Characterization of local and peripheral immune system in pregnant and nonpregnant ewes

Abstract

Modulation of the immune system is known to be important for successful pregnancy but how immune function might differ between the lymph nodes draining the reproductive tract and peripheral lymph nodes is not well understood. Additionally, if immune system changes in response to the presence of an embryo during early pregnancy, and if this response differs in local versus peripheral immune tissue, has not been well characterized. To address these questions, we examined expression of genes important for immune function using NanoString technology in the ampulla and isthmus of the oviduct, endometrium, lymph nodes draining the reproductive tract (lumbo-aortic and medial iliac) as well as a peripheral lymph node (axillary), the spleen and circulating immune cells from ewes on day 5 of the estrous cycle or pregnancy. Concentrations of estradiol and progesterone in plasma were also determined. Principal component analysis revealed separation of the local from the peripheral lymph nodes (MANOVA P = 3.245e-08, R 2 = 0.3) as well as separation of tissues from pregnant and non-pregnant animals [lymph nodes (MANOVA P = 2.337e-09, R 2 = 0.5), reproductive tissues (MANOVA P = 2.417e-14, R 2 = 0.47)]. Nine genes were differentially (FDR <0.10) expressed between lymph node types, with clear difference in expression of these genes between the lumbo-aortic and axillary lymph nodes. Expression of these genes in the medial iliac lymph node was not consistently different to either the axillary or the lumbo-aortic lymph node. Expression of IL10RB was increased (P < 0.05) by 24% in the reproductive tissue of the pregnant animals comparing to non-pregnant animals. Analysis of gene categories revealed that expression of genes of the T cell receptor pathway in reproductive tract tissues was associated (P < 0.05) with pregnancy status. In conclusion, assessment of gene expression of reproductive and immune tissue provides evidence for a specialization of the local immune system around the reproductive tract potentially important for successful establishment of pregnancy. Additionally, differences in gene expression patterns in reproductive tissue from pregnant and non-pregnant animals could be discerned as early as day 5 of pregnancy. This was found to be associated with expression of genes important for T-cell function and thus highlights the important role of these cells in early pregnancy.

Expression of IkappaB Family in the Ovine Liver during Early Pregnancy

“…The maternal immune system undergoes major adaptive modifications that result in multiple immunological-associated changes in immune cell populations with the time of pregnancy in humans [ 2 ]. During early pregnancy in sheep, the embryo regulates the gene expression of the maternal immune system with pregnancy status, which is essential for the successful establishment of the pregnancy [ 3 ]. Conceptus signalling (interferon-tau, IFNT) works in parallel with the pattern recognition receptors to modulate the maternal innate immune system and prevent conceptus rejection through paracrine and endocrine manners during early pregnancy in ruminants [ 4 ].…”

Early Pregnancy Regulates Expression of IkappaB Family in Ovine Spleen and Lymph Nodes

“…Ruminant conceptus signaling (interferon-tau, IFNT) modulates the innate immune system in paracrine and endocrine manners, which is essential for successful pregnancy establishment and prevention of rejection against the allogenic conceptus by the mother [ 3 ]. The immune system changes in response to the presence of an embryo, and these responses are different in local and peripheral immune tissues during early pregnancy in sheep [ 4 ]. Nuclear factor kappa B (NF-κB) is implicated in both physiological and pathological processes; NF-κB regulation is essential during pregnancy, and dysregulation results in premature termination of pregnancy, with bad outcomes for the mother and the fetus [ 5 ].…”

“…There is a downregulation of the specific alloreactivity during the pre-implantation and implantation stages of pregnancy, but the specific and non-specific alloreactivities are upregulated at mid-pregnancy in para-aortic lymph node cells [ 19 ]. The immune functions of the lymph nodes around the reproductive tract and other peripheral lymph nodes are different during pregnancy, which are involved in the modulation of the maternal immune system in ewes [ 4 ]. Lymphatic endothelial cells modulate progesterone bioavailability, which is essential for regulating immune tolerance during pregnancy in humans [ 20 ].…”

Early Pregnancy Modulates Expression of the Nod-like Receptor Family in Lymph Nodes of Ewes

“…Regulation of innate cell microenvironments within lymph nodes plays critical roles in generating adaptive responses [ 22 ]. There is a modulation of the maternal immune system during successful pregnancy, and the immune functions of lymph nodes are different between them around the reproductive tract and others in ewes [ 23 ]. Progesterone and its metabolites (PGRs and PIBF1) in lymphatic endothelial cells modulate tumor necrosis factor (TNF) α and interferon-γ (IFN-γ) production, which are critical in regulating immune tolerance during gestation [ 24 ].…”