Thymus Growth and Fetal Immune Responses in Diabetic Pregnancies

Abstract

Type 1 diabetes (T1D) during pregnancy possibly affects the development of the thymus and the maturation of the immune system in the offspring. The aim of the ImmunDiabRisk study was to investigate thymus growth and maternal and fetal immune responses in pregnancies with and without T1D. The thymus circumferences of the fetuses of pregnant women with T1D (n=49) and without diabetes (n=59) were measured using ultrasound around the 29th gestational week and standardized for gestational age. Simultaneously, the frequencies and total numbers of cell markers were analyzed by flow cytometry in maternal peripheral blood, and at birth in umbilical cord blood. The standardized circumference of the thymus was similar in fetuses of mothers with and without T1D (p=0.26). We observed higher numbers of FOXP3 Tregs, memory Tregs, erythrocytes, and lymphocytes in the cord blood from T1D pregnancies (p=0.01, p=0.002, p=0.002 and p=0.02, respectively). The frequencies of CD4+/CD8+ T cells correlated positively in maternal blood and umbilical cord blood of mother-child pairs, as did the levels of neutrophils (Spearman’s correlation coefficient r=0.43, p=0.02 for CD4+/CD8+ cells; r=0.46, p=0.03 for neutrophils), while no significant correlations were observed between thymus circumference and any cell markers in the child. Parts of the prenatal immune system seem to develop differently in the offspring of mothers with and without T1D. The correlation of Tregs between maternal blood and cord blood may indicate a significant cross-talk between the maternal and fetal immune system.

Key words

type 1 diabetes - pregnancy - thymus - ultrasound - regulatory T cells

^* Shared last authorship

• References

• 1 Bonifacio E, Pflüger M, Marienfeld S, Winkler C, Hummel M, Ziegler AG. Maternal type 1 diabetes reduces the risk of islet autoantibodies: relationships with birthweight and maternal HbA(1c). Diabetologia 2008; 51: 1245-1252
• 2 Warram JH, Krolewski AS, Gottlieb MS, Kahn CR. Differences in risk of insulin-dependent diabetes in offspring of diabetic mothers and diabetic fathers. N Engl J Med 1984; 311: 149-152
• 3 Warram JH, Krolewski AS, Kahn CR. Determinants of IDDM and perinatal mortality in children of diabetic mothers. Diabetes 1988; 37: 1328-1334
• 4 Borgelt JM, Möllers M, Falkenberg MK, Amler S, Klockenbusch W, Schmitz R. Assessment of first-trimester thymus size and correlation with maternal diseases and fetal outcome. Acta Obstet Gynecol Scand 2016; 95: 210-216
• 5 Sakaguchi S. The origin of FOXP3-expressing CD4+ regulatory T cells: thymus or periphery. J Clin Invest 2003; 112: 1310-1312
• 6 Di Naro E, Cromi A, Ghezzi F, Raio L, Uccella S, D'Addario V, Loverro G. Fetal thymic involution: a sonographic marker of the fetal inflammatory response syndrome. Am J Obstet Gynecol 2006; 194: 153-159
• 7 Jeppesen DL, Hasselbalch H, Nielsen SD, Sørensen TU, Ersbøll AK, Valerius NH, Heilmann C. Thymic size in preterm neonates: a sonographic study. Acta Paediatr 2003; 92: 817-822
• 8 Eviston DP, Quinton AE, Benzie RJ, Peek MJ, Martin A, Nanan RK. Impaired fetal thymic growth precedes clinical preeclampsia: a case-control study. J Reprod Immunol 2012; 94: 183-189
• 9 Sarkhail P, Mehran L, Askari S, Tahmasebinejad Z, Tohidi M, Azizi F. Maternal thyroid function and autoimmunity in 3 trimesters of pregnancy and their offspring’s thyroid function. Horm Metab Res. 2016; 48: 20-26
• 10 Yinon Y, Zalel Y, Weisz B, Mazaki-Tovi S, Sivan E, Schiff E, Achiron R. Fetal thymus size as a predictor of chorioamnionitis in women with preterm premature rupture of membranes. Ultrasound Obstet Gynecol 2007; 29: 639-643
• 11 De Leon-Luis J, Ruiz Y, Gamez F, Pintado P, Oyelese Y, Pereda A, Ortiz-Quintana L, Santolaya-Forgas J. Comparison of measurements of the transverse diameter and perimeter of the fetal thymus obtained by magnetic resonance and ultrasound imaging. J Magn Reson Imaging. 2011; 33: 1100-1105
• 12 Willett WC, Howe GR, Kushi LH. Adjustment for total energy intake in epidemiologic studies. Am J Clin Nutr 1997; 65 4 Suppl 1220S-1228S discussion 1229S–1231S
• 13 Varga I, Toth F, Uhrinova A, Nescakova E, Polak S. Association among size of thymus, anthropometric dimensions and number of lymphocytes in peripheral blood in newborns from slovakia. Biomed Pap Med Fac Univ Palacky Olomouck Czech Repub 2009; 153: 229-234
• 14 Diemert A, Hartwig I, Pagenkemper M, Mehnert R, Hansen G, Tolosa E, Hecher K, Arck P. Fetal thymus size in human pregnancies reveals inverse association with regulatory T cell frequencies in cord blood. J Reprod Immunol 2016; 113: 76-82
• 15 Dörnemann R, Koch R, Möllmann U, Falkenberg MK, Möllers M, Klockenbusch W, Schmitz R. Fetal thymus size in pregnant women with diabetic diseases. J Perinat Med 2017; 45: 595-601
• 16 Much D, Jaschinski H, Lack N, Hummel S, Füchtenbusch M, Hummel M, Ziegler AG, Beyerlein A. Risk stratification in women with gestational diabetes according to and beyond current WHO Criteria. Horm Metab Res 2016; 48: 16-19
• 17 Luopajärvi K, Nieminen JK, Ilonen J, Akerblom HK, Knip M, Vaarala O. Expansion of CD4+CD25+FOXP3+ regulatory T cells in infants of mothers with type 1 diabetes. Pediatr Diabetes 2012; 13: 400-407
• 18 Lapolla A, Sanzari MC, Zancanaro F, Masin M, Guerriero A, Piva I, Toniato R, Erle G, Plebani M, Fedele D. A study on lymphocyte subpopulation in diabetic mothers at delivery and in their newborn. Diabetes Nutr Metab 1999; 12: 394-399
• 19 Santner-Nanan B, Straubinger K, Hsu P, Parnell G, Tang B, Xu B, Makris A, Hennessy A, Peek MJ, Busch DH, da Costa CP, Nanan R. Fetal-maternal alignment of regulatory T cells correlates with IL-10 and Bcl-2 upregulation in pregnancy. J Immunol 2013; 191: 145-153
• 20 Erlebacher A. Immunology of the maternal-fetal interface. Annu Rev Immunol 2013; 31: 387-411
• 21 Svensson-Arvelund J, Mehta RB, Lindau R, Mirrasekhian E, Rodriguez-Martinez H, Berg G, Lash GE, Jenmalm MC, Ernerudh J. The human fetal placenta promotes tolerance against the semiallogeneic fetus by inducing regulatory T cells and homeostatic M2 macrophages. J Immunol 2015; 194: 1534-1544
• 22 Ulff-Møller CJ, Jørgensen KT, Pedersen BV, Nielsen NM, Frisch M. Reproductive factors and risk of systemic lupus erythematosus: nationwide cohort study in Denmark. J Rheumatol 2009; 36: 1903-1909
• 23 Runmarker B, Andersen O. Pregnancy is associated with a lower risk of onset and a better prognosis in multiple sclerosis. Brain 1995; 118: 253-261