대한진단검사의학회지제 26 권제 3 호 2006 Korean J Lab Med 2006;26:198-203 원저 진단면역학 습관성유산환자단핵구에서의 CD56/CD16 항원표현과혈청 TNF-alpha 정량 김혜련 1 박애자 1 이미경 1 조동희 2 중앙대학교의과대학진단검사의학과교실 1, 성균관의대삼성제일병원진단검사의학과 2 CD56/CD16 Expression on Mononuclear Cells and Concentration of Serum TNF- Recurrent Spontaneous Abortion in Hye-Ryoun Kim, M.D. 1, Ae-Ja Park, M.D. 1, Mi-Kyung Lee, M.D. 1, and Dong-Hee Cho, M.D. 2 Departments of Laboratory Medicine, Chung-Ang University College of Medicine 1 and Sungkyunkwan University School of Medicine, Cheil General Hospital 2, Seoul, Korea Background : Recurrent spontaneous abortion (RSA) is defined as the occurrence of three or more consecutive spontaneous abortion before 20 gestational weeks. But, 40-50% of RSA still remain unexplained. Cytokines seem to play a critical role in the pathogenesis of unexplained RSA, and Th1 cytokines have been shown to exert deleterious effects on pregnancy. NK cytotoxicity has been reported to be predictive of subsequent abortion in women who had unexplained recurrent abortions. The aim of this study was to investigate immunophenotypic characteristics of peripheral blood mononuclear cells and evaluate Th1 cytokine (TNF- ) production in women with RSA. Methods : The study group comprised 93 women with RSA, and the control group consisted of 40 healthy pregnant women. The population of CD56/CD16 cells was observed by using a two-color scattergram in FACScan (Becton Dickinson, San Jose CA, USA). Concentration of TNF- was measured by an enzyme-linked immunoabsorbant assay (ELISA) using commercial kits (NEOGEN corporation, Lexington KY, USA). Results : The percentage of CD56+/CD16- cells were significantly higher (P<0.05) in the patients with RSA (13.40±7.95%) than in the pregnant control group (9.12±3.93%). We observed a significantly higher level of TNF- (medians: 85.59±8.29 pg/ml versus 44.80±9.78 pg/ml; P<0.05) in RSA women compared to controls. Conclusions : This study indicates that an increased proportion of CD56+/CD16- mononuclear cells and increased level of serum TNF- are related to RSA. Thus, the two factors could be used as an indicator of subsequent successful implantation and maintenance of gestation. (Korean J Lab Med 2006;26:198-203) Key Words : Recurrent spontaneous abortion, CD56+/CD16- mononuclear cell, Tumor necrosis factor- 접 수 : 2006년 2월 17일 접수번호 : KJLM1929 수정본접수 : 2006년 5월 22일 게재승인일 : 2006년 5월 23일 교신저자 : 박애자 우 140-757 서울시동작구흑석동 224-1 중앙대학교병원진단검사의학과 전화 : 02-6299-2718, Fax: 02-6263-6410 E-mail: ajcp@unitel.co.kr * 본논문은 2004학년도중앙대학교학술연구비지원에의한것임. 서론습관성유산은임신 20주이전에연속하여 3회이상임신이자연종료되는것을말한다 [1]. 이는임신의약 15% 에서생길수있는가장흔한합병증중의하나이며그중 50-60% 는태아의염색체이상, 감염, 모계의내분비적이상또는해부학적이상이원인이고그외 40-50% 는아직원인을알수없다 [2]. 모태면역계 198
RSA 에서 CD56/CD16 표현과 TNF- 의정량 199 의부계항원인지여부가임신유지에중요하며이를면역학적으로설명하나아직까진정상임신에서태아가모태의면역계로부터안전하게보호되는기전이모두밝혀지지는않았다 [3]. 면역에관여하는 T helper (Th) 세포들은시토카인 (cytokine) 을생성하며, 작용하는시토카인에따라 Th1과 Th2 림프구로나누어진다. 각각의시토카인들은습관성유산의병태생리에결정적인역할을할것으로생각되어지며, Th1 림프구에서생성하는시토카인들은태아의성장과발육을저해하고 Th2 림프구의시토카인들은성공적인임신에영향을주는것으로보고되고있다 [4, 5]. Hill 등은정상임신에서말초혈액의단핵세포를자극시켰을때 Th2에서 IL-4와 IL-10의분비가증가되고 Th1에서 IFN- 나 tumor necrosis factor-alpha (TNF- ) 의분비가관찰되지않아정상임신에서습관성유산보다 IL-4와 IL-10은증가되어있고 TNF- 의혈중농도는감소되어있었다고보고하였다 [6]. 말초혈액의자연살림프구는전체림프구의 4-10% 이며 3개의다른항원표현형으로나타난다. CD56+/CD16+ 와 CD56-/CD16+ 군이약 90% 를차지하며나머지는이두군에비하여세포독성이약한 CD56+/CD16-군인것으로알려져있다 [7]. 말초혈액의자연살림프구의양과활성도는습관성유산과관련이있어자연살림프구의기능적인분석이임신성공의감시와치료에유용하게사용되어져왔다 [8-10]. 면역항체나동종림프구의정맥주사치료는결과적으로자연살림프구의활성도를떨어뜨려임신을잘유지시켜주게되는것이며, 그중말초혈액 CD56+ 자연살림프구는습관성유산에서정상임신에비하여증가되어있어습관성유산환자에서임신실패여부를예견하는인자로쓸수있다고하였다 [11, 12]. 또한자연살림프구가 IFN-, TNF- 와 IL-2 등에의해 Lymphokine activated killer (LAK) 세포로전환되면영양막 (trophoblast) 를파괴시켜유산의원인이될수있다고도하였다 [13]. 이에본연구에서는습관성유산과정상산모의말초혈액에서 CD56과 CD16을측정하여습관성유산을예견할수있는인자로 RSA 10 3 E1 E2 단핵구중어떤세포표현형이의미가있는지알아보고자연살림프구가 LAK 세포로전환되는데영향을주는시토카인중하나인 TNF- 의정량검사를실시하여습관적유산예측인자로사용할수있는지를알아보려고하였다. 대상및방법 1. 대상 2004년 8월부터 2005년 8월까지본원에내원한임신 20주이전에 3회이상유산한경험이있는환자를습관성유산으로정의하여 93명을대상으로하였고이때유산경험이없는임산부 40 명을정상대조군으로하였다. 습관성유산환자군이나정상대조군모두정기적인검진을위해내원한경우를대상으로하였다. 습관성유산환자군의임신주수는 4주에서 12주사이에정상대조군은 7주에서 12주사이인초기임신 (first trimester) 상태에서검체를채취하였다. 습관성유산환자군은임신전에기본검사인자궁난관조영술, 복강경, 자궁내시경, 배란초음파검사, 배란 7 일후황체호르몬검사, 자궁내막검사, 자가항체검사 ( 항카디오리핀항체, 항핵항체, 항DNA 항체, 항갑상선글로부린항체, 루푸스항응고인자 ), 감염검사 (TORCH), 그리고부부의염색체검사등을시행하였다. 이런검사를통해염색체이상, 자궁의형태적이상, 내분비이상및감염에의한습관성유산등을제외시켰다. 2. 방법 1) 이중염색세포표지자를이용한 CD56과 CD16의분석두군의말초혈액을채혈하여각각의검체 100 L를튜브 (BD Falcon, Cat. No. 352008) 에넣고형광표지자가부착된단클론성항체 (Monoclonal Antobody: mab, Becton Dickinson, San Control 10 3 E1 E2 10 2 10 2 CD16-FITC 10 1 10 0 E3 E4 CD56+/CD16+ CD16-FITC 10 1 10 0 E3 E4 CD56+/CD16+ CD56+/CD16- CD56+/CD16-10 0 10 1 10 2 10 3 CD56 PE 10 0 10 1 10 2 10 3 CD56 PE Fig. 1. Two color flow cytometric analysis of peripheral mononuclear cells from recurrent spontaneous abortion and control individuals. The X-axis represents the CD56-PE and the y-axis the CD16-FITC. The percentage in the upper right represents the CD56+/CD16+ mononuclear cells, and the lower right quadrant represents the percentage of CD56+/CD16- mononuclear cells. Abbreviation: RSA, recurrent spontaneous abortion.
200 김혜련 박애자 이미경외 1 인 Jose CA, USA) 인항CD16-FITC와항CD56-PE를각각 20 L 씩검체에넣었고잘혼합후실온암소에서 20분간반응시켰다. 여기에 2 ml의 1 FACS lysing solution (X10, Cat. No. 349202, Becton Dickinson, San Jose CA, USA) 를넣고암소, 실온에서 10분간방치하여적혈구를용해시켰으며, 2 ml의 PBS 완충액으로 2회세척후 PBS 완충액 1 ml로세포를부유시켜 FACScan (Becton Dickinson) 를이용하여측정하고분석하였다 (Fig. 1). 데이터분석은 isotype control을포함하여 FACScan (Becton Dickinson) 에서 CellQuest TM 을이용하여분석하였다. 2) TNF-alpha 정량 TNF-alpha 농도는 TNF-alpha에대한토끼의다클론항인 TNF-alpha 항체를붙이고항토끼항체에대해발색을시켜측정하는 Sandwich ELISA (NEOGEN corporation, Lexington KY, USA) 방법으로측정하였다. 검체는혈청을이용하였으며측정한흡광도와양을알고있는표준곡선의흡광도와비교하여농도를구하였다. 3) 통계학적분석습관성유산환자군과대조군의단핵구항원과 TNF-alpha의농도의비교는 Student t-test를하였으며, 통계프로그램은 Microsoft Excel (Microsoft, Redmond, WA, USA) 을사용하였다. 자료는평균값 ± 표쥰편차로나타내었다. P<0.05이면유의한것으로판정하였다. 결 과 1. 습관성유산환자와대조군의비교 습관성유산군 93명과대조군 40명의평균연령과표준편차는각각 31.0±3.27년과 31.3±2.95년이었고, 임신주수에따른검체채취시기도 7.36±3.49주와 8.68±2.09주로통계학적차이는없었다 (P>0.05). 습관성유산환자군에서는검체채취후면역글로부 Table 1. Mononuclear cells in patients with a history of recurrent abortions and in control individuals Mononuclear cells RSA patients (n=93) % positive MN cells Controls (n=40) % positive MN cells Significance (P) CD56+ 23.78±8.59* 23.60±6.33 NS CD16+ 12.38±6.73 19.39±8.30 NS CD56+/CD16+ 10.40±6.61 14.35±5.21 P<0.05 CD56+/CD16-13.40±7.95 9.12±3.93 P<0.05 CD56-/CD16+ 1.99±1.35 5.06±4.27 NS *Expressed as mean±standard deviation; P<0.05, Significant difference in % positive mononuclear cells between the recurrent spontaneous abortion patients and the controls. Abbreviations: RSA, recurrent spontaneous abortion; MN, mononuclear; NS, statistically non significant. 린치료를받은경우도있었다. 습관성유산군과대조군에서각각 8명과 5명이추적검사를시행하지못해정상분만여부를확인할수없었으며추적검사결과습관성유산군에서 14명 (16.5%) 이대조군에서 2명 (5.7%) 이자연유산되었다. 2. 습관성유산환자와대조군의세포표현형비교 유세포분석기에서단핵구를대상으로이중염색표지방법으로측정한 CD56+ (CD56+/CD16+ 와 CD56+/CD16-의합계 ) 세포와 CD16+ (CD56+/CD16+ 와 CD56-/CD16+ 의합계 ) 세포의수는습관성유산환자군과대조군두군사이에통계학적의의가없었으나 (P>0.05), CD56+/CD16- 단핵구수는습관성유산환자군에서 13.40±7.95% 로, 대조군의 9.12±3.93% 보다유의하게증가되어있었다 (P<0.05). 또한 CD56+/CD16+ 단핵구수는습관성유산환자군에서 10.40±6.61% 로, 대조군의 14.35±5.21% 보다유의하게감소되어있었다 (P<0.05) (Table 1). 3. 습관성유산환자와대조군의시토카인 (TNF- ) 의비교 TNF-alpha의농도는환자군에서 85.59±8.29 (pg/ml) 와대조군에서 44.80±9.78 (pg/ml) 로환자군에서유의하게증가되어있었다 (P<0.05) (Fig. 2). 고 골수에서생성된자연살림프구는초기성숙과정중에말초혈액을순환하고이중인테그린 2 L (integrin 2 L ) 과상호작용을한림프구는말초혈액에남아있고탈락막혈관내피세포의세 pg/ml 500.0 450.0 400.0 350.0 300.0 250.0 200.0 150.0 100.0 50.0 0.0 Control Fig. 2. Distribution of TNF-alpha concentration in controls individuals and patients with recurrent spontaneous abortion. Median is indicated on the graph with a line. Abbreviation: RSA, recurrent spontaneous abortion. 찰 TMF-alpha RSA P<0.05
RSA 에서 CD56/CD16 표현과 TNF- 의정량 201 포내부착분자 1 (intracellular adhesion molecule-1) 과상호작용한자연살림프구는자궁내막과탈락막으로이동하는것으로생각되고있다 [14]. 말초혈액의자연살림프구는보통 CD56 항원과 CD16 항원을발현하고그외에도 CD94, CD69, CD128, CD122 그리고 CD25 등을발현하는것으로알려져있으나 [15], 세포독성이강한탈락막의 LAK 세포는전형적인자연살림프구항원인 CD56은발현하나 CD16, CD3과같은항원은발현하지않아말초혈액의자연살림프구와는다른항원표현형을가진다. 아직그정확한기능은밝혀지지않았으나과다한영양막의침입을조절하고국소감염을예방하며 [16], 착상과임신유지에중요한역할을하는것으로알려져있고임신초기가지난후에는감소하는것으로보고되고있다 [17]. 말초혈액과탈락막에있는자연살림프구의면역표현형은서로다르나말초혈액의단핵구중탈락막 LAK 세포와같은면역표현형을보이는세포가탈락막의 LAK 세포의기능적상태를반영할수있다고생각되어져검체채취가용이한말초혈액을사용한면역표현형연구가계속되고있다 [15]. 습관성유산환자의말초혈액에서 CD56+ 세포가정상임신군보다높다는보고가있으며유세포분석기의형광강도에따라 CD56의발현을 bright와 dim으로나누어비교하는 CD56의아집단 (subset) 평가가중요하다는보고도있다 [18]. 본연구에서는말초혈액에서탈락막과자궁내막에나타나는 LAK 세포와같은면역표현형을가지는세포의존재를확인하기위하여 CD56과 CD16을이중염색을이용하여유세포분석기로분석하여보았다. 전체 CD56+ 또는 CD16+ 세포는습관성유산군과정상임신군에서차이를발견할수없었으나탈락막이나자궁내막의주림프구로알려져있는 CD56+/CD16-인 LAK 세포는습관성유산군에서의미있게증가되어있었다. 이는검체를얻기어려운탈락막이나자궁내막에비하여말초혈액에서유세포분석기를이용해쉽게얻을수있는결과여서의미가있었으나말초혈액의단핵구를 bright와 dim CD56으로나눈분석은시도하였으나두군을명확히나눠줄수없어분석할수없었다. 습관성유산환자탈락막에서 CD69+/CD25+ T 세포가증가하였고말초혈액에서도 CD69+ 인자연살세포가습관성유산군에서증가되었다는보고는말초혈액에서나타나는항원이의미있게탈락막을반영할수있다는증거이다 [15, 19]. 이에말초혈액의 CD56+/CD16- 단핵구가탈락막의그것을반영해줄수있으며습관성유산환자군에서말초혈액의 CD56+/CD16- 단핵구항원을검사하여임신유지여부를예견할수있을것으로생각된다. 정상인말초혈액의 CD56+/CD16- 림프구는비교적세포독성이약한편으로알려져있으나습관성유산환자군의탈락막및말초혈액에서증가된 CD56+/CD16- 림프구는좀더강력한세포독성을보인다. 이는 CD56+/CD16- 림프구가다양한시토카인을분비하고또한그시토카인에대한수용체가있어시토카인이다시 CD56+/CD16- 림프구를활성화시키는것으로생각되어진다. 1993년 Th1 시토카인이 CD56+/CD16- 림프구를활성화시켜유산을유발하는것을보고하였고 IL-2가 CD56+/CD16- 림 프구에서영양막에대한세포독성을유발하는것을실험적으로도증명하였다 [20, 21]. 그래서 CD56+/CD16- 림프구의주기능은세포자체를파괴시키는것이아니라다양한시토카인을분비시켜이시토카인들이영양막들의성장을촉진, 저해하고또는영양막을공격하는탐식구 (macrophage) 를활성화시키기도한다는것이알려졌다 [22, 23]. 다양한연구에서습관성유산에서 Th1/Th2 시토카인의비를보고하였으며 Th1 시토카인은임신실패에 Th2 시토카인은임신유지에영향을준다고하며 Th1 시토카인중하나인 TNF- 는배아독성의원인이되기도한다 [24, 25]. TNF- 는프로스타글란딘의합성을증가시키고프로스타글란딘은자궁수축을시작시키며세포자멸사를초래하고혈관에혈전을일으켜배아로가는혈류를감소하게한다. 이런결과로 TNF- 는유산에중요하며 TNF- 치가증가되어있는것이유산을미리예견할수있는인자로생각되어진다 [25]. 또한 Th2 시토카인의경우는태반의발달과임신유지에중요하다는연구도있지만의미있게차이가없다는연구도있다 [26, 27]. 이에결론적으로 TNF- 의증가가다른 Th2 시토카인의감소보다임신실패에치명적인인자로생각되어진다. 본실험에서도 TNF- 치가습관성유산환자에서정상임신군에비해의미있게증가했으며이결과는 TNF- 를포함한 Th1 면역이반복유산에서중요한작용을한다는그전의결과들을뒷받침해주는결과로생각된다. 결론적으로습관성유산군과정상대조군에서유산을예견하는지표로총 CD56+ 단핵구를단독으로측정하는것보다이중염색을이용하여 CD56+/CD16- 단핵구를측정하는것이더효과적일것으로사료되며혈청내 TNF- 의정량은유산을예견할수있는단독시토카인으로중요하나향후임신주수에따른추가검사나다른시토카인과함께검사를시도하여분석할필요가있다고생각된다. 요약배경 : 습관성유산은임신 20주이전에연속하여 3회이상임신이자연종료되는것을말한다. 아직 40-50% 에서정확한원인을알수는없으나시토카인이중요한인자로인식되어있다. Th1 시토카인은임신에유해하고자연살림프구의세포독성도임신유지에영향을미쳐유산예견인자로사용할수있다고한다. 본연구에서는습관성유산군에서말초혈액단핵구에서항원의특성과 Th1 (TNF- ) 생성의차이를알아보고자하였다. 방법 : 3회이상의유산경험이있는습관성유산환자 93명과정상대조군으로건강산모 40명을대상으로하였다. 말초혈액에서 CD56과 CD16은단핵구를각각의형광항체로이중염색을시행한후 FACScan (Becton Dickinson, San Jose CA, USA) 으로측정하고분석하였다. 혈청 TNF- 정량은 ELISA (NEOGEN corporation, Lexington KY, USA) 방법으로측정하였다.
202 김혜련 박애자 이미경외 1 인 결과 : 단핵구에서 CD56+/CD16-의항원은습관성유산군이정상대조군보다유의하게증가되어있었다 (13.40±7.95% vs 9.12±3.93%, P<0.05). 또한혈청 TNF- 의농도도습관성유산환자군이정상대조군에비해증가된소견이었다 (85.59±8.29 pg/ ml vs 44.80±9.78 pg/ml, P<0.05). 결론 : 본연구결과습관성유산에서말초혈액내 CD56+/ CD16- 단핵구와혈청 TNF- 의양이의미있게증가되어있어, 임산부에서이두인자를성공적인임신유지여부를예견할수있는지표로이용할수있을것으로생각되었다. 참고문헌 1. Regan L and Rai R. Epidemiology and the medical causes of miscarriage. Baillieres Best Pract Res Clin Obstet Gynaecol 2000;14:839-54. 2. Druckmann R and Druckmann MA. Progesterone and the immunology of pregnancy. J Steroid Biochem Mol Biol 2005;97:389-96. 3. Laird SM, Tuckerman EM, Cork BA, Linjawi S, Blakemore AI, Li TC. A review of immune cells and molecules in women with recurrent miscarriage. Hum Reprod Update 2003;9:163-74. 4. Raghupathy R. Th1-type immunity is incompatible with successful pregnancy. Immunol Today 1997;18:478-82. 5. Choudhury SR and Knapp LA. Human reproductive failure I: immunological factors. Hum Reprod Update 2001;7:113-34. 6. Hill JA, Polgar K, Anderson DJ. T-helper 1-type immunity to trophoblast in women with recurrent spontaneous abortions. J Am Med Assoc 1995;273:1933-6. 7. King A, Hiby SE, Verma S, Burrows T, Gardner L, Loke YW. Uterine NK cells and trophoblast HLA class I molecules. Am J Reprod Immunol 1997;37:459-62. 8. Aoki K, Kajiura S, Matsumoto Y, Ogasawara M, Okada S, Yagami Y, et al. Preconceptional natural-killer-cell activity as a predictor of miscarriage. Lancet 1995;345:1340-2. 9. Coulam CB, Goodman C, Roussev RG, Thomason EJ, Beaman KD. Systemic CD56+ cells can predict pregnancy outcome. Am J Reprod Immunol 1995;33:40-6. 10. Yamada H, Kato EH, Kobashi G, Ebina Y, Shimada S, Morikawa M, et al. High NK cell activity in early pregnancy correlates with subsequent abortion with normal chromosomes in women with recurrent abortion. Am J Reprod Immunol 2001;46:132-6. 11. Ruiz JE, Kwak JY, Baum L, Gilman-Sachs A, Beaman KD, Kim YB, et al. Intravenous immunoglobulin inhibits natural killer cell activity in vivo in women with recurrent spontaneous abortions. Am J Reprod Immunol 1996;35:370-5. 12. Ramhorst R, Agriello E, Zittermann S, Pando M, Larriba J, Irigoyen M, et al. Is the paternal mononuclear cells immunization a successful treatment for recurrent spontaneous abortion? Am J Reprod Immunol 2000;44:129-35. 13. Clark DA. Are there immune abortions? Res Immunol 1990;141:202-7. 14. Moller MJ, Kammerer R, von Kleist S. A distinct distribution of natural killer cell subgroups in human tissues and blood. Int J Cancer 1998;78:533-8. 15. Ntrivalas EI, Kwak-Kim JY, Gilman-Sachs A, Chung-Bang H, Ng SC, Beaman KD, et al. Status of peripheral blood natural killer cells in women with recurrent spontaneous abortions and infertility of unknown aetiology. Hum Reprod 2001;16:855-61. 16. Day CP, Grove J, Daly AK, Stewart MW, Avery PJ, Walker M. Tumour necrosis factor-alpha gene promoter polymorphism and decreased insulin resistance. Diabetologia 1998;41:430-4. 17. King A, Wellings V, Gardner L, Loke YW. Immunocytochemical characterization of the unusual large granular lymphocytes in human endometrium throughout the menstrual cycle. Hum Immunol 1989; 24:195-205. 18. Lachapelle MH, Miron P, Hemmings R, Roy DC. Endometrial T, B, and NK cells in patients with recurrent spontaneous abortion. Altered profile and pregnancy outcome. J Immunol 1996;156:4027-34. 19. Vassiliadou N, Searle RF, Bulmer JN. Elevated expression of activation molecules by decidual lymphocytes in women suffering spontaneous early pregnancy loss. Hum Reprod 1999;14:1194-200. 20. Wegmann TG, Lin H, Guilbert L, Mosmann TR. Bidirectional cytokine interactions in the maternal-fetal relationship; is successful pregnancy a TH2 phenomenon? Immunol Today 1993;14:353-6. 21. Ferry BL, Sargent IL, Starkey PM, Redman CW. Cytotoxic activity against trophoblast and choriocarcinoma cells of large granular lymphocytes from human early pregnancy decidua. Cell Immunol 1991; 132:140-9. 22. Loke YW and King A. Immunology of human placental implantation: clinical implications of our current understanding. Mol Med Today 1997;3:153-9. 23. Hunt JS and Robertson SA. Uterine macrophages and environmental programming for pregnancy success. J Reprod Immunol 1996; 32:1-25. 24. Carp HJ, Toder V, Mashiach S, Nebel L, Serr DM. Recurrent miscarriage: a review of current concepts, immune mechanisms, and results of treatment. Obstet Gynecol Surv 1990;45:657-69. 25. Gilstrap LC 3rd, Hauth JC, Bell RE, Ackerman NB Jr, Yoder BA, Delemos R. Survival and short-term morbidity of the premature neonate. Obstet Gynecol 1985;63:37-41. 26. Arslan E, Colakoglu M, Celik C, Gezginc K, Acar A, Capar M, et al. Serum TNF-, IL-6, Lupus anticoagulant and anticardiolipin antibody in women with and without a past history of recurrent miscarriage. Arch Gynecol Obstet 2004;270:227-9.
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