- Email: [email protected]
Menstruation protects women from B-cell chronic lymphocytic leukemia
Bioscience Hypotheses (2009) 2, 257e260
available at www.sciencedirect.com
journal homepage: www.elsevier.com/locate/bihy
Menstruation protects women from B-cell chronic lymphocytic leukemia ¨chler* M. Du Department of Toxicology and Carcinogenesis, Nofer Institute of Occupational Medicine, _ Poland 8 Sw. Teresy Street, 91-348 Ło´dz, Received 16 February 2009; accepted 28 February 2009
KEYWORDS B-cell chronic lymphocytic leukemia; Menstruation; Sex-related risk; CD23
Abstract B-cell chronic lymphocytic leukemia (B-CLL) affects women and men with different frequency: men show a more than double as high risk to acquire this disease than women. The reason for this sex-related difference is unknown. It is proposed here that menstruation confers advantages to women in two ways: i) early stage B-CLL cells and/or their potential precursors are partially removed from the body with menstrual bleeding which includes shedding of endometrial tissue; and ii) during degradation of the remaining endometrial tissue an immune response against B-CLL is triggered. The regular reduction of potential B-CLL cells throughout pre-menopausal life as well as the immunization against B-CLL would enable the female organism to better control outbreak and course of the disease. Both processes depend on specific binding of the leukemic cells to the endometrial tissue. CD23 expressed on the surface of B-CLL cells is suggested to mediate binding to the vitronectin receptor/CD47 expressed on endometrium. The menstrual inflammatory process includes danger signals that might facilitate initiation of an anti-leukemia immune response. Menstrual immunization might explain sex-related differences in clinical features of other malignancies as well and might therefore have broad implications for the development of individualized therapies. ª 2009 Elsevier Ltd. All rights reserved.
Introduction B-cell chronic lymphocytic leukemia is the most common leukemia in the Western hemisphere [1]. The typical course of the disease is characterized by the accumulation of monoclonal CD5/CD19/CD23-positive resting B cells, exhibiting
* Tel.: þ48 42 631 45 04, 661 859147(mobile); fax: þ48 42 656 83 31. E-mail address: [email protected]
a defect in initiating apoptosis. The origin of the malignant clone in B-CLL is still not unambiguously identified. In about 3.5% of otherwise healthy persons, a small population of B cells with B-CLL phenotype is detectable [2] which are considered as potential B-CLL precursor cells [3]. As in B-CLL, subclinical disease was also detected in myeloma and follicular lymphoma, as well as other B-cell disorders, suggesting that common chronic lymphoproliferative disorders have a premalignant counterpart [4]. The risk of developing CLL increases progressively with age. Interestingly, incidence for getting B-CLL is 2.8 times
1756-2392/$ - see front matter ª 2009 Elsevier Ltd. All rights reserved. doi:10.1016/j.bihy.2009.02.010
258
M. Du ¨chler
higher for men than for women [5]. The reason for this sexrelated risk difference is an open question since decades. So far, genetic, molecular and hormonal differences were considered as potential cause [6] but the final answer is still lacking [7].
and specificity to the endometrium. Part of them would be removed from the body during menstruation together with endometrium. In advanced stages of the disease, sCD23 would block the interaction of VnR with cell surface CD23 and prevent B-CLL cell clearance.
The hypothesis
Immunization against B-CLL during menstruation
To explain the sex-related risk to acquire B-CLL it is proposed that menstruation promotes the superior survival of women in two ways. Firstly, early stage B-CLL cells and/ or their potential precursors are removed from women’s bodies with menstrual bleeding. Secondly, women achieve an immune response against B-CLL during endometrial tissue degradation.
The suggested removal of B-CLL-like cells to explain the female advantage has some shortcomings. It can account for reduced leukemia risk only during the part of life with active menstrual cycle. After menopause, the advantage for women would cease. B-CLL mainly occurs in elderly women and men, at a time when reproductive cycling is over. Even if women start their post-menopausal life period with a much lower level of B-CLL precursor cells than men their advantage would not last long enough to explain the risk difference 10 or 20 years later. In addition, not only reduced incidence but also superior survival has been reported for female patients with B-CLL [13]. Therefore, a second mechanism is proposed to explain how menstruation might confer its advantage. Menstruation occurs as an inflammatory process during which endometrial tissue is disintegrated, mainly by matrix metalloproteinases which are activated in the endometrium [14]. Prior to and during menstruation, the human endometrium contains high numbers of neutrophils, eosinophils, and macrophages, likely to be critical for inflammatory endometrial destruction [12]. It is assumed that endometrial cells and tissue which is not removed with menstrual bleeding are effectively taken up by macrophages [15]. Macrophages also express VnR which participates in phagocytosis of apoptotic neutrophils at sites of inflammation [16,17]. In a similar way, B-CLL-like cells associated with endometrium could be engulfed by macrophages. As macrophages are professional antigen presenting cells presentation of leukemia-related antigens derived from B-CLL-like cells might stimulate an immune response against B-CLL which would help to control disease initiation and progression. Also immature dendritic cells were described to migrate into the uterus during the menstrual phase [18] and might be involved in the activation of the immune system. Stimulation of immune responses is most efficient under the influence of danger signals which can be given by extracellular-matrix breakdown products or inflammatory signals [19,20]. Inflammation and disintegration of endometrium result in a wealth of danger signals thus constituting an ideal surrounding for effective immunization.
The clearance of the female blood from B-CLL-like cells B-CLL is a slowly developing disease and monthly removal of early stage B-CLL cells or their potential precursors (which consequently will be summarized as ‘B-CLL-like cells’) could significantly slow down disease outbreak. On average, about 1% of total blood is lost during menstruation. This amount is too small to account for any significant reduction of B-CLL-like cells. But menstruation also includes shedding of the endometrial lining that appears as tissue mixed with the blood. If B-CLL-like cells would bind with high affinity to the endometrium before its shedding a substantial amount of them could be removed every month during subclinical disease. Until onset of menopause, the level of potential leukemic cells could be kept at significant lower levels than in men. Is there any indication that B-CLL-like cells would bind to the endometrium? A prominent feature of B-CLL cells is the overexpression of the transmembrane glycoprotein CD23. CD23 is also shed from the surface giving rise to soluble CD23 (sCD23) which is detected in high concentrations in sera from patients with B-CLL and reflects disease activity and tumor load [8]. In 1999, the group leaded by M. Sarfati demonstrated that the vitronectin receptor (VnR) in association with CD47 binds sCD23 [9]. VnR is a member of the integrin family composed from alpha V and beta 3 chains. CD47 (IAP, integrin associated protein) is a multispan transmembrane receptor which physically and functionally associates with VnR. sCD23 directly binds to VnR, but coexpression of CD47 increases binding [9]. On endometrium, integrins are dynamically expressed and have been largely accepted as markers of uterine receptivity [10]. In a study by Nardo et al. [11], VnR expression was detected on all biopsy specimens taken from endometrium at postovulatory day 8. VnR appears during the opening of the putative window of implantation and seems to be important for blastocyst implantation. Thus, VnR expression is highest during the time preceding menstruation. Although B-cells are not a major population among leukocytes in endometrium small numbers of normal B-cells have been detected demonstrating their presence in this tissue [12]. The suggested interaction of surface CD23 of B-CLL cells with VnR/CD47 would be an attractive possibility how B-CLL-like cells could bind with high affinity
Critical evaluation of the hypothesis Careful analysis of population-based registry of leukemias and lymphomas revealed three ‘peaks’ of male-to-female risk ratio for B-CLL: around the age of 40, of 60 and of 75 years [21]. The proposed hypothesis fits almost perfectly to this observation. Removal of a substantial amount of B-CLLlike cells every month before menopause could account for the reduced incidence of disease outbreak around the age of 40. During post-menopausal life, the immune memory would favour women over men at higher age.
Menstruation protects women from B-CLL The high expression of CD23 on B-CLL-like cells and the expression of its counter receptor VnR on endometrium especially during the period preceding menstruation may explain why B-CLL-like cells could bind with higher affinity than other leukocytes. CD47 is ubiquitously expressed in all tissues including placenta [22]. CD23 can bind VnR also without its associated CD47 although with lower affinity [9]. So far, binding to VnR/CD47 was demonstrated for soluble CD23 only, not for CD23 molecules expressed at the cell surface. The proposed high affinity binding B-CLL cells to endometrium via CD23 is therefore purely hypothetical. As an alternative, chemokines which are produced in high concentrations in endometrial tissue to attract migratory leukocytes before menstruation might also attract leukemic cells. For example, the chemokine receptors CCR1 and CCR3 are expressed on B-CLL cells and the chemokines CXCL12 and CXCL13 are able to trigger their migration [23]. How likely is the proposed ‘menstrual immunization’ to occur? Among other factors, efficient immunization requires that danger signals coincide with antigen exposure. Accumulation of leukemic cells and the inflammatory conditions during endometrial tissue breakdown might facilitate priming of immune responses which would otherwise not easily occur. Furthermore, the periodical occurrence of menstruation through many years would greatly increase the probability for immunization to take place.
259 Several studies have reported families with an increased risk for B-CLL indicative of an inherited predisposition. The frequency of B-CLL precursor cells was higher in members of such families (13.5%) than in average population (3.5%) [4]. If it turns out that menstruation really clears the bloodstream from B-CLL-like cells, people with a genetic predisposition for B-CLL could benefit from regular application of a mechanistically similar ‘cleaning’ procedure. Sex-specific differences in clinical features are commonly observed in a variety of cancers including hematological malignancies [4,21]. Mainly female survival advantages are observed. Eventually, menstrual immunization occurs not only for B-CLL but other leukemias as well. The proposed hypothesis therefore might have broad impact on understanding sex-related differences and the development of individualized therapies.
Acknowledgement The author would like to thank Malgorzata Czyz for helpful discussions.
Conflict of interest I declare that there are no conflicts of interest of any kind.
References Testing the hypothesis The most direct way to test the proposed hypothesis is the demonstration of interaction and binding of B-CLL-like cells to endometrium with relatively high affinity. The blood of about 3.5% of seemingly healthy people contains B-cells which share the phenotype with B-CLL cells [2]. In women possessing such B-CLL-like cells their binding to endometrium could be verified by isolating lymphocytes from endometrial tissue shedded during normal menstruation and analyzing their surface antigen expression by flow cytometry. Cells with high CD23 surface expression should be enriched in the isolate. Furthermore, stimulation of an immune response might be demonstrated with isolated B-CLL cells in mixed lymphocyte cultures.
Consequences of the hypothesis One major obstacle for successful therapy of B-CLL is the heterogeneity of this disease. Major improvements are expected when standard treatment uniformly applied to large groups of patients is replaced by more individualized therapeutic approaches. Understanding sex-related differences in disease control will facilitate to better tailor treatment modalities to sex. As a consequence from the menstrual immunization hypothesis, therapy for women could put an accent on strengthening the pre-existing immune response. The manifestation of B-CLL mainly in mature life might be the consequence of the compromised immune control in aged people [24]. Menstrual immunization would underline the importance of immune protection not only to withstand disease outbreak but also to prolong post-chemotherapeutic survival.
[1] Dighiero G, Hamblin TJ. Chronic lymphocytic leukemia. Lancet 2008;371:1017e29. [2] Rawstron AC, Green MJ, Kuzmicki A, et al. Monoclonal Blymphocytes with the characteristics of ‘‘indolent’’ chronic lymphocytic leukemia are present in 3.5% of adults with normal blood counts. Blood 2002;100:635e9. [3] Caligaris-Cappio F, Ghia P. Novel insights in chronic lymphocytic leukemia: are we getting closer to understanding the pathogenesis of the disease? J Clin Oncol 2008;26:4497e503. [4] Rawstron AC, Yuille MR, Fuller J, et al. Inherited predisposition to CLL is detectable as subclinical monoclonal B-lymphocyte expansion. Blood 2002;100:2289e91. [5] Diehl LF, Hynds Karnell L, Menck HR. The National Cancer Data base Report on age, gender, treatment, and outcomes of patients with chronic lymphocytic leukemia. Cancer 1999;86: 2684e92. [6] Oscier DG, Gardiner AC, Mould SJ, et al. Multivariate analysis of prognostic factors in CLL: clinical stage, IGVH gene mutational status, and loss or mutation of p53 gene are independent prognostic factors. Blood 2002;100:1177e84. [7] Hamblin TJ, Orchard JA, Davies ZA, et al. In chronic lymphocytic leukemia females survive longer than males even in patients with unmutated immunoglobulin genes. Blood 2004; 104:9a. [8] Schwarzmeier JD, Hubmann R, Du ¨chler M, Jaeger U, Shehata M. Regulation of CD23 expression by Notch2 in B-cell chronic lymphocytic leukemia. Leuk Lymphoma 2005;46:157e65. [9] Hermann P, Armant M, Brown E, et al. The vitronectin receptor and its associated CD47 molecule mediates proinflammatory cytokine synthesis in human monocytes by interaction with soluble CD23. J Cell Biol 1999;144:767e75. [10] Lessey BA, Ilesanmi AO, Lessey MA, Riben M, Harris JE, Chwalisz K. Luminal and glandular endometrial epithelium express integrins differentially throughout the menstrual cycle: implications for implantation, contraception, and infertility. Am J Reprod Immunol 1996;35:195e204.
260 [11] Nardo LG, Bartoloni G, Di Mercurio S, Nardo F. Expression of alpha(v)beta3 and alpha4 beta1 integrins throughout the putative window of implantation in a cohort of healthy fertile women. Acta Obstet Gynecol Scand 2002;81:753e8. [12] Salamonsen LA, Lathbury LJ. Endometrial leukocytes and menstruation. Hum Reprod Update 2000;6:16e27. [13] Molica S. Sex differences in incidence and outcome of chronic lymphocytic leukemia patients. Leuk Lymphoma 2006;47: 1477e80. [14] Salamonsen LA. Current concepts of the mechanisms of menstruation: a normal process of tissue destruction. Trends Endocrinol Metab 1998;9:305e9. [15] Santanam N, Murphy AA, Parthasarathy S. Macrophages, oxidation, and endometriosis. Ann N Y Acad Sci 2002;955: 183e98. [16] Fadok VA, Warner ML, Bratton DL, Henson PM. CD36 is required for phagocytosis of apoptotic cells by human macrophages that use either a phosphatidylserine receptor or the vitronectin receptor (avß3). J Immunol 1998;161:6250e7. [17] Ren Y, Stuart L, Lindberg FP, et al. Nonphlogistic clearance of late apoptotic neutrophils by macrophages: efficient
M. Du ¨chler
[18]
[19] [20] [21]
[22]
[23]
[24]
phagocytosis independent of beta 2 integrins. J Immunol 2001;166:4743e50. Schulke L, Manconi F, Markham R, Fraser IS. Endometrial dendritic cell populations during the normal menstrual cycle. Hum Reprod 2008;23:1574e80. Gallucci S, Matzinger P. Danger signals: SOS to the immune system. Curr Opin Immunol 2001;13:114e9. Matzinger P. The danger model: a renewed sense of self. Science 2002;296:301e5. Cartwright RA, Gurney AK, Mooreman AV. Sex ratios and risks of hematological malignancies. Br J Haematol 2002;118: 1071e7. Brown E, Hooper L, Ho T, Gresham H. Integrin-associated protein: a 50-kD plasma membrane antigen physically and functionally associated with integrins. J Cell Biol 1990;111: 2785e94. Trentin L, Cabrelle A, Facco M, et al. Homeostatic chemokines drive migration of malignant B cells in patients with nonHodgkin lymphomas. Blood 2004;104:502e8. Hakim FT, Gress RE. Immunosenescence: deficits in adaptive immunity in the elderly. Tissue Antigens 2007;70:179e89.
available at www.sciencedirect.com
journal homepage: www.elsevier.com/locate/bihy
Menstruation protects women from B-cell chronic lymphocytic leukemia ¨chler* M. Du Department of Toxicology and Carcinogenesis, Nofer Institute of Occupational Medicine, _ Poland 8 Sw. Teresy Street, 91-348 Ło´dz, Received 16 February 2009; accepted 28 February 2009
KEYWORDS B-cell chronic lymphocytic leukemia; Menstruation; Sex-related risk; CD23
Abstract B-cell chronic lymphocytic leukemia (B-CLL) affects women and men with different frequency: men show a more than double as high risk to acquire this disease than women. The reason for this sex-related difference is unknown. It is proposed here that menstruation confers advantages to women in two ways: i) early stage B-CLL cells and/or their potential precursors are partially removed from the body with menstrual bleeding which includes shedding of endometrial tissue; and ii) during degradation of the remaining endometrial tissue an immune response against B-CLL is triggered. The regular reduction of potential B-CLL cells throughout pre-menopausal life as well as the immunization against B-CLL would enable the female organism to better control outbreak and course of the disease. Both processes depend on specific binding of the leukemic cells to the endometrial tissue. CD23 expressed on the surface of B-CLL cells is suggested to mediate binding to the vitronectin receptor/CD47 expressed on endometrium. The menstrual inflammatory process includes danger signals that might facilitate initiation of an anti-leukemia immune response. Menstrual immunization might explain sex-related differences in clinical features of other malignancies as well and might therefore have broad implications for the development of individualized therapies. ª 2009 Elsevier Ltd. All rights reserved.
Introduction B-cell chronic lymphocytic leukemia is the most common leukemia in the Western hemisphere [1]. The typical course of the disease is characterized by the accumulation of monoclonal CD5/CD19/CD23-positive resting B cells, exhibiting
* Tel.: þ48 42 631 45 04, 661 859147(mobile); fax: þ48 42 656 83 31. E-mail address: [email protected]
a defect in initiating apoptosis. The origin of the malignant clone in B-CLL is still not unambiguously identified. In about 3.5% of otherwise healthy persons, a small population of B cells with B-CLL phenotype is detectable [2] which are considered as potential B-CLL precursor cells [3]. As in B-CLL, subclinical disease was also detected in myeloma and follicular lymphoma, as well as other B-cell disorders, suggesting that common chronic lymphoproliferative disorders have a premalignant counterpart [4]. The risk of developing CLL increases progressively with age. Interestingly, incidence for getting B-CLL is 2.8 times
1756-2392/$ - see front matter ª 2009 Elsevier Ltd. All rights reserved. doi:10.1016/j.bihy.2009.02.010
258
M. Du ¨chler
higher for men than for women [5]. The reason for this sexrelated risk difference is an open question since decades. So far, genetic, molecular and hormonal differences were considered as potential cause [6] but the final answer is still lacking [7].
and specificity to the endometrium. Part of them would be removed from the body during menstruation together with endometrium. In advanced stages of the disease, sCD23 would block the interaction of VnR with cell surface CD23 and prevent B-CLL cell clearance.
The hypothesis
Immunization against B-CLL during menstruation
To explain the sex-related risk to acquire B-CLL it is proposed that menstruation promotes the superior survival of women in two ways. Firstly, early stage B-CLL cells and/ or their potential precursors are removed from women’s bodies with menstrual bleeding. Secondly, women achieve an immune response against B-CLL during endometrial tissue degradation.
The suggested removal of B-CLL-like cells to explain the female advantage has some shortcomings. It can account for reduced leukemia risk only during the part of life with active menstrual cycle. After menopause, the advantage for women would cease. B-CLL mainly occurs in elderly women and men, at a time when reproductive cycling is over. Even if women start their post-menopausal life period with a much lower level of B-CLL precursor cells than men their advantage would not last long enough to explain the risk difference 10 or 20 years later. In addition, not only reduced incidence but also superior survival has been reported for female patients with B-CLL [13]. Therefore, a second mechanism is proposed to explain how menstruation might confer its advantage. Menstruation occurs as an inflammatory process during which endometrial tissue is disintegrated, mainly by matrix metalloproteinases which are activated in the endometrium [14]. Prior to and during menstruation, the human endometrium contains high numbers of neutrophils, eosinophils, and macrophages, likely to be critical for inflammatory endometrial destruction [12]. It is assumed that endometrial cells and tissue which is not removed with menstrual bleeding are effectively taken up by macrophages [15]. Macrophages also express VnR which participates in phagocytosis of apoptotic neutrophils at sites of inflammation [16,17]. In a similar way, B-CLL-like cells associated with endometrium could be engulfed by macrophages. As macrophages are professional antigen presenting cells presentation of leukemia-related antigens derived from B-CLL-like cells might stimulate an immune response against B-CLL which would help to control disease initiation and progression. Also immature dendritic cells were described to migrate into the uterus during the menstrual phase [18] and might be involved in the activation of the immune system. Stimulation of immune responses is most efficient under the influence of danger signals which can be given by extracellular-matrix breakdown products or inflammatory signals [19,20]. Inflammation and disintegration of endometrium result in a wealth of danger signals thus constituting an ideal surrounding for effective immunization.
The clearance of the female blood from B-CLL-like cells B-CLL is a slowly developing disease and monthly removal of early stage B-CLL cells or their potential precursors (which consequently will be summarized as ‘B-CLL-like cells’) could significantly slow down disease outbreak. On average, about 1% of total blood is lost during menstruation. This amount is too small to account for any significant reduction of B-CLL-like cells. But menstruation also includes shedding of the endometrial lining that appears as tissue mixed with the blood. If B-CLL-like cells would bind with high affinity to the endometrium before its shedding a substantial amount of them could be removed every month during subclinical disease. Until onset of menopause, the level of potential leukemic cells could be kept at significant lower levels than in men. Is there any indication that B-CLL-like cells would bind to the endometrium? A prominent feature of B-CLL cells is the overexpression of the transmembrane glycoprotein CD23. CD23 is also shed from the surface giving rise to soluble CD23 (sCD23) which is detected in high concentrations in sera from patients with B-CLL and reflects disease activity and tumor load [8]. In 1999, the group leaded by M. Sarfati demonstrated that the vitronectin receptor (VnR) in association with CD47 binds sCD23 [9]. VnR is a member of the integrin family composed from alpha V and beta 3 chains. CD47 (IAP, integrin associated protein) is a multispan transmembrane receptor which physically and functionally associates with VnR. sCD23 directly binds to VnR, but coexpression of CD47 increases binding [9]. On endometrium, integrins are dynamically expressed and have been largely accepted as markers of uterine receptivity [10]. In a study by Nardo et al. [11], VnR expression was detected on all biopsy specimens taken from endometrium at postovulatory day 8. VnR appears during the opening of the putative window of implantation and seems to be important for blastocyst implantation. Thus, VnR expression is highest during the time preceding menstruation. Although B-cells are not a major population among leukocytes in endometrium small numbers of normal B-cells have been detected demonstrating their presence in this tissue [12]. The suggested interaction of surface CD23 of B-CLL cells with VnR/CD47 would be an attractive possibility how B-CLL-like cells could bind with high affinity
Critical evaluation of the hypothesis Careful analysis of population-based registry of leukemias and lymphomas revealed three ‘peaks’ of male-to-female risk ratio for B-CLL: around the age of 40, of 60 and of 75 years [21]. The proposed hypothesis fits almost perfectly to this observation. Removal of a substantial amount of B-CLLlike cells every month before menopause could account for the reduced incidence of disease outbreak around the age of 40. During post-menopausal life, the immune memory would favour women over men at higher age.
Menstruation protects women from B-CLL The high expression of CD23 on B-CLL-like cells and the expression of its counter receptor VnR on endometrium especially during the period preceding menstruation may explain why B-CLL-like cells could bind with higher affinity than other leukocytes. CD47 is ubiquitously expressed in all tissues including placenta [22]. CD23 can bind VnR also without its associated CD47 although with lower affinity [9]. So far, binding to VnR/CD47 was demonstrated for soluble CD23 only, not for CD23 molecules expressed at the cell surface. The proposed high affinity binding B-CLL cells to endometrium via CD23 is therefore purely hypothetical. As an alternative, chemokines which are produced in high concentrations in endometrial tissue to attract migratory leukocytes before menstruation might also attract leukemic cells. For example, the chemokine receptors CCR1 and CCR3 are expressed on B-CLL cells and the chemokines CXCL12 and CXCL13 are able to trigger their migration [23]. How likely is the proposed ‘menstrual immunization’ to occur? Among other factors, efficient immunization requires that danger signals coincide with antigen exposure. Accumulation of leukemic cells and the inflammatory conditions during endometrial tissue breakdown might facilitate priming of immune responses which would otherwise not easily occur. Furthermore, the periodical occurrence of menstruation through many years would greatly increase the probability for immunization to take place.
259 Several studies have reported families with an increased risk for B-CLL indicative of an inherited predisposition. The frequency of B-CLL precursor cells was higher in members of such families (13.5%) than in average population (3.5%) [4]. If it turns out that menstruation really clears the bloodstream from B-CLL-like cells, people with a genetic predisposition for B-CLL could benefit from regular application of a mechanistically similar ‘cleaning’ procedure. Sex-specific differences in clinical features are commonly observed in a variety of cancers including hematological malignancies [4,21]. Mainly female survival advantages are observed. Eventually, menstrual immunization occurs not only for B-CLL but other leukemias as well. The proposed hypothesis therefore might have broad impact on understanding sex-related differences and the development of individualized therapies.
Acknowledgement The author would like to thank Malgorzata Czyz for helpful discussions.
Conflict of interest I declare that there are no conflicts of interest of any kind.
References Testing the hypothesis The most direct way to test the proposed hypothesis is the demonstration of interaction and binding of B-CLL-like cells to endometrium with relatively high affinity. The blood of about 3.5% of seemingly healthy people contains B-cells which share the phenotype with B-CLL cells [2]. In women possessing such B-CLL-like cells their binding to endometrium could be verified by isolating lymphocytes from endometrial tissue shedded during normal menstruation and analyzing their surface antigen expression by flow cytometry. Cells with high CD23 surface expression should be enriched in the isolate. Furthermore, stimulation of an immune response might be demonstrated with isolated B-CLL cells in mixed lymphocyte cultures.
Consequences of the hypothesis One major obstacle for successful therapy of B-CLL is the heterogeneity of this disease. Major improvements are expected when standard treatment uniformly applied to large groups of patients is replaced by more individualized therapeutic approaches. Understanding sex-related differences in disease control will facilitate to better tailor treatment modalities to sex. As a consequence from the menstrual immunization hypothesis, therapy for women could put an accent on strengthening the pre-existing immune response. The manifestation of B-CLL mainly in mature life might be the consequence of the compromised immune control in aged people [24]. Menstrual immunization would underline the importance of immune protection not only to withstand disease outbreak but also to prolong post-chemotherapeutic survival.
[1] Dighiero G, Hamblin TJ. Chronic lymphocytic leukemia. Lancet 2008;371:1017e29. [2] Rawstron AC, Green MJ, Kuzmicki A, et al. Monoclonal Blymphocytes with the characteristics of ‘‘indolent’’ chronic lymphocytic leukemia are present in 3.5% of adults with normal blood counts. Blood 2002;100:635e9. [3] Caligaris-Cappio F, Ghia P. Novel insights in chronic lymphocytic leukemia: are we getting closer to understanding the pathogenesis of the disease? J Clin Oncol 2008;26:4497e503. [4] Rawstron AC, Yuille MR, Fuller J, et al. Inherited predisposition to CLL is detectable as subclinical monoclonal B-lymphocyte expansion. Blood 2002;100:2289e91. [5] Diehl LF, Hynds Karnell L, Menck HR. The National Cancer Data base Report on age, gender, treatment, and outcomes of patients with chronic lymphocytic leukemia. Cancer 1999;86: 2684e92. [6] Oscier DG, Gardiner AC, Mould SJ, et al. Multivariate analysis of prognostic factors in CLL: clinical stage, IGVH gene mutational status, and loss or mutation of p53 gene are independent prognostic factors. Blood 2002;100:1177e84. [7] Hamblin TJ, Orchard JA, Davies ZA, et al. In chronic lymphocytic leukemia females survive longer than males even in patients with unmutated immunoglobulin genes. Blood 2004; 104:9a. [8] Schwarzmeier JD, Hubmann R, Du ¨chler M, Jaeger U, Shehata M. Regulation of CD23 expression by Notch2 in B-cell chronic lymphocytic leukemia. Leuk Lymphoma 2005;46:157e65. [9] Hermann P, Armant M, Brown E, et al. The vitronectin receptor and its associated CD47 molecule mediates proinflammatory cytokine synthesis in human monocytes by interaction with soluble CD23. J Cell Biol 1999;144:767e75. [10] Lessey BA, Ilesanmi AO, Lessey MA, Riben M, Harris JE, Chwalisz K. Luminal and glandular endometrial epithelium express integrins differentially throughout the menstrual cycle: implications for implantation, contraception, and infertility. Am J Reprod Immunol 1996;35:195e204.
260 [11] Nardo LG, Bartoloni G, Di Mercurio S, Nardo F. Expression of alpha(v)beta3 and alpha4 beta1 integrins throughout the putative window of implantation in a cohort of healthy fertile women. Acta Obstet Gynecol Scand 2002;81:753e8. [12] Salamonsen LA, Lathbury LJ. Endometrial leukocytes and menstruation. Hum Reprod Update 2000;6:16e27. [13] Molica S. Sex differences in incidence and outcome of chronic lymphocytic leukemia patients. Leuk Lymphoma 2006;47: 1477e80. [14] Salamonsen LA. Current concepts of the mechanisms of menstruation: a normal process of tissue destruction. Trends Endocrinol Metab 1998;9:305e9. [15] Santanam N, Murphy AA, Parthasarathy S. Macrophages, oxidation, and endometriosis. Ann N Y Acad Sci 2002;955: 183e98. [16] Fadok VA, Warner ML, Bratton DL, Henson PM. CD36 is required for phagocytosis of apoptotic cells by human macrophages that use either a phosphatidylserine receptor or the vitronectin receptor (avß3). J Immunol 1998;161:6250e7. [17] Ren Y, Stuart L, Lindberg FP, et al. Nonphlogistic clearance of late apoptotic neutrophils by macrophages: efficient
M. Du ¨chler
[18]
[19] [20] [21]
[22]
[23]
[24]
phagocytosis independent of beta 2 integrins. J Immunol 2001;166:4743e50. Schulke L, Manconi F, Markham R, Fraser IS. Endometrial dendritic cell populations during the normal menstrual cycle. Hum Reprod 2008;23:1574e80. Gallucci S, Matzinger P. Danger signals: SOS to the immune system. Curr Opin Immunol 2001;13:114e9. Matzinger P. The danger model: a renewed sense of self. Science 2002;296:301e5. Cartwright RA, Gurney AK, Mooreman AV. Sex ratios and risks of hematological malignancies. Br J Haematol 2002;118: 1071e7. Brown E, Hooper L, Ho T, Gresham H. Integrin-associated protein: a 50-kD plasma membrane antigen physically and functionally associated with integrins. J Cell Biol 1990;111: 2785e94. Trentin L, Cabrelle A, Facco M, et al. Homeostatic chemokines drive migration of malignant B cells in patients with nonHodgkin lymphomas. Blood 2004;104:502e8. Hakim FT, Gress RE. Immunosenescence: deficits in adaptive immunity in the elderly. Tissue Antigens 2007;70:179e89.