title: Low circulating CD4(+) CD25(+) Foxp3(+) T regulatory cell levels predict miscarriage risk in newly pregnant women with a history of failure.
abstract: PROBLEM  The purpose of this study was to determine whether quantification of peripheral blood Treg cell levels could be used as an indicator of miscarriage risk in newly pregnant women with a history of immunologic reproductive failure. METHOD OF STUDY  Fifty-four pregnant women with a history of immunologic infertility and/or pregnancy loss were retrospectively evaluated (mean age: 36.7 ± 4.9 years, 2.8 ± 2.5 previous miscarriages; 1.5 ± 1.9 previous IVF failures). Twenty-three of these women experienced another first trimester miscarriage, and 31 of these women continued their current pregnancies past 12 weeks ('pregnancy success'). The following immunologic parameters were assessed in the first trimester: NK cell 50:1 cytotoxicity, CD56(+)  16(+)  CD3(-) (NK), CD56(+)  CD3(+) (NKT), TNFα/IL-10, IFNγ/IL-10, CD4(+)  CD25(-) Foxp3(+) , total CD4(+)  Foxp3(+) (CD4(+ ) CD25(+)  Foxp3 plus CD25(- ) Foxp3(+) ), and CD4(+)  CD25(+)  Foxp3(+) levels. RESULTS  Patients with successful ongoing pregnancies experienced a mean (CD4(+)  CD25(+)  Foxp3(+) ) 'Treg' level of 0.72 ± 0.52%, while those that miscarried in the first trimester experienced a mean Treg level of 0.37 ± 0.29% (P = 0.005). Markers not significantly different between the loss and success groups were NK 50:1 cytotoxicity (P = 0.63), CD56(+)  16(+)  3(+) NK cells (P = 0.63), CD56(+)  3(+)   NKT (P = 0.30), TNFα(+) IL-10(+) (P = 0.13), IFNg(+) IL-10(+) (P = 0.63), and CD4(+)  25(-)  Foxp3(+) cells (P = 0.10), although total CD4(+)  Foxp3(+) levels remained significant (P = 0.02) and CD4(+)  25(+) Foxp3(+) showed the most significant difference (P = 0.005). Mean day of blood draw was 49.2 ± 36.1 days pregnant (median 39.0 days). In addition, patients with a low Treg level (<0.7%) in the first trimester experienced a significantly lower ongoing pregnancy rate than those with a higher Treg level (>0.7%) in the first trimester [44% (15/34) versus 80% (16/20); P = 0.01]. Of the 18 successful pregnancies with sequential Treg results, 85% (11/13) showed a T-regulatory-cell-level increase (mean Treg change 0.33 ± 0.32), while only 40% (2/5) of the failed pregnancies showed a Treg increase (mean Treg change -0.08 ± 0.28; P = 0.02). CONCLUSIONS  From these data, we propose that CD4(+)  CD25(+)  Foxp3(+) T regulatory cells may serve as a superior pregnancy marker for assessing miscarriage risk in newly pregnant women. Larger follow-up studies are needed for confirmation.
authors.affiliation: Laboratory for Reproductive Medicine & Immunology, San Jose, CA, USA. ewinger@sbcglobal.net
authors.forename: Edward E
authors.initials: EE
authors.lastname: Winger
authors.forename: Jane L
authors.initials: JL
authors.lastname: Reed
mesh_terms: D000022:Abortion, Spontaneous / Q000097:blood* / Q000453:epidemiology / Q000276:immunology / Q000473:pathology; D000328:Adult; D015415:Biomarkers / Q000097:blood*; D015704:CD4 Antigens / Q000096:biosynthesis / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D005260:Female; D005434:Flow Cytometry; D005500:Follow-Up Studies; D051858:Forkhead Transcription Factors / Q000096:biosynthesis / Q000276:immunology; D006801:Humans; D007371:Interferon-gamma / Q000096:biosynthesis / Q000276:immunology; D016753:Interleukin-10 / Q000096:biosynthesis / Q000276:immunology; D053645:Interleukin-2 Receptor alpha Subunit / Q000096:biosynthesis / Q000276:immunology; D007694:Killer Cells, Natural / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D018655:Lymphocyte Count; D011247:Pregnancy; D011256:Pregnancy Outcome; D011261:Pregnancy Trimester, First / Q000097:blood* / Q000276:immunology; D012189:Retrospective Studies; D012307:Risk Factors; D050378:T-Lymphocytes, Regulatory / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D014481:United States
chemical_list: D015415:Biomarkers; D015704:CD4 Antigens; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D053645:Interleukin-2 Receptor alpha Subunit; D016753:Interleukin-10; D007371:Interferon-gamma