Immunological Testing

Immunological Testing

Natural Killer Cells

NK cells are lymphocytes responding mainly to viral infection and tumor formation. Over the last few decades, it was found that NK cells play an important role in pregnancy implantation however Increased activity (cytotoxicity) of those cells was associated with increased risk of recurrent pregnancy loss (repeated miscarriages) and repeated implantation failure (multiple IVF failures).

NK cells are located within the inner lining of the uterus and one of their main roles is to remodel blood vessels within the lining so they can accommodate adequate blood supply to the pregnancy. Overactivity or increased cytotoxicity of NK cells can lead to defect in implantation.

Testing the Natural killer cells is performed by a blood test (NK cytotoxicity assay) and endometrial biopsy (tissue sample from the inner lining of the uterus). Immune therapy will be decided based on the results. The blood test will be repeated multiple times during the cycle and pregnancy to make sure the NK cells activity is under control.

T-Helper 1 / T-Helper 2 Cytokines ratio

T- helper cells are lymphocytes that play an important role in regulating the immune response by secreting immune mediators (cytokines). They are called “helper” because they help or mediate the function of other immune cells. T-helper 1 to T-helper 2 ratio represents the balance between pro-inflammatory and anti-inflammatory cytokines. In a normal pregnancy, this ratio tends to decrease due to an increase in anti-inflammatory cytokines, however, in patients with repeated miscarriages or implantation failure, this ratio can be elevated.

Testing of T-helper 1 to T-helper 2 ratio is performed by flow cytometry assay. If the ratio is elevated, immune therapy will be adjusted accordingly and repeat testing will be indicated. The goal is to modulate the immune system to prevent miscarriage or implantation failure.

Antiphospholipid Antibodies

Antiphospholipid antibodies are autoantibodies that can lead to blood clotting inside the blood vessels “thrombosis” and cause repeated miscarriages and other pregnancy complications such as preeclampsia, preterm delivery, and stillbirth.

Extensive testing needed to identify those antibodies and their titers. The main treatment is blood thinners including aspirin and heparin (low molecular weight or unfractionated heparin). The patient will benefit as well from immune therapy to suppress those antibodies.

Other Autoantibodies

Several autoantibodies will be tested such as ANA, anti-DNA, anti-SCL70, anti-Histones, anti-TPO, and others. Many autoimmune diseases have been associated with reproductive failures such as repeated miscarriages (or recurrent pregnancy loss) and multiple implantation failures. Immune therapy is used to suppress those autoantibodies.

References:

  • Kwak-Kim JY, Chung-Bang HS, Ng SC, Ntrivalas EI, Mangubat CP, Beaman KD, Beer AE, Gilman-Sachs A. Increased T helper 1 cytokine responses by circulating T cells are present in women with recurrent pregnancy losses and in infertile women with multiple implantation failures after IVF. Hum Reprod. 2003 Apr;18(4):767-73.
  • Kwak JY, Kwak FM, Ainbinder SW, Ruiz AM, Beer AE. Elevated Peripheral Blood Natural Killer Cells Are Effectively Downregulated by Immunoglobulin G Infusion in Women with Recurrent Spontaneous Abortions. Am J Reprod Immunol. 1996 Apr;35(4):363-9.
  • Kwak JY, Beaman KD, Gilman-Sachs A, Ruiz JE, Schewitz D, Beer AE. Up-regulated expression of CD56+, CD56+/CD16+, and CD19+ cells in peripheral blood lymphocytes in pregnant women with recurrent pregnancy losses. Am J Reprod Immunol. 1995 Aug;34(2):93-9.
  • Lee SK, Kim JY, Han AR, Hur SE, Kim CJ, Kim TH, Cho BR, Han JW, Han SG, Na BJ, Kwak-Kim J. Intravenous Immunoglobulin G Improves Pregnancy Outcome in Women with Recurrent Pregnancy Losses with Cellular Immune Abnormalities. Am J Reprod Immunol. 2016 Jan;75(1):59-68.
  • Lee SK, Na BJ, Kim JY, Hur SE, Lee M, Gilman-Sachs A, Kwak-Kim J. Determination of clinical cellular immune markers in women with recurrent pregnancy loss. Am J Reprod Immunol. 2013 Nov;70(5):398-411.
  • Lédée N, Petitbarat M, Chevrier L, Vitoux D, Vezmar K, Rahmati M, Dubanchet S, Gahéry H, Bensussan A, Chaouat G. The Uterine Immune Profile May Help Women With Repeated Unexplained Embryo Implantation Failure After In Vitro Fertilization. Am J Reprod Immunol. 2016 Mar;75(3):388-401.
  • Lédée N, Prat-Ellenberg L, Chevrier L, Balet R, Simon C, Lenoble C, Irani EE, Bouret D, Cassuto G, Vitoux D, Vezmar K, Bensussan A, Chaouat G, Petitbarat M. Uterine immune profiling for increasing live birth rate: A one-to-one matched cohort study. J Reprod Immunol. 2017 Feb;119:23-30.
  • Yetman DL, Kutteh WH. Antiphospholipid antibody panels and recurrent pregnancy loss: prevalence of anticardiolipin antibodies compared with other antiphospholipid antibodies. Fertil Steril. 1996 Oct;66(4):540-6.
  • Coulam CB, Kaider BD, Kaider AS, Janowicz P, Roussev RG. Antiphospholipid antibodies associated with implantation failure after IVF/ET. J Assist Reprod Genet. 1997 Nov;14(10):603-8.
  • Kutteh WH. Antiphospholipid antibody-associated recurrent pregnancy loss: treatment with heparin and low-dose aspirin is superior to low-dose aspirin alone. Am J Obstet Gynecol. 1996 May;174(5):1584-9.
  • Vaquero E,Lazzarin N,Valensise H, Menghini S, Di Pierro G, Cesa F, Romanini C. Pregnancy outcome in recurrent spontaneous abortion associated with antiphospholipid antibodies: a comparative study of intravenous immunoglobulin versus prednisone plus low-dose aspirin. Am J Reprod Immunol. 2001 Mar;45(3):174-9.
  • Mumusoglu S, Beksac MS, Ekiz A, Ozdemir P, Hascelik G. Does the presence of autoantibodies without autoimmune diseases and hereditary thrombophilia have an effect on recurrent pregnancy loss? J Matern Fetal Neonatal Med. 2016;29(14):2352-7.
  • Kiprov DD, Nachtigall RD, Weaver RC, Jacobson A, Main EK, Garovoy MR. The use of intravenous immunoglobulin in recurrent pregnancy loss associated with combined alloimmune and autoimmune abnormalities. Am J Reprod Immunol. 1996 Oct;36(4):228-34.

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