Journal of Blood Disorders Symptoms and Treatments

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NK cells and Unexplained Recurrent Pregnancy Loss, a Well-Known but Rarely Considered Association

Pierpaolo Di Micco, Ida Strina, Corrado Lodigiani

Correspondence Address :

Pierpaolo Di Micco, MD, PhD
Fatebenefratelli Hospital of Naples
Email: pdimicco@libero.it

Received on: September 06 , 2018, Accepted on: September 17, 2018, Published on: September 21, 2018

Citation: Pierpaolo Di Micco, Ida Strina, Corrado Lodigiani (2018). NK cells and Unexplained Recurrent Pregnancy Loss, a Well-Known but Rarely Considered Association

Copyright: Pierpaolo Di Micco, Ida Strina, Corrado Lodigiani (2018). NK cells and Unexplained Recurrent Pregnancy Loss, a Well-Known but Rarely Considered Association

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Recurrent pregnancy loss (RPL) is a daily intriguing work in women in reproductive age. Differential diagnosis should always be considered because RPL could be related to several clinical condition as chromosomal aberration, endocrine abnormalities, uterine malformations, uterine infections thrombophilia and so on. Immunological abnormalities have also been considered in this clinical setting both as chronic inflammatory diseases as abnormal levels of subset of immune cells or antigens. Immunological abnormalities in fact are frequently considered for unexplained RPL although a clear clinical and therapeutic approach actually is not available.
In this editorial corner most commonly associated immunological abnormalities associated to RPL as peripheral NK cells levels or impairment of lymphocytes T helper type 1 and 2 have been reported as well documented cause of RPL in selected population. This alteration could better address the clinical management of RPL but should be better studied also from a prognostic point of view in future studies.
Editorial Corner
Recurrent pregnancy loss (RPL) represents a major health problem with two to three or more losses in up to 5% of women of reproductive age and it has been considered as one of the most common causes of female infertility [1].
Several reports identified several clinical condition and diseases potentially responsible of RPL such as endocrine diseases (e.g. ovarian dysfunction, anovulation, hypopituitarism, diabetes), uterine malformations, genetic alterations (e.,g. chromosomal aberrations), hypercoagulable state and thrombophilia (e.g. inherited thrombophilia, antiphospholipid syndrome, combined thrombophilia), chronic inflammatory diseases (in particular systemic lupus erythematosus), infectious diseases and immunological abnormalities [2-6].
A significant portion of unexplained pregnancy loss is associated with immune etiology in fact, and we may include immunopathological conditions as erythematosus lupus or antiphospolipid syndrome or autoimmune and cellular abnormalities. Although at the beginning of the century several immune dysfunctions have been described in mice with RPL but the same dysfunctions were not confirmed in humans, recently further immune abnormalities were found in selected population of women with RPL.
In several reports in the Literature in fact an impaired ratio of T helper lymphocyte type 1 and type 2 or an increased percentage of NK lymphocytes have been associated to RPL [7]. However, it has always been difficult to establish a thorough magnitude of immune etiology of RPL because its incidence in each study may be different because of the adopted different inclusion and exclusion criteria.
From a pathophysiological point of view several abnormalities in immune balance have been underlined and reported as markers of RPL. The impairment of immunological functions of a pregnant woman has the recognition of paternal antigens present on the fetus and this mechanism is related to the following RPL [8]. Several immune functions as migration of immune cells, cytokine production and impaired lymphocytes T ratio have benn the most frequently underlined in the literature. Immune cells most frequently associated to migration to uterine district are peripheral blood monocytes (PBMc) and Natural Killer cells (NKc), yet cytokines are mainly produced by PBMc and lymphocytes T helper. Moreover an impairment of levels of lymphocytes T helper type 1 and 2 has benn frequently reported in women with RPL [8]. Endocrine and paracrine productions of female sexual hormones seem to be also associated to the increase of NKc in the decidual endometrium during the implantation [9] so giving further attention to levels of peripheral NKc vs uterine NKc as potential responsible of abnormal immune response toward fetus [9,10].
So, as confirm levels of peripheral NKc have been found increased in selected populations of patients with RPL vs healthy subjects and vs patients with end stage kidney failure [11,12]. Moreover also other markers of immune activation in the same study were reported in patients with RPL vs controls as interleukin 4 levels, interleukin 4 antigens, transforming growth factor beta levels and trasforming growth factors beta antigens levels [11].
These alterations may be relevant from a clinical point of view too, actually in fact the percentage of unexplained RPL varies from 20 to 35% and immunological alterations seem to be to most involved. However a real magnitude of this recognized immunological abnormalities as the increase of peripheral NKc cannot be found actually because available studies are mainly retrospective or in selected populations. Of course the levels of increased peripheral NKc should be considered together to uterine, malformation, uterine infections, chromosomal abnormalities and thrombophilia in the evaluation of a patients with RPL.
On the other side besides these several immunological alterations have been identified, little is known from a therapeutic point of view. First of all although the reduction of levels of NKc seem to possible with the use of steroids, none reported an appropriated dose of steroids that can be used in this clinical setting and furthermore none suggested how this therapeutic approach can be monitored during the treatment. So haemocrome with total lypmhocytes count and a repetition of peripheral NKc levels have been considered but actually without any type of confirm from a clinical point of view. Thereafter also studies on the prognosis of women with RPL and increased peripheral NKc are treated with steroids or other drugs lacking in the Literature so underling that we are at the beginning of an unsolved problem. In conclusion we can assert that immunological abnormalities other than immunological systemic disease should be involved in the pathophysiology of RPL in particular for cases with unexplained RPL; however appropriated clinical strategies and studies to identify, to treat and to monitor this clinical problem should be planned in next years.

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