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Rapid Responses: Rapid Responses published:
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Natural killer cells, miscarriage, and infertility and nutritional deficiencies
- Ellen C G Grant (28 November 2004)
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A Timely Defence Against Exploitation
- Frances H Rushworth, Joanne Bibby, Consultant (29 November 2004)
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Re: A Timely Defence Against Exploitation
- Siobhan Quenby (29 November 2004)
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A timely rebuttal of internet advertised practices!
- Gerard CP CHAOUAT (5 December 2004)
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Uterine large granular lymphocytes are not natural killer cells
- Lionel Carbillon (11 December 2004)
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Infertility and IVF - Assessing activated NK cell numbers may be helpful
- Amolak Singh Bansal, Shree Bhaskaran, Brian Ford and Hassan Shehata (31 December 2004)
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Ellen C G Grant, physician and medical gynaecologist 20 Coombe Ridings, kingston-upon-Thames, KT2 7JU, UK
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Moffatt and colleagues’ conclusions, that peripheral blood measurements of natural killer (NK) cells, the main type of lymphocyte in the uterine mucosa at implantation and during early pregnancy, gives no useful information on uterine NK cells, and that the use of powerful therapies to reduce levels of NK cells in women with infertility or recurrent miscarriage is unjustified and is associated with known side effects to mother and fetus, are very welcome.1 Some of the hundreds of women I have screened for nutritional status have been alarmed to be told that they must be treated to reduce NK cells when they become pregnant. The reality is that the commonest abnormalities causing immune system dysfunction and impairing the activities of hundreds of enzymes in women with either unexplained infertility and/or recurrent miscarriages, are deficiencies of zinc, copper and magnesium.2,3 The monitored correction of such serious essential nutrient deficiencies results in a much higher success rate than the well documented success achieved with such patients simply using care and reassurance in a dedicated miscarriage clinic. This was, among 160 women, a next pregnancy miscarriage rate of 26% among women attending an early pregnancy clinic compared with 51% among non-attendants.4 In contrast, a low-allergy high-protein diet, together with monitored repletion of mineral, vitamin and essential fatty acid deficiencies gives excellent outcomes.2 In 1985 we had reported that 107 babies born to women with poor reproductive histories (mostly infertility and recurrent miscarriages) were normal after completing the Foresight programme and only two of them were premature.5 The 1997-1999 survey, which is available from Foresight, Godalming, Surrey, recorded a miscarriage rate of 3.2% for 779 conceptions. This was achieved by mostly using a hair analysis, which is less reliable than sweat or blood cells for diagnosing zinc, magnesium and copper deficiencies. Anyone interested in preventing miscarriages can easily replicate these results by using monitored nutritional repletion. Peripheral blood tests for white cell zinc and red cell magnesium concentrations and red cell superoxidase (SODase) function are available at a commercial laboratory in London. The cost is refundable to patients with private health insurance, if they also have systemic signs of immune dysfunction such as headaches, migraine or allergies. Many studies, including the very latest, listed in NBCI Pub Med, prove the importance of zinc, copper and magnesium and SODase deficiencies in numerous illnesses. The sharp increase in a range of serious childhood illnesses is appalling. It is puzzling if the largest miscarriage clinic in Europe omits to test for nutrient deficiencies before or during pregnancy. An important cause of nutritional deficiencies is the use of exogenous progesterones and oestrogens and fertility drugs. 1 Moffatt A, Regan L, Braude P. Natural killer cells, miscarriage, and infertility. BMJ 2004;329:1283-1285 (27 November), doi:10.1136/bmj.329.7477.1283 2 Grant ECG. Nutritional supplements to prevent pregnancy complications. http://bmj.com/cgi/eletters/329/7458/152#67502, 16 Jul 2004 3 Scholl TO, Reilly TM. Trace element and mineral nutrition in human pregnancy. In Bodgen JD, Klevay LM, eds. Clinical Nutrition of the Essential Trace Elements and Minerals: The Guide for Health Professionals. Totawa, NJ: Humana Press Inc., 2000: 115-138. 4 Clifford K, Rai R, Regan L Future pregnancy outcome in unexplained recurrent first trimester miscarriage. Hum Reprod 1997;12: 387-9. 5 Barnes B, Grant ECG, Kingsley P, et al. Nutrition and pre- conception care. Lancet 1985; 2:1297. Competing interests: None declared |
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Frances H Rushworth, SpR O&G Singleton Hospital, Sketty, Swansea SA2 8QA, Joanne Bibby, Consultant
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EDITOR- We wish to congratulate Moffett et al on their timely and authoritative debunking of the current demonisation of Natural Killer cells as a cause of recurrent miscarriage. We intend to have copies on hand to dissuade any more of our patients from embarking on the implausible and unproven tests and treatments that have been promulgated through the popular press and Internet. Reports in national newspapers have prompted patients to seek investigation in the private sector. Peripheral blood NK cells have been measured, but treatment with steroids, low molecular weight heparin and aspirin has been unsuccessful, and there has been no recruitment to trials. We also wish to endorse the Royal College of Obstetricians and Gynaecologists Guideline on Recurrent Miscarriage. A recent audit of five years of investigation of patients in Swansea demonstrated the same levels of balanced translocations and antiphospholipid antibody syndrome in our local population as has been identified by large tertiary referral centres. A retrospective review of our patients’ next pregnancy outcome confirmed a miscarriage rate of only 29% in those given supportive care alone. We shall be more than delighted when further evidence supports new modes of investigation, since it is indeed hard for both for women and doctors to accept that our diagnostic options often draw a blank. In the past five years, we have striven to provide evidence based care and to discourage the use of non proven treatments. As a result, less than 10% of our patients used empiric treatment in their next pregnancy. We agree that these women are vulnerable to hyped media recommendations of apparent advances in care, and will independently seek private consultations. It has been our experience that unproven treatment regimes with potential harm have been strongly recommended. This practise has been outside the setting of a randomised controlled trial, which is not only wrong in the individual case, but sets precedents that muddy the data and damage options for future research. Competing interests: None declared |
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Siobhan Quenby, Senior Lecturer/Honorary Consultant University of Liverpool
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Moffett, Regan & Braude [329:1283-5] review the associations between natural killer (NK) cells, miscarriage and infertility. My interest is in recurrent miscarriage and my work is cited in the article in, I think, a way that might mislead the reader. I will not comment on either blood NK cells or infertility. I agree that there is a lack of understanding of the biological mechanisms that link endometrial NK cells and miscarriage, but there is an undoubted link, demonstrated in three separate studies, including an un-cited report by one of the review authors [1]. Women with high numbers of endometrial NK cells, pre-pregnancy, are more likely to have recurring miscarriage. Whether that association is causal or casual is, at present, not known. Further research work (in progress) has shown that steroid treatment usually reduces the number of endometrial NK cells in women with high concentrations. Whether or not that improves outcome in substantive terms ? the birth of live babies ? is also unknown. I agree that there is no basis for recommending steroid treatment for women with high concentrations of endometrial NK cells unless a randomised trial shows this to be effective and safe. I am trying to find funding for such a study at present. In the meantime, I have gone to some lengths to engage with the public about the often neglected problem of recurrent early pregnancy, including appearing on Women?s Hour on BBC Radio 4. At all times, I have stressed that steroid treatment is experimental and unproven, and that it is not appropriate to extrapolate from a single, and unusual, case history. I also agree with the review authors that couples afflicted by infertility and recurrent miscarriage are vulnerable to exploitation. I therefore attach the following: Competing interests: SQ has no private clinical practice, and therefore receives no remuneration from couples with recurrent miscarriage. 1. Clifford K., Flanagan A.M., Regan L. (1999) Endometrial CD56+ natural killer cells in women with recurrent miscarriage: a histomorphometric study. Hum. Reprod., 14:2727-30 Competing interests: None declared |
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Gerard CP CHAOUAT, directeur de recherches CNRS INSERM U 131 Clamart 92141 France
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In my country, steroids have been used to treat RSA in the 80s (not surprisingly by lymphocyte alloimmunisation advocates) and their use has receded except by a small bunch of individuals. But more stunning, I see on the internet that centres are charging enormous amounts to monitor “bad guys” and “good guys” cytokines, and NK activity in the peripheral blood ! These centres also claim to monitor NK activity in the uterus, but indeed neither the day of the cycle when sampling is performed is standardised, not is the biopsy performed under conditions which would minimise the variations akin , as you rightly point out, to the location and depth of the biopsy. Even if enhanced uNKs numbers can in my mind be in some cases linked to abortion or implantation failure, numbering the cells cannot per se ascertain whether , for example, they produce TNF or angiopoietin 2. It is even more stupendous to read in one centre that “the NK assay ….against placental like cells has been widely accepted and is now used worldwide.” At present, we do NOT know hor to identify the (very small) percentage of women which might benefit from a specific anti NK treatment bu we KNOW that this treatment will worsen the condition of a large number of non responding women. Furthermore, the high rate of success claimed is meaningless since we know that stress is involved in abortion and implantation failure. Thus, impressive pseudo science will have an effect, and what would be required would be a double blind comparison of the same approach with or w/o treatment (replaced here by a double placebo) Given earlier stray Pedersen data, I would nor be surprised if results would not necessarily favour the “treatment”, given its known risks and side effects ! Unfortunately, as psychoanalysts know, paying is an important element of psychotherapy and psychoanalysis cures ….. Indeed, even more stupendous is the use of “anti rheumatoid arthritis drugs”. These FDA proved drugs are NOT approved for use in pregnancy, and can harm the mother (patients are NOT made aware that fatal case side effects have been reported !) or interfere with TNF functions on foetal development (and indeed no long term follow up nor register are installed). I could find pages detailing the advertisements of these centres showing not only that there is no rationale for what they propose, and that what they advertise often even contains errors, but you did that in an excellent way. These people simply make money on the credulity of distressed women, but, even worse, they in several case endanger them as well as the long term future of their babies Competing interests: None declared |
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Lionel Carbillon, Professor of Obstetrics and Gynecology Hopital Jean Verdier avenue du 14 juillet 93140 Bondy
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Ashley Moffett, Lesley Regan and Peter Braude rightly warn against the danger of misinterpreting the compelling name of “uterine NK cells”, and the questionable treatments this confusion may lead to (1). Indeed, these large granular lymphocytes (LGL) infiltrating the decidua at the late secretory phase of the menstrual cycle and in early pregnancy have a CD56bright CD16- CD3- CD57- phenotype, and these cells are quite distinct from the CD56dimCD16+CD57+ lymphocytes with natural killer activity (2). Considerable differences have also been demonstrated in the cell surface marker profile between decidual LGL and peripheral blood natural killer lymphocytes (3), supporting the authors’ recommendation that decidual LGL should be regarded as a separate lymphoid subset. Lastly, decidual LGL interact with extracellular matrix components and modulate their integrin repertoire (4) while extravillouscytotrophoblast migrates and differentiates (4, 5, 6) and an adequate uteroplacental circulation develops (7), strongly suggesting they have an important physiologic role in normal placentation. Robertson et al (8) judiciously observed about 20 years ago « it cannot be fortuitous that only in species with hemochorial placentation, characterized by migratory nonvillous trophoblast, is a true stromal decidua formed ». As LGL appear as an essential physiologic component of the decidua, new insight into their function is urgently needed before giving treatments aiming at suppressing them. 212 words Professor Lionel Carbillon Department of Obstetrics and Gynecology Hopital Jean Verdier Avenue du 14 juillet 93140 Bondy University of Paris 13 REFERENCES 1) Moffett A, Regan L, Braude P. BMJ 2004; 329(7477):1283-5. Natural killer cells, miscarriage, and infertility. 2) Carbillon L, Lemaistre AI, Manoux A, Cedrin-Durnerin I, Tepper M, Hugues JN, Guettier C, Uzan M. Immunohistochemical characterization of the inflammatory infiltrate in the human endometrium prior to in vitro fertilization and embryo transfer. Pathol Biol (Paris) 1998; 46: 21-8. 3) Schallhammer L, Walcher W, Wintersteiger R, Dohr G, Sedlmayr P. Phenotypic comparison of natural killer cells from peripheral blood and from early pregnancy decidua. Early Pregnancy. 1997; 3: 15-22. 4) Burrows TD, King A, Loke YW. Expression of adhesion molecules by human decidual large granular lymphocytes. Cell Immunol 1993; 147: 81-94. 5) Merviel P, Challier JC, Carbillon L, Foidart JM, Uzan S. The role of integrins in human embryo implantation. Fetal Diagn Ther. 2001; 16: 364- 71. 6) Challier JC, Carbillon L, Kacemi A, Vervelle C, Bintein T, Galtier M, Espie MJ, Uzan S. Characterization of first trimester human fetal placental vessels using immunocytochemical markers. Cell Mol Biol (Noisy-le-grand). 2001;47 Online Pub:OL79-87. 7) Carbillon L, Ziol M, Challier JC, Perrot N, Uzan M, Prevot S, Uzan S. Doppler and immunohistochemical evaluation of decidual spiral arteries in early pregnancy. Gynecol Obstet Invest. 2004; 59: 24-28. 8) Robertson WB, Brosens I, Landells WN. Abnormal placentation. Obstet Gynecol Annu 1985; 14: 411-26. Competing interests: None declared |
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Amolak Singh Bansal, Consultant in Immunology Dept of Immunology, St Helier Hospital, Wrythe Lane, Carshalton, Surrey. SM5 1AA., Shree Bhaskaran, Brian Ford and Hassan Shehata
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We read with interest the article by Moffett et al (BMJ 27 November, 2004, page 1283 - 1285) suggesting that there is no point in assessing peripheral blood natural killer (NK) cell numbers or function in women with recurrent miscarriage (RM) or those undergoing in-vitro fertilisation (IVF) treatment. They fail to mention, or are unaware, how the theoretical inconsistencies may be reconciled with the now considerable literature attesting to the value of such measurements. We agree that the NK cell population found in the uterine endometrium and in the decidua (typically CD16 negative, CD56 bright) are both phenotypically and functionally different from those NK cells in the peripheral circulation (typically CD16+, CD56 dim). However, Fukui et al (1999) have shown a significant increase in the percentage of endometrial CD16+ CD56dim peripheral blood type NK cells in women who failed IVF and embryo transfer compared to those who were successful. Additionally, Polgar and Hill (2002) have shown peripheral blood NK cells to produce embyrotoxic levels of Th1 type cytokines when stimulated with a trophoblast antigen extract. Thus, some of the NK cells that accumulate at the site of implantation are potentially of peripheral blood origin and are capable of damaging trophoblastic cells. Several factors encourage NK cell activation but particularly the Th1 type cytokines. These include interleukin 21 and interferon gamma especially in the presence of interleukin 2, 12, 15 and 18 (Strengell M et al, 2002; Strengell M et al, 2003). Thus, the detection of activated NK cells in the peripheral circulation suggests a general skewing towards increased Th1 type immunity. While such immunity appears necessary for implantation by coordinating angiogenesis and tissue remodelling (Chaouat et al, 2004), at critical stages of the pregnancy unregulated and excessive Th1 type immunity may be harmful to the foetus. We have recently shown a reduced rate of embryo implantation in women undergoing IVF treatment with a raised peripheral blood CD69+ activated NK cell count (Thum et al, 2004). This and increased NK cell cytotoxicity was also observed by Coulam et al (2003). Thus women with the higher levels of activated NK cells have a higher than average Th1 type immunity and the enumeration of these cells may represent a surrogate marker for exaggerated Th1 type immunity. Regardless these cells and the associated Th1 type cytokines have the ability to either directly or indirectly damage the developing foetus and placenta. In consequence, we believe that an analysis of activated NK cells does provide information helpful in predicting the outcome of IVF treatment. This method is certainly more robust than measuring serum or plasma Th1/Th2 cytokines or looking at intracellular cytokines. Clearly, much research is required to translate the value of this test in guiding treatment strategies. However, our provisional work does suggest that therapy aimed at reducing NK cell activation leads to an improved outcome of IVF treatment. Indeed glucocorticoids may be helpful in RM or recurrent idiopathic failed IVF precisely because they can inhibit the production of Th1 type cytokines and encourage Th2 type cytokines by antigen presenting cells and T helper cells (Elenkov, 2004). We do agree, however, with Moffett et al that there is little merit or scientific validity in the simple enumeration of NK cell numbers. Indeed, we have recently shown the total absence of any correlation between NK cell numbers and IVF treatment outcome (Thum et al, in Print, Human Reproduction). Chaouat G, Ledee-Bataille N, Dubanchet S, Zourbas S, Sandra O, Martal J. TH1/TH2 paradigm in pregnancy: paradigm lost? Cytokines in pregnancy/early abortion: reexamining the TH1/TH2 paradigm. Int Arch Allergy Immunol. 2004; 134(2): 93-119. Coulam CB, Roussev RG. Correlation of NK cell activation and inhibition markers with NK cytoxicity among women experiencing immunologic implantation failure after in vitro fertilization and embryo transfer. J Assist Reprod Genet. 2003; 20: 58-62. Elenkov IJ. Glucocorticoids and the Th1/Th2 balance. Ann N Y Acad Sci. 2004; 1024: 138-46. Fukui A, Fujii S, Yamaguchi E, Kimura H, Sato S, Saito Y. Natural killer cell subpopulations and cytotoxicity for infertile patients undergoing in vitro fertilization. Am J Reprod Immunol. 1999; 41: 413-22. Polgar K, Hill JA. Identification of the white blood cell populations responsible for Th1 immunity to trophoblast and the timing of the response in women with recurrent pregnancy loss. Gynecol Obstet Invest. 2002;53(1):59-64. Strengell M, Matikainen S, Siren J, Lehtonen A, Foster D, Julkunen I, Sareneva T. IL-21 in synergy with IL-15 or IL-18 enhances IFN-gamma production in human NK and T cells. J Immunol. 2003; 170: 5464-9. Strengell M, Sareneva T, Foster D, Julkunen I, Matikainen S. IL-21 up -regulates the expression of genes associated with innate immunity and Th1 response. J Immunol. 2002; 169: 3600-5. Thum MY, Bhaskaran S, Abdalla HI, Ford B, Sumar N, Shehata H, Bansal AS. An increase in the absolute count of CD56dimCD16+CD69+ NK cells in the peripheral blood is associated with a poorer IVF treatment and pregnancy outcome. Hum Reprod. 2004; 19(10): 2395-400. Competing interests: None declared |
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