is therefore conceivable thatmicrochimerism also occurs in nonautoimmune thyroid dis-orders if there is a fetal-maternal constellation of immuno-genetic susceptibility through HLA DQ or other genes.Ifmicrochimerismcontributestothyroidautoimmunity,aquantitative effect might be observed by the increased ex-posure of a woman toward fetal antigens during and afterpregnancy. However, we only observed a slightly higherprevalence of microchimerism in multiparous women com-pared with women with one son, and this is not significantdue to the small numbers.Nevertheless, we observed the highest prevalence (60%)with one or more Y-chromosome-positive cells in the thy-roids of patients with Hashimoto’s thyroiditis, followed by40%inGraves’diseaseandonly22.2%infollicularadenoma,indicating a higher degree of microchimerism in autoim-mune thyroid disease than in the benign proliferative dis-order. The immunogenetic susceptibility markers, HLADQA1*0501-DQB1*0201 and DQB1*0301, that are more fre-quent in patients with thyroid autoimmunity are also morecommon in patients of mother-child pairs with microchi-merism, raising the question of whether these histocompat-ibility alleles predispose to microchimerism  per se  or to thy-roid autoimmunity that may occur as a secondary event. Arecent observation of maternal circulating cells in the fetusduring pregnancy suggests an association of maternal HLADQB1*0301 with microchimerism (14). Therefore, an im-mune reaction against microchimeric cells could be targetedon the immunogenetic basis of an HLA-restricted peptide/antigen recognition leading in some cases to cross-immunityagainst thyroid cells.Whether this higher prevalence of microchimerism in thy-roid autoimmunity is mere coincidence or is a marker forimmune-mediated disease needs to be further investigated.The frequent postpartum thyroiditis during the first yearafter giving birth in women without previous thyroid auto-immunity and the exacerbation of such disorders in thosewith previous Graves’ disease and Hashimoto’s thyroiditisrepresent the most common immune deviations after preg-nancy (2). This may be due to an altered state of immunitythat is geared toward tolerance in pregnancy and switches back thereafter. The state of tolerance that is necessary for asuccessfulpregnancyisachievedthroughaThelpercelltype2immuneresponsebyanalternativeactivationofmonocytesthrough the expression of factors such as pregnancy-specificglycoprotein 1a (15). Therefore, antigen presentation is dif-ferent after childbirth, and persistent fetal-maternal micro-chimeric cells could cause alloimmunity derived from HLAhalf-mismatched cell-cell interaction.Fetal-maternal microchimerism may be detected up to 38yr postpartum (16), a phenomenon that has been studied insclerodermaorconnectivetissuesyndrome,whereupto26%of female patients may carry such cells compared with alower,butdetectable,frequencyinnormalwomenwithsons(17). In addition to pregnancies there are other sources of microchimerism, such as missed abortions, blood transfu-sions, bone marrow or organ transplants, or unrecognizedtwins. Fetal pluripotent stem cells or T lymphocyte precur-sors may persist and home in organs such as the thyroid,where they could induce an autoimmune reaction similar toa graft  vs.  host disease. Alternatively, these cells may berecognized as partially alloimmune and thus give rise to animmunereaction.Fetalmicrochimericcellsmaydifferentiateeven into cells with epithelial lineage; a recent report of asmall series of these found 14–60% of microchimeric cellsexpressing cytokeratin in three thyroid tissues derived fromgoiters (18). Although we did not detect microchimeric cellswith thyroid epithelial features, we cannot rule out such apossibility. This course of events would indicate that thesecells might process and present thyroid antigens and lead toorgan-specific autoimmunity. The immunogenetic suscepti- bility marker, HLA DQA1*0501-DQB1*0201, would therebyenhancethelikelihoodofanimmunereactiontargetedinthethyroid, thus explaining the high risk in women with thepredisposing HLA specificities of experiencing thyroid au-toimmunity after childbirth.However, our pilot study can only be seen as proof of principle. It needs to be extended to larger numbers to con-firm our findings and elucidate the mechanism by whichmicrochimerism is linked to thyroid autoimmunity and im-munogenetic risk.  Acknowledgments Received June 3, 2004. Accepted July 28, 2004.Address all correspondence and requests for reprints to: Dr. K. Ba-denhoop,DepartmentofInternalMedicineI,DivisionofEndocrinology,University Hospital Frankfurt, Theodor-Stern-Kai 7, D-60596 Frankfurtam Main, Germany. E-mail: badenhoop@em.uni-frankfurt.de.This investigation was made possible by funding of the EuropeanFoundation for the Study of Diabetes (EFSD) and the German DiabetesAssociation (DDG).C.R., E.R.L., and S.A.S.-G. contributed equally to this study. References 1.  Waller DK, Anderson JL, Lorey F, Cunningham GC  2000 Risk factors forcongenitalhypothyroidism:aninvestigationofinfant’sbirthweight,ethnicity,and gender in California, 1990–1998. Teratology 62:36–412.  Davies TF  1999 The thyroid immunology of the postpartum period. Thyroid9:675–6843.  Thellin O, Coumans B, Zorzi W, Igout A, Heinen E  2000 Tolerance to thefoeto-placental ‘graft:’ ten ways to support a child for nine months. Curr OpinImmunol 12:731–7374.  LeMaoult J, Krawice-Radanne I, Dausset J, Carosella ED  2004 HLA-G1-expressing antigen-presenting cells induce immunosuppressive CD4  T cells.Proc Natl Acad Sci USA 101:7064–70695.  Colonna M, Samaridis J, Cella M, Angman L, Allen RL, O’Callaghan CA,Dunbar R, Ogg GS, Cerundolo V, Rolink A  1998 Human myelomonocyticcells express an inhibitory receptor for classical and nonclassical MHC class Imolecules. J Immunol 160:3096–31006.  NavarroF,LlanoM,BellonT,ColonnaM,GeraghtyDE,Lopez-BotetM 1999The ILT2(LIR1) and CD94/NKG2A NK cell receptors respectively recognizeHLA-G1 and HLA-E molecules co-expressed on target cells. Eur J Immunol29:277–2837.  Rajagopalan S, Long EO  1999 A human histocompatibility leukocyte antigen(HLA)-G-specific receptor expressed on all natural killer cells. J Exp Med189:1093–11008.  Klintschar M, Schwaiger P, Mannweiler S, Regauer S, Kleiber M  2001 Ev-idence of fetal microchimerism in Hashimoto’s thyroiditis. 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Eur J Immunol 32:3405–341318.  KhosrotehraniK,JohnsonKL,ChaDH,SalomonRN,BianchiDW 2004Transferof fetal cells with multilineage potential to maternal tissue. JAMA 292:75–80  JCEM is published monthly by The Endocrine Society (http://www.endo-society.org), the foremost professional society serving the endocrinecommunity. 5814  J Clin Endocrinol Metab, November 2004, 89(11):5810–5814 Renne´  et al.  • Thyroid Fetal Male Microchimerisms
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