44 y.o. white female with a history of 5 spontaneous abortions, recurrent cellulitis, 3 episodes of Zoster - immune evaluation (immunoglobulin levels, pneumococcal titers, CH 50 were normal) - however she did have low NK cell counts on 2 occasions. The patient has plaque psoriasis. She also has a family history of Sjogren's syndrome and "immune deficiency" of undetermined nature in a grandparent. Are there any references for NK cell deficiency in adults? I have seen reports associated with Still's disease. She also had an ANA <1:40.


Thank you for your inquiry.

First of all, I am calling your attention to an excellent review of NK cells in general written by Dr. Jordan Orange. The abstract of that review is copied below for your convenience.

Secondly, I am not aware of any patient description related to NK cell deficiency that fits the profile of your patient. However, it is of note that NK cell abnormalities have been associated with spontaneous abortions (as well as infertility), and below you will find abstracts of studies in this area.

In addition, there are other adult diseases besides Still’s disease that have been associated with NK cell deficiencies. These include rheumatoid arthritis, chronic myelogenous leukemia, and human immunodeficiency virus infections. Abstracts of these associations are also copied for you below.

In summary, in answer to your question, there are other references for NK cell deficiency in adults. There is a rich body of literature regarding spontaneous abortions and infertility, and there are scattered reports of NK deficiencies in the conditions mentioned above. However, unfortunately, none of these fit your patient exactly and there is no, to my knowledge, definitive therapy in regards to this defect.

Nonetheless, because I could not provide you with any strategy by which you might approach this patient therapeutically, I am going to ask Dr. Zuhair Ballas to share his thoughts regarding your inquiry. Dr. Ballas has published in the area of NK cell deficiency. As soon as we receive his response, we will forward it to you. In the meantime, I hope this information is of help to you.

Thank you again for your inquiry.

Endometriosis and unexplained recurrent spontaneous abortion: pathological states resulting from aberrant modulation of natural killer cell function?
Hum. Reprod. Update (1999) 5 (1): 40-51. doi: 10.1093/humupd/5.1.40
The observation that natural killer (NK) cell activity is abnormally low in endometriosis patients and abnormally high in women with otherwise unexplained recurrent spontaneous abortion represents, at present, an intriguing curiosity. There is evidence suggesting that these conditions are associated with an opposite regulation of NK cell behaviour. This review discusses these observations and potential relationships.

Hum Reprod. 2010 Jan;25(1):52-8. Epub 2009 Oct 9.
Detailed analysis of peripheral blood natural killer (NK) cells in women with recurrent miscarriage.
King K, Smith S, Chapman M, Sacks G.
St George Hospital, UNSW and IVF Australia, Sydney, Australia.
Background: Increased peripheral blood natural killer (NK) cell activity has been associated with unexplained reproductive failure including recurrent (three or more) miscarriages (RM). Studies have reported abnormalities in both numbers (absolute and proportion) and activation. This study assessed numerous NK cell parameters to determine which (if any) are altered in women with RM compared with controls, which parameter best differentiated women with RM from controls, and what NK levels should be considered high.
Methods: Luteal-phase blood samples from women with RM (n = 104) and controls (n = 33) were analysed by four-colour flow cytometry. NK cells were analysed as a percentage of lymphocytes, total NK concentration, CD56(Dim) subtype concentration and percentage, activated CD69(+)CD56(Dim) subtype concentration and percentage and CD56(+Bright):CD56(+Dim) subtype ratio. Women with RM were analysed in two subgroups: those positive in > or =1 RM screening tests (karyotype, uterine, antiphospholipid syndrome, thrombophilia) (n = 48) and those who had negative screening tests (n = 56).
Results: Women with RM had significantly higher NK percentage (P < 0.001), and significantly lower CD56(+Bright):CD56(+Dim) ratio (P < 0.05) than controls. NK percentage was the only significantly higher variable in the RM screening test negative subgroup (P < 0.01). A ROC analysis (AUC = 0.71) found that an NK percentage >18% was highly specific for women with RM (97.0%), and defined 12.5% of women with RM as having high NK percentage, compared with 2.9% of controls.
Conclusion: Women with RM have altered peripheral blood NK parameters. NK cells as a percentage of lymphocytes best discriminated RM and control populations. Women with RM and high NK levels may have an immunological disorder.

The activity of natural killer cells in patients with rheumatoid arthritis: I. The effect of drugs used in vivo.
Russell AS, Miller C
Clin Exp Rheumatol. 1984;2(3):227.
The role of natural killer (NK) cells in vivo remains uncertain, but they have been implicated in a number of protective and aggressive host responses. We have found the NK activity of most patients with rheumatoid arthritis (RA) to be significantly depressed below the values for a control healthy population. This depression is not related to the use of myochrysine, methotrexate or penicillamine. Auranofin, which has a stimulatory effect in vitro, seemed in vivo to cause a further depression. ASA and indomethacin, when given to normal subjects, stimulated NK activity. The reduced NK activities seen in patients with RA taking these and other non-steroidal anti-inflammatory agents remains unexplained.

Natural killer-cell immunodeficiency in patients with chronic myelogenous leukemia. I. Analysis of the defect using the monoclonal antibodies HNK-1 (LEU-7) and B73.1.
Fujimiya Y, Bakke A, Chang WC, Linker-Israeli M, Udis B, Horwitz D, Pattengale PK
Int J Cancer. 1986;37(5):639.
Quantitative evaluation of natural killer (NK) cells using the HNK-1 (Leu-7) and B73.1 monoclonal antibodies (MAbs) was correlated with NK activity in 13 patients with chronic myelogenous leukemia (CML) and compared to normal donor controls. A consistent observation was the presence of normal absolute numbers of B73.1+ lymphocytes as well as normal to increased absolute numbers of HNK-1+ lymphoid cells in the peripheral blood of chronic-phase CML patients. Despite normal to increased numbers of B73.1+ and HNK-1+ lymphoid cells, these patients consistently demonstrated a significant impairment of lymphocyte-mediated NK activity in their peripheral blood. Further experiments demonstrated that chronic-phase CML patients, in contrast to normal controls, had significantly increased percentages of HNK-1+, E+ and B73.1+, E+ lymphoid cells and significantly decreased percentages of HNK-1+, E- and B73.1, E- lymphoid cells, which resulted in significant reversals of the HNK-1+, E+ to HNK-1+, E- and B73.1+, E+ to B73.1+, E- lymphoid cell ratios. (HNK-1+ [E+/E-]greater than B73.1+ [E+/E-]). Furthermore, as compared to normals, both FACS-sorted HNK-1+ and B73.1+ lymphoid cells from the E+ fraction of CML patients were consistently defective in NK activity, and could not be substantially augmented with alpha-interferon preparations. Although markedly defective in their ability to lyse K-562, HNK-1+ lymphoid cells from the E+ fraction of CML patients were not defective in their ability to bind to the NK-sensitive target, K-562. In contrast, NK-defective B73.1+ lymphoid cells were partially defective in their ability to bind to K-562.

Defective natural immunity: an early manifestation of human immunodeficiency virus infection.
Ullum H, Gøtzsche PC, Victor J, Dickmeiss E, Skinhøj P, Pedersen BK
J Exp Med. 1995;182(3):789.
Cytotoxicity mediated by natural killer (NK) and lymphokine-activated killer (LAK) cells may be of significance in host defense against viral infections. This study included 347 patients infected with human immunodeficiency syndrome virus (HIV) type 1 and 110 controls. The NK cell activity, either unstimulated or stimulated with interferon-alpha (IFN-alpha) or interleukin-2 (IL-2), and the LAK cell activity were suppressed in patients, but the NK/LAK cell activity did not differ between patients with AIDS and patients without AIDS. However, the IFN-alpha-stimulated NK cell activity and LAK cell activity were reduced in patients with symptoms of HIV disease (CDCIV) when compared with asymptomatic patients (CDCII+III). When the data were analyzed by multiple linear regression, the percentage of CD4+ cells had a positive effect on these two parameters in patients without AIDS, whereas the percentage of CD4+ cells had no significant effect on unstimulated and IL-2-stimulated NK cell activity in these patients. In controls and AIDS patients, the percentage of CD4+ cells had no effect on NK/LAK cell activity in multiple linear models. The total number of CD16+ cells was low in patients compared to controls, whereas the percentages of CD16+, CD56+, and CD16+CD56+ were either normal or elevated. Therefore, the decrease in NK cell subpopulations did not contribute to the observed depression in NK/LAK cell activity in vitro. It is concluded that natural immunity is suppressed in HIV-seropositive patients primarily because of a qualitative defect of the NK/LAK cells. This qualitative defect includes a reduced responsiveness to IFN-alpha, which is progressive until the onset of symptoms, and possibly related to the loss of CD4+ cells.

J Clin Invest. 2012 Mar 1;122(3):798-801. doi: 10.1172/JCI62620. Epub 2012 Feb 22.
Unraveling human natural killer cell deficiency.
Orange JS.
University of Pennsylvania School of Medicine, Department of Pediatrics, Children’s Hospital of Philadelphia Research Institute, Philadelphia, Pennsylvania 19104, USA.
NK cells are a component of the innate immune system identified in animals as serving an essential role in antiviral immunity. Establishing their role in human health has been challenging, with the most direct insight coming from the study of NK cell-deficient individuals. However, NK cell deficiencies are rare, and more research is needed. In this issue of the JCI, two independent groups of researchers have simultaneously identified the genetic cause of a human NK cell deficiency as mutation in the MCM4 gene, encoding minichromosome maintenance complex component 4. These reports suggest a critical role for the minichromosome maintenance helicase complex in NK cells and NK cell-mediated host defense.

Phil Lieberman, M.D.

We received a response from Dr. Zuhair Ballas. Thank you again for your inquiry and we hope this response is helpful to you.
Phil Lieberman, M.D.
Response from Dr. Zuhair Ballas:
The limited clinical history certainly suggests an underlying immune dysfunction. However, just having low NK cell numbers on two occasions is not a sufficient indication of NK cell deficiency. Recurrent Zoster certainly may indicate a T cell abnormality and/or an NK cell abnormality. However, NK cell distribution between cytotoxic and cytokine-seceting subsets need to be undertaken before one can assume an NK cell abnormality. Here is a link to a case report we published a while back that indicates such an abnormality. The spontaneous abortions may suggest an anti-phospholipid syndrome which can be associated with immune deficiency as well. The recurrent cellulitis suggests an antibody response. Obviously, if there is an underlying immune abnormality, it is a multifactorial abnormality. It is not clear as to whether the normal pneumococcal titers were random or whether the patient actually had a four-fold increase in titers after vaccination.

I suggest that the patient be referred to a person or center who focus on such immune abnormalities.

Hope this helps.

Zuhair K Ballas, M.D.
Professor and Director
Immunology Division
Department of Internal Medicine
University of Iowa

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