Original Paper Gynecol Obstet Invest 1992;34:27-30
Departments of Obstetrics and Gynecology and Parasitology. Yamagata University School of Medicine, Yamagata, Japan
Decreased Natural Killer Cell Activity in Women with Endometriosis
Key Words
Abstract
Endometriosis Natural killer cell activity Immunology
Natural killer (NK) cell activity is characterized by the spontaneous capacity of lymphoid cells derived from nonimmunized hosts to recognize and lyse certain tumor cell lines, virus-infected cells and transplanted tumor cell lines. Endometriosis is characterized by implantation and proliferation of autolo gous ectopic tissue in the pelvic cavity. Therefore, we focused on examining NK cell activity in women with endometriosis. NK cell activity in peripheral blood from women with endometriosis was lower than in women without endometriosis. On the basis of this finding, we analyzed also the effect of peripheral sera of women with endometriosis on NK cell activity. In the pres ence of peripheral sera of women with endometriosis. NK cell activity was significantly suppressed as compared with the sera of women without endo metriosis. The suppressive effect of sera of women with endometriosis on NK cell activity showed dose-dependent curves. These studies provide the specu lation that natural immunity mediated by NK cells may modulate the devel opment of endometrial implants.
Introduction
Natural killer (NK) cells are lymphoid cells that mani fest cytotoxic activity against certain virally infected cells and tumor cells without previous sensitization [1-3]. It has been reported afterwards that NK cells also play an important role in the rejection of transplanted tumor cells, the prevention of metastasis and in bone marrow graft rejection. The antitumor effect of NK cells is a kind of first line of a defense mechanism against a tumor nidus [3], Endometriosis is a disease characterized by tumor like ectopic growth of the autologous endometrium whose pathogenesis is poorly understood. Recently, an increas ing number of reports suggest that endometriosis is linked to abnormal immune function [4-8], We have thought that abnormal immune mechanisms may permit ectopic
Received: December 3. 1991 Accepted: January 10, 1992
endometrial implantation and proliferation, and so we have examined peripheral blood NK cell activity in women with endometriosis.
Materials and Methods Patients The subjects in this study were 56 women who underwent lapa roscopy as part of their infertility evaluation. The study groups con sisted of: (1) w'omen with evidence of endometriosis (n = 51; stage I; n= 12: stage II; n= 14; stageIII;n= 14; stage IV ;n= ll);(2)women with a normal pelvis (n = 48). Endometriosis was staged according to the revised American Fertility Society classification [21]. The age range for the endometriosis group was 25-39 years with a median of 31.5. and for the nonendometriosis group it was 24-40 years with a median of 32.4.
Hiichi Tanaka Department of Obstetrics and Gynecology Yamagata University School of Medicine 2-2-2 lida-nishi, Yamagata 990-23 (Japan)
©1992 S. Karger AG, Basel 0378-7346/92/0341-0027 $2.75/0
Downloaded by: UCL 144.82.238.225 - 12/18/2017 11:39:40 AM
Eiichi Tanakaa Fujiro Sendob Shinnosuke Kawagoea Masahiko Hiroia
Peripheral Serum Preparation A blood sample was drawn from a peripheral vein. The serum was separated and passed through a 0.22-pm cellulose-acetate millipore filter (Milliporc Co.. Mass. USA) and frozen at -7 0 °C until used.
Cytotoxic Assay The human NK assay was performed on 96-wcll microplates (167008; Nunc, Roskilde, Denmark) using the 4-hour 5lCr-release assay as previously described [9], The human cell line K562, derived from a patient with chronic myeloid leukemia in blast crisis, was used as the target for NK activity. Target cells adjusted to 1 X 107/ml were labeled with lOOpCi/ml ofN a 25lCr04 (New England Nuclear. Boston, Mass., USA) for 4 h at 37 °C and washed 3 times with mini mum essential medium (MEM). 51Cr-labeled target cells (5 X 10J in 0.1 ml) were mixed with effector cells (0.1 ml) at effector-target (E:T) ratios of 50:1 on the microplate totaling a volume of 0.2 ml. At the end of incubation, 0.1 ml of supernatant was aspirated, and radioac tivity was measured in a gamma counter (ARC-351: Aloka Co. Ltd., Tokyo, Japan). Each sample was tested in triplicate and each experi ment was repeated at least 3 times. Spontaneous release was deter mined by culturing labeled targets alone, and maximum release was determined by the addition of 1 N HC1 instead of effector cells. The percentage of lysis was calculated with the following formula: , . test cpm - spontaneous cpm w ,_ Percent lysis-------------------- - -------------- - ------ X 100. maximum cpm - spontaneous cpm Peripheral Blood NK Cell Activity in Endometriosis Peripheral blood NK cell activity was determined according to the 4-hour 5lCr-release assay. Peripheral blood mononuclear cells of patients with and without endometriosis were used as effector cells. Effect o f Peripheral Blood Serum o f Women with Endometriosis on NK Cel! Activity Mononuclear cells of male volunteers were incubated in RPMI 1640 supplemented with 5-40% sera of women with or with out endometriosis at 37 °C in a humidified atmosphere and 5%COj in air. After 20 h. the culture medium was removed. The cells were washed twice with PBS and used as effector cells for cytotoxicity assay. Statistical A nalysis All data are presented as the mean ± standard error (SE). The unpaired Student t test was used to calculate statistical significance.
28
l i i i iy Nonendometriosis
Fig. 1. Peripheral blood NK cell activity in women with and with out endometriosis. Mean ± SE was 18.2 ± 1.2 and 21.8 ± 1.3%, respectively (p < 0.05). NK cell activity was determined by cytotox icity assay. Effector cells were peripheral blood mononuclear cells from women with and without endometriosis. Target cells were K562. E:T ratio was 50:1. The unpaired Student’s t test was used to determine differences between means.
Results
Peripheral Blood NK Cell Activity in Women with Endometriosis
Peripheral blood mononuclear cell viability as assessed by trypan blue dye exclusion was greater than 95% in all samples studied. The concentration of peripheral blood mononuclear cells was not statistically different between women with and without endometriosis. Peripheral blood NK cell activity of women with or without endometriosis is shown in figure 1 (E:T ratios = 50:1). NK cell activity in women with endometriosis was lower than in women without endometriosis (18.1 ± 1.2 vs. 21.3 ± 1 .3 % ,p < 0.05). When endometriosis patients were subdivided ac cording to the stage of disease, there was no significant difference on NK cell activity among the various stages (data not shown). Effect o f Peripheral Sera o f Women with Endometriosis on NK Activity
Next, we studied also the effect of sera of patients with endometriosis on NK cell activity (fig. 2). Peripheral blood mononuclear cells from normal volunteers were incubated in RPMI 1640 medium supplemented with 540% sera of endometriosis patients for 20 h at 37 °C in a humidified atmosphere and 5% CCU in 95% air. NK cell
T anaka/Scndo/Kawagoe/Hiroi
Participation of NK Cells in the Pathogenesis of Endometriosis
Downloaded by: UCL 144.82.238.225 - 12/18/2017 11:39:40 AM
Lymphocyte Preparation Peripheral blood mononuclear cells were obtained from patients with and without endometriosis and from healthy male volunteers who were not taking medications and were free of disease. Peripheral blood mononuclear cells were prepared by Ficoll-hypaquc centrifu gation and depletion of plastic-adherent cells. Isolated cells were washed twice and resuspended in Roswell Park Memorial Institute (RPMI) 1640 medium (Gibco, Grand Island. N.Y., USA). The via bility of the cells was determined microscopically with trypan blue (viability was always > 90%). Mononuclear cells of women with and without endometriosis were used as effector cells. Mononuclear cells obtained from normal male volunteers were used when we examined the effect of peripheral sera of endometriosis patients on NK cell activity.
m
Endometriosis Nonendometriosis
0
1 5
1
I
10
I
1
I
20
1
T
40
Concentration of serum, %
Fig. 2. Effect of peripheral sera of women with and without endometriosis on NK cell activity. Mean ± SE was 14.0 ± 1.0 and 20.4 ± 1.4%. respectively (p < 0.01). NK cell activity was deter mined by cytotoxicity assay. Mononuclear cells of male volunteers were incubated in RPMI 1640 supplemented with 5-40% serum of women with or without endometriosis at 37 °C in humidified atmo sphere and 5% CCT in air. After 20 h, the culture medium was removed. The cells w'ere washed twice with PBS and used as effector cells for cytotoxicity assay. Target cells were K562. E:T ratio was 50:1. The unpaired Student's t test was used to determine differences between means.
Fig. 3. NK cell activity of mononuclear cells preincubated with sera of women with and without endometriosis at various concentra tions (5-40%). The symbols show the mean percent cytotoxicity and the vertical lines show SE. ■ = Endometriosis group (n = 10); • = nonendometriosis group (n = 10).
activity (E:T ratios = 50:1) was lower for mononuclear cells preincubated with peripheral sera of women with endometriosis than for those preincubated with sera of women without endometriosis (fig. 2). The suppressive effect of peripheral sera of endometriosis patients on NK cell activity was dose dependent (fig. 3). When analyzed individually, there was no relationship between the pe ripheral blood NK cell activity and the suppressive effect of peripheral serum in the same patient.
presence and proliferation of endometrial tissue outside the uterus [5, 18, 20], At the point of implantation of normal tissue on ectopic sites, endometriosis is similar to hamartoma. Some reports suggest that hamartoma may be associated with abnormal immune function [12-14], Moreover, de creased NK cell activity has been reported in hamartoma disease [12], In this study, we focused on examining NK cell activity in women with endometriosis which is characterized by tumor-like ectopic growth of autologous tissue, and we observed decreased NK cell activity in a majority of endometriosis patients. Moreover, we have demonstrated that there is a suppressive factor on NK cell activity in the sera of patients with endometriosis. Our hypothesis that NK cells may modulate the development of the endome triosis process was supported by our results. NK cells are a subpopulation of lymphoid cells with a spontaneous cytolytic activity against a variety of tumor cells and apparently against some normal cells as well [13, 10], There is growing evidence that NK cells play an important role in host resistance against cancer and virus
Discussion
The pathogenesis of endometriosis remains unclear. Although Sampson’s [11] theory that in some women the menstrual flow containing viable endometrial fragments is reversed and that these fragments are ‘regurgitated’ through the fallopian tubes and implant in ectopic loca tions in the pelvis has become generally accepted, it fails to explain completely why some women develop endome triosis and others do not. In recent years, abnormal immune response has been implicated in the cause of
29
Downloaded by: UCL 144.82.238.225 - 12/18/2017 11:39:40 AM
□
infections [4]. Besides their cytolytic activities, NK cells have been reported to regulate B-cell differentiation and immunoglobulin production. Some recent reports have described alterations in hu moral immunity in endometriosis [15-20]. Mathur et al. [15] have reported that antibody titers to the endometri um, ovary and theca and granulosa cells were higher in the sera of patients with endometriosis. Several investigators have detected immunoglobulins and immune complexes in the uterine endometrium of patients with endometrio sis [16-19], Autoimmune antibodies identified in pa tients with endometriosis include antiendometrial anti bodies, antinuclear antibodies, lupus anticoagulant and antiphospholipid antibodies. When considering the regu lation of B-cell differentiation and immunoglobulin pro duction by human NK cells, these reports may be linked
with decreased NK cell activity in patients with endome triosis. It is quite interesting to consider the possibility that decreased NK cell activity in patients with endome triosis not only permits ectopic endometrial implantation and proliferation, but also induces abnormal humoral immune responses. In conclusion, we found decreased activity of periph eral blood NK cells in most of the patients with endome triosis. In addition, the suppressive effect of sera of women with endometriosis on NK cell activity was found. It remains to be determined whether or not cytolytic activity against endometrial cells can be detected in vitro and to identify suppressive factors on NK cell activity from sera of endometriosis patients. Such studies are presently under way.
1 Herberman RB. Holden HT: Natural cell-me diated immunity. Adv Cancer Res 1978;27: 305-377. 2 Herberman RB. Djcu JY. Kay DH, Ortaldo JR. Riccardi C, Bonnard GD, Holden HT, Fagnani R. Santoni A. Puccetti P: Natural killer cells: Characteristics and regulation o f activity. Immunol Rev 1979;44:43-70. 3 Herberman RB: Augmentation of NK Activity: Natural Cell-Mediated Immunity against Tu mors. New York. Academic Press, 1980, pp 707-709. 4 Grimes DA. Lebolt SC. Grimes KR, Wingo PA: Systemic lupus erythematosus and repro ductive function: A case control study. Am J Obstet Gynecol 1985;153:179-186. 5 Gleicher N, Dmowski WP. Siegel I, Liu TL. Friberg J. Radwanska F. Toder V: Lymphocyte subsets in endometriosis. Obstet Gynecol 1984;63:463-466. 6 Haney AF. Muscato JJ. Weinberg JB: Perito neal fluid cell populations in infertility pa tients. Fcrtil Steril 1981:35:696-698. 7 Halme J. Becker S. Hammond MG, Raj MH, Raj S: Increased activation of pelvic macro phages in infertile women with mild endome triosis. Am J Obstet Gynecol 1983; 145:333337.
8 Fakih H, Baggett B. Holtz G. Tsang K-Y. Lee JC. Williamson HO: interleukin-1: A possible role in the infertility associated with endome triosis. Fertil Stcril 1987:47:213-217. 9 Timonen T. Sakscla E: Isolation of human NK cells by density gradient centifugation. J Im munol Methods 1980:36:285-291. 10 Welsh RM Jr: Cytotoxic cells induced during lymphocytic choriomeningitis virus infection of mice. I. Characterization of natural killer cell induction. J Exp Med 1978; 148:163-181. 11 Sampson JA: The life history of ovarian hema tomas (hemorrhagic cysts) of endometrial (Müllerian) type. Am J Obstet Gynecol 1922:4: 451-512. 12 Starink TM, Van Der Veen JP, Goldschmeding R: Decreased natural killer cell activity in Cowden’s syndrome (letter). J Am Acad Der matol 1986:15:294-296. ¡3 Halevy S. Sanbank M. Pick AI. Feurman EJ: Cowden’s disease in three siblings: Electronmicroscope and immunological studies. Acta Derm Venereol (Stockh) 1985;65:126-131. 14 Shohat B, Cohen 1. Fogel R, Zaizov R: Sup pressor mononuclear cells in giant lymph node hyperplasia and thymoma. Cancer 1981:48: 923-926.
15 Mathur S. Peress MR. Williamson HO, Youmans CD, Maney SA. Garvin AJ. Rust PE, Fuderberg HH: Autoimmunity to endome trium and ovary in endometriosis. Clin Exp Immunol 1982:50:259—266. 16 Badawy SZ, Cuenca V, Stitzel A, Jacobs RD. Tumar RH: Autoimmune phenomena in infer tile patients with endometriosis. Obstet Gyne col 1984:63:271-275. 17 Wild RA. Shivers CA: Antiendometrial anti bodies in patients with endometriosis. Am J Reprod Immunol Microbiol 1985:8:84-86. 18 Kreiner D. Fromowitz FB. Richardson DA. Kenigsbcrg D: Endometrial immunofluores cence associated with endometriosis and pelvic inflammatory disease. Fertil Steril 1986:46: 243-246. 19 Gleicher N. El-Roeiy A, Confino E. Friberg J: Is endometriosis an autoimmune disease? Ob stet Gynecol 1987:70:115-122. 20 Dmowski WP: Immunologic aspects of endo metriosis. Contrib Gynecol Obstet 1987:16: 48-55. 2 1 The American Fertility Society: Revised Amer ican Fertility Society classification of endome triosis. 1985. Fertil Steril 1985:43:351-352.
30
Tanaka/Scndo/Kawagoe/Hiroi
Participation of NK Cells in the Pathogenesis of Endometriosis
Downloaded by: UCL 144.82.238.225 - 12/18/2017 11:39:40 AM
References
Departments of Obstetrics and Gynecology and Parasitology. Yamagata University School of Medicine, Yamagata, Japan
Decreased Natural Killer Cell Activity in Women with Endometriosis
Key Words
Abstract
Endometriosis Natural killer cell activity Immunology
Natural killer (NK) cell activity is characterized by the spontaneous capacity of lymphoid cells derived from nonimmunized hosts to recognize and lyse certain tumor cell lines, virus-infected cells and transplanted tumor cell lines. Endometriosis is characterized by implantation and proliferation of autolo gous ectopic tissue in the pelvic cavity. Therefore, we focused on examining NK cell activity in women with endometriosis. NK cell activity in peripheral blood from women with endometriosis was lower than in women without endometriosis. On the basis of this finding, we analyzed also the effect of peripheral sera of women with endometriosis on NK cell activity. In the pres ence of peripheral sera of women with endometriosis. NK cell activity was significantly suppressed as compared with the sera of women without endo metriosis. The suppressive effect of sera of women with endometriosis on NK cell activity showed dose-dependent curves. These studies provide the specu lation that natural immunity mediated by NK cells may modulate the devel opment of endometrial implants.
Introduction
Natural killer (NK) cells are lymphoid cells that mani fest cytotoxic activity against certain virally infected cells and tumor cells without previous sensitization [1-3]. It has been reported afterwards that NK cells also play an important role in the rejection of transplanted tumor cells, the prevention of metastasis and in bone marrow graft rejection. The antitumor effect of NK cells is a kind of first line of a defense mechanism against a tumor nidus [3], Endometriosis is a disease characterized by tumor like ectopic growth of the autologous endometrium whose pathogenesis is poorly understood. Recently, an increas ing number of reports suggest that endometriosis is linked to abnormal immune function [4-8], We have thought that abnormal immune mechanisms may permit ectopic
Received: December 3. 1991 Accepted: January 10, 1992
endometrial implantation and proliferation, and so we have examined peripheral blood NK cell activity in women with endometriosis.
Materials and Methods Patients The subjects in this study were 56 women who underwent lapa roscopy as part of their infertility evaluation. The study groups con sisted of: (1) w'omen with evidence of endometriosis (n = 51; stage I; n= 12: stage II; n= 14; stageIII;n= 14; stage IV ;n= ll);(2)women with a normal pelvis (n = 48). Endometriosis was staged according to the revised American Fertility Society classification [21]. The age range for the endometriosis group was 25-39 years with a median of 31.5. and for the nonendometriosis group it was 24-40 years with a median of 32.4.
Hiichi Tanaka Department of Obstetrics and Gynecology Yamagata University School of Medicine 2-2-2 lida-nishi, Yamagata 990-23 (Japan)
©1992 S. Karger AG, Basel 0378-7346/92/0341-0027 $2.75/0
Downloaded by: UCL 144.82.238.225 - 12/18/2017 11:39:40 AM
Eiichi Tanakaa Fujiro Sendob Shinnosuke Kawagoea Masahiko Hiroia
Peripheral Serum Preparation A blood sample was drawn from a peripheral vein. The serum was separated and passed through a 0.22-pm cellulose-acetate millipore filter (Milliporc Co.. Mass. USA) and frozen at -7 0 °C until used.
Cytotoxic Assay The human NK assay was performed on 96-wcll microplates (167008; Nunc, Roskilde, Denmark) using the 4-hour 5lCr-release assay as previously described [9], The human cell line K562, derived from a patient with chronic myeloid leukemia in blast crisis, was used as the target for NK activity. Target cells adjusted to 1 X 107/ml were labeled with lOOpCi/ml ofN a 25lCr04 (New England Nuclear. Boston, Mass., USA) for 4 h at 37 °C and washed 3 times with mini mum essential medium (MEM). 51Cr-labeled target cells (5 X 10J in 0.1 ml) were mixed with effector cells (0.1 ml) at effector-target (E:T) ratios of 50:1 on the microplate totaling a volume of 0.2 ml. At the end of incubation, 0.1 ml of supernatant was aspirated, and radioac tivity was measured in a gamma counter (ARC-351: Aloka Co. Ltd., Tokyo, Japan). Each sample was tested in triplicate and each experi ment was repeated at least 3 times. Spontaneous release was deter mined by culturing labeled targets alone, and maximum release was determined by the addition of 1 N HC1 instead of effector cells. The percentage of lysis was calculated with the following formula: , . test cpm - spontaneous cpm w ,_ Percent lysis-------------------- - -------------- - ------ X 100. maximum cpm - spontaneous cpm Peripheral Blood NK Cell Activity in Endometriosis Peripheral blood NK cell activity was determined according to the 4-hour 5lCr-release assay. Peripheral blood mononuclear cells of patients with and without endometriosis were used as effector cells. Effect o f Peripheral Blood Serum o f Women with Endometriosis on NK Cel! Activity Mononuclear cells of male volunteers were incubated in RPMI 1640 supplemented with 5-40% sera of women with or with out endometriosis at 37 °C in a humidified atmosphere and 5%COj in air. After 20 h. the culture medium was removed. The cells were washed twice with PBS and used as effector cells for cytotoxicity assay. Statistical A nalysis All data are presented as the mean ± standard error (SE). The unpaired Student t test was used to calculate statistical significance.
28
l i i i iy Nonendometriosis
Fig. 1. Peripheral blood NK cell activity in women with and with out endometriosis. Mean ± SE was 18.2 ± 1.2 and 21.8 ± 1.3%, respectively (p < 0.05). NK cell activity was determined by cytotox icity assay. Effector cells were peripheral blood mononuclear cells from women with and without endometriosis. Target cells were K562. E:T ratio was 50:1. The unpaired Student’s t test was used to determine differences between means.
Results
Peripheral Blood NK Cell Activity in Women with Endometriosis
Peripheral blood mononuclear cell viability as assessed by trypan blue dye exclusion was greater than 95% in all samples studied. The concentration of peripheral blood mononuclear cells was not statistically different between women with and without endometriosis. Peripheral blood NK cell activity of women with or without endometriosis is shown in figure 1 (E:T ratios = 50:1). NK cell activity in women with endometriosis was lower than in women without endometriosis (18.1 ± 1.2 vs. 21.3 ± 1 .3 % ,p < 0.05). When endometriosis patients were subdivided ac cording to the stage of disease, there was no significant difference on NK cell activity among the various stages (data not shown). Effect o f Peripheral Sera o f Women with Endometriosis on NK Activity
Next, we studied also the effect of sera of patients with endometriosis on NK cell activity (fig. 2). Peripheral blood mononuclear cells from normal volunteers were incubated in RPMI 1640 medium supplemented with 540% sera of endometriosis patients for 20 h at 37 °C in a humidified atmosphere and 5% CCU in 95% air. NK cell
T anaka/Scndo/Kawagoe/Hiroi
Participation of NK Cells in the Pathogenesis of Endometriosis
Downloaded by: UCL 144.82.238.225 - 12/18/2017 11:39:40 AM
Lymphocyte Preparation Peripheral blood mononuclear cells were obtained from patients with and without endometriosis and from healthy male volunteers who were not taking medications and were free of disease. Peripheral blood mononuclear cells were prepared by Ficoll-hypaquc centrifu gation and depletion of plastic-adherent cells. Isolated cells were washed twice and resuspended in Roswell Park Memorial Institute (RPMI) 1640 medium (Gibco, Grand Island. N.Y., USA). The via bility of the cells was determined microscopically with trypan blue (viability was always > 90%). Mononuclear cells of women with and without endometriosis were used as effector cells. Mononuclear cells obtained from normal male volunteers were used when we examined the effect of peripheral sera of endometriosis patients on NK cell activity.
m
Endometriosis Nonendometriosis
0
1 5
1
I
10
I
1
I
20
1
T
40
Concentration of serum, %
Fig. 2. Effect of peripheral sera of women with and without endometriosis on NK cell activity. Mean ± SE was 14.0 ± 1.0 and 20.4 ± 1.4%. respectively (p < 0.01). NK cell activity was deter mined by cytotoxicity assay. Mononuclear cells of male volunteers were incubated in RPMI 1640 supplemented with 5-40% serum of women with or without endometriosis at 37 °C in humidified atmo sphere and 5% CCT in air. After 20 h, the culture medium was removed. The cells w'ere washed twice with PBS and used as effector cells for cytotoxicity assay. Target cells were K562. E:T ratio was 50:1. The unpaired Student's t test was used to determine differences between means.
Fig. 3. NK cell activity of mononuclear cells preincubated with sera of women with and without endometriosis at various concentra tions (5-40%). The symbols show the mean percent cytotoxicity and the vertical lines show SE. ■ = Endometriosis group (n = 10); • = nonendometriosis group (n = 10).
activity (E:T ratios = 50:1) was lower for mononuclear cells preincubated with peripheral sera of women with endometriosis than for those preincubated with sera of women without endometriosis (fig. 2). The suppressive effect of peripheral sera of endometriosis patients on NK cell activity was dose dependent (fig. 3). When analyzed individually, there was no relationship between the pe ripheral blood NK cell activity and the suppressive effect of peripheral serum in the same patient.
presence and proliferation of endometrial tissue outside the uterus [5, 18, 20], At the point of implantation of normal tissue on ectopic sites, endometriosis is similar to hamartoma. Some reports suggest that hamartoma may be associated with abnormal immune function [12-14], Moreover, de creased NK cell activity has been reported in hamartoma disease [12], In this study, we focused on examining NK cell activity in women with endometriosis which is characterized by tumor-like ectopic growth of autologous tissue, and we observed decreased NK cell activity in a majority of endometriosis patients. Moreover, we have demonstrated that there is a suppressive factor on NK cell activity in the sera of patients with endometriosis. Our hypothesis that NK cells may modulate the development of the endome triosis process was supported by our results. NK cells are a subpopulation of lymphoid cells with a spontaneous cytolytic activity against a variety of tumor cells and apparently against some normal cells as well [13, 10], There is growing evidence that NK cells play an important role in host resistance against cancer and virus
Discussion
The pathogenesis of endometriosis remains unclear. Although Sampson’s [11] theory that in some women the menstrual flow containing viable endometrial fragments is reversed and that these fragments are ‘regurgitated’ through the fallopian tubes and implant in ectopic loca tions in the pelvis has become generally accepted, it fails to explain completely why some women develop endome triosis and others do not. In recent years, abnormal immune response has been implicated in the cause of
29
Downloaded by: UCL 144.82.238.225 - 12/18/2017 11:39:40 AM
□
infections [4]. Besides their cytolytic activities, NK cells have been reported to regulate B-cell differentiation and immunoglobulin production. Some recent reports have described alterations in hu moral immunity in endometriosis [15-20]. Mathur et al. [15] have reported that antibody titers to the endometri um, ovary and theca and granulosa cells were higher in the sera of patients with endometriosis. Several investigators have detected immunoglobulins and immune complexes in the uterine endometrium of patients with endometrio sis [16-19], Autoimmune antibodies identified in pa tients with endometriosis include antiendometrial anti bodies, antinuclear antibodies, lupus anticoagulant and antiphospholipid antibodies. When considering the regu lation of B-cell differentiation and immunoglobulin pro duction by human NK cells, these reports may be linked
with decreased NK cell activity in patients with endome triosis. It is quite interesting to consider the possibility that decreased NK cell activity in patients with endome triosis not only permits ectopic endometrial implantation and proliferation, but also induces abnormal humoral immune responses. In conclusion, we found decreased activity of periph eral blood NK cells in most of the patients with endome triosis. In addition, the suppressive effect of sera of women with endometriosis on NK cell activity was found. It remains to be determined whether or not cytolytic activity against endometrial cells can be detected in vitro and to identify suppressive factors on NK cell activity from sera of endometriosis patients. Such studies are presently under way.
1 Herberman RB. Holden HT: Natural cell-me diated immunity. Adv Cancer Res 1978;27: 305-377. 2 Herberman RB. Djcu JY. Kay DH, Ortaldo JR. Riccardi C, Bonnard GD, Holden HT, Fagnani R. Santoni A. Puccetti P: Natural killer cells: Characteristics and regulation o f activity. Immunol Rev 1979;44:43-70. 3 Herberman RB: Augmentation of NK Activity: Natural Cell-Mediated Immunity against Tu mors. New York. Academic Press, 1980, pp 707-709. 4 Grimes DA. Lebolt SC. Grimes KR, Wingo PA: Systemic lupus erythematosus and repro ductive function: A case control study. Am J Obstet Gynecol 1985;153:179-186. 5 Gleicher N, Dmowski WP. Siegel I, Liu TL. Friberg J. Radwanska F. Toder V: Lymphocyte subsets in endometriosis. Obstet Gynecol 1984;63:463-466. 6 Haney AF. Muscato JJ. Weinberg JB: Perito neal fluid cell populations in infertility pa tients. Fcrtil Steril 1981:35:696-698. 7 Halme J. Becker S. Hammond MG, Raj MH, Raj S: Increased activation of pelvic macro phages in infertile women with mild endome triosis. Am J Obstet Gynecol 1983; 145:333337.
8 Fakih H, Baggett B. Holtz G. Tsang K-Y. Lee JC. Williamson HO: interleukin-1: A possible role in the infertility associated with endome triosis. Fertil Stcril 1987:47:213-217. 9 Timonen T. Sakscla E: Isolation of human NK cells by density gradient centifugation. J Im munol Methods 1980:36:285-291. 10 Welsh RM Jr: Cytotoxic cells induced during lymphocytic choriomeningitis virus infection of mice. I. Characterization of natural killer cell induction. J Exp Med 1978; 148:163-181. 11 Sampson JA: The life history of ovarian hema tomas (hemorrhagic cysts) of endometrial (Müllerian) type. Am J Obstet Gynecol 1922:4: 451-512. 12 Starink TM, Van Der Veen JP, Goldschmeding R: Decreased natural killer cell activity in Cowden’s syndrome (letter). J Am Acad Der matol 1986:15:294-296. ¡3 Halevy S. Sanbank M. Pick AI. Feurman EJ: Cowden’s disease in three siblings: Electronmicroscope and immunological studies. Acta Derm Venereol (Stockh) 1985;65:126-131. 14 Shohat B, Cohen 1. Fogel R, Zaizov R: Sup pressor mononuclear cells in giant lymph node hyperplasia and thymoma. Cancer 1981:48: 923-926.
15 Mathur S. Peress MR. Williamson HO, Youmans CD, Maney SA. Garvin AJ. Rust PE, Fuderberg HH: Autoimmunity to endome trium and ovary in endometriosis. Clin Exp Immunol 1982:50:259—266. 16 Badawy SZ, Cuenca V, Stitzel A, Jacobs RD. Tumar RH: Autoimmune phenomena in infer tile patients with endometriosis. Obstet Gyne col 1984:63:271-275. 17 Wild RA. Shivers CA: Antiendometrial anti bodies in patients with endometriosis. Am J Reprod Immunol Microbiol 1985:8:84-86. 18 Kreiner D. Fromowitz FB. Richardson DA. Kenigsbcrg D: Endometrial immunofluores cence associated with endometriosis and pelvic inflammatory disease. Fertil Steril 1986:46: 243-246. 19 Gleicher N. El-Roeiy A, Confino E. Friberg J: Is endometriosis an autoimmune disease? Ob stet Gynecol 1987:70:115-122. 20 Dmowski WP: Immunologic aspects of endo metriosis. Contrib Gynecol Obstet 1987:16: 48-55. 2 1 The American Fertility Society: Revised Amer ican Fertility Society classification of endome triosis. 1985. Fertil Steril 1985:43:351-352.
30
Tanaka/Scndo/Kawagoe/Hiroi
Participation of NK Cells in the Pathogenesis of Endometriosis
Downloaded by: UCL 144.82.238.225 - 12/18/2017 11:39:40 AM
References
