IMMUNOLOGY OF THE MATERNAL – FETAL INTERFACE

Asha Ann Philip

MVSc Scholar

Division of Pathology (VPL)

IVRI,Izatnagar, UP-243122

OVERVIEW

INTRODUCTION

HISTORICAL PERSPECTIVE AND SIGNIFICANCE

PREGNANCY –MOUSE Vs HUMAN

MATERNAL FETAL INTERFACE

IMMUNE CELLS (d NK cells, Macrophages, DC, T

cells )

ANTIGEN SPECIFICITY AND TRAFFICKING

INFECTIOUS DISEASE CONTROL

PERSPECTIVE VIEW

CONCLUSION

pregnancy complications

preeclampsia

congenital infections

IUGR

abortion,

Interface :-

Composition and functions vary locally- Uterine decidua

(NK cells, Dendritic cells, Macrophages, T cells)

Immune cells play a role in pregnancy /failure

Mouse and human studies

Pathogenesis of pregnancy complications

INTRODUCTIONd NK cells,

Dendritic cells

Macrophages,

T cells

? Paternal histocompatibility by fetus should provoke tissue rejection response (Medawar ,1953)

? Unusual kind of decidual NK ( d NK ) cells perform key developmental role in human and mice .

? Immunological lesions underlying pregnancy complication.

Uterine vasculature remodeling in gestation

Preeclampsia (5-7%)

(Impaired activation of d NK cells)

Reproductive

success in placental

(eutherian)

mammals

Placenta Uterus

HISTORICAL PERSPECTIVE AND SIGNIFICANCE

PREGNANCY –MOUSE VS HUMAN

•20 days

•Placental trophoblast do not

invade deep in decidual

arteriole.

•Preeclampsia and IUGR rare

•Decidualisation only at

implantation

• 9 months

• Trophoblast temporarily replace

maternal endothelial cells

• Common

• Decidualisation at

Secretory phase and implantation

•Haemochorial placentation

•Decidual accumilation of NK cells (Moffett,2006) and (Maltepe et al,

2010)

MATERNAL FETAL INTERFACE

Flow cytometry and

Immuno staining

(Bulmer et al, 2010)

NK Cells- 70%

Macrophages- 20%

T cells - 10-20%

DC & B cells- rare

Cellular constituents in first trimester of human decidua

MATERNAL IMMUNE CELLS

d NK cells,

Dendritic cells

Macrophages,

T cells

Placental Development and

function

Minimise chance of placenta

being attacked.

To combat infection

Trophoblast

(PLACENTA)Uterine MucosaDecidualization

NATURAL KILLER CELLS (D NK CELLS)

1.Transforming spiral arteriole in decidua

Replacing endothelium by trophoblast

Incomplete spiral transformation and failure of trophoblast

Preeclampsia & IUGR (Khong et al, 1986)

Role of IFN γ in Remodelling of spiral arteriole (Apps et al, 2011)

Preeclampsia: KIR lack Tel-B for HLA-C.

Inhibitory signal to d NK Cell RSA & IUGR (Hiby et al, 2010)

No mice shows gestational hypertension

Trophoblast endovascular migration

FUNCTIONS

Second phase

First phase

d NK cell

Hypoxia

2. Role in I/U inflammation & Abortion

d NK cell Cytotoxic granules (perforin and granzyme) (Manaster, 2010)

Why d NK cell do not threaten fetal survival?

d NK cell cytolytic action is low at base line

Non classical MHC I molecule interaction (HLA-E, HLA-G)

on trophoblast cell (App et al, 2008) ( Chazara et al, 2011)

D NK cell is embryotoxic at certain circumstances

IL-10 TNF- α , IL-6: Embryo resorption

Appear in secretory endometrium prior to implantation.( CD 56 bright,

CD16-) (Koopman et al, 2003)

Pregnancy specific functions :TGF-β, IL-15 (Keskin et al, 2007)

MACROPHAGES

2nd most abundant : 20% ( 50-100 cells/mm² in first trimester)

Marker : CD 14 , CD 209 (IL-10 level)

Remodelling: (fibronectin, collagen components, matrix metalloproteinase-9, C1q)

d macrophage in 3rd trimester: Preeclampsia

Role in parturition:Pro inflammatory mediators (IL-6, TNF- α )

PAMPs Acute chorio amnionitis preterm birth

Remodelling

Pathogen sensors

Immune effector cell

macrophage

CD 14

Monocytes

CSF

IL-10

d Macrophage

D stromal cells

dNK cell

glandular epithelial cells

F4/80+MHCII hi (CD 209-)

F4/80+ MHCII lo (CD 209 +)

Growing myometrium

CSF

dNK cell

DENDRITIC CELLS

Adaptive immune responses

D C are scarce at Interface (1-5 cells) (Tagliani,2011)

Decidualisation : fall of DC cells 9/mm²to 2/mm²

DC ENTRAPMENT Mouse endometrium lack lymphatic vessel (Collins et al, 2009)

Inflammation

pathogen

DENDRITIC CELLS

Lymphatic vessel

Lymph node

FUNCTIONS

Dendritic cell as decidua

Tissue remodelling

Uterine mucosa to

survey pathogen

T cell immunostimulation

T CELLS

10-20% of leucocytes in first trimester is CD3 TCR

10-20% T cell

CD4

(30-45 %)

50% Memory

5% Regul

CD8

(45-75%)

40% Memory

Th2

Th 17

Th1

•5%

•2 %

•Spontaneous Abortion

•5-30%

•RSA

Spontaneous Abortion

Preeclampsia

T Reg

Th 17

Activated T cell accumilate at

inflammatory site: chronic

deciduitis, chronic

chorioamnionitis and VUE.

ANTIGEN SPECIFICITY AND TRAFFICKING

How many T cells have fetal/ placental specificity?

Human: CD 25 ( activated/ memory) CD4+ T cell in pregnancy is elevated (10%) if mismatch in fetal-matetnal HLA-C allele (Tilburgs et al,

2009)

Differentiating decidual stromal cells silences expression of the key Th1/CTL-attracting chemokines (CXCL9 ,CXCL10 ,CXCL11 and CCL5)

Loss of chemokine silencing: Late pregnancy complications.

Naive maternal CD8+ T cells fail to

encounter Ag and differentiation into

Th1 cells and CTLs (Reinchart et al, 2003)

INFECTIOUS DISEASE CONTROL

Organisms infect placenta and amniotic membrane.

Preterm birth

IUGR

Still birth

Congenital Abnormalities

P.falciparumMaternal

bloodVillous

tree

Other organisms

Decidua Placenta

Decidua is GROUND

ZERO for avoiding

immunological assault

& infection

CYTOMEGALO VIRUS

Haemopoiticprogenitor

Mononuclear phagocytes

Stromalcells

(MICE)

RESERVOIRHumoral immunity is the only defense.

Placental infection -vely corelated by Maternal IgG Titres

( Mc Donagh eta l, 2004)

CMV DNA detected in 89% of first trimester

Elective termination : +ve for i/c Staining Decidual biopsy

Immunocompetant host: Controlled by Memory T cells

organ transplant patients HIV patients

Latent infection: 30-70% population (Gandhi & Khanna, 2004)

LISTERIA MONOCYTOGENES

EXTRAVILLOUS TROPHOBLAST anchoring villi

PLACENTA

Organism carried by extravasating Leucocytes

Immunoprivilaged environment (T cells):

Survival

Decidua not at mercy of pathogen

Controlled by T cells

MACROPHAGESNEUTROPHILS

TROPHOBLAST

ACUTE CHORIOAMNIONITIS

IL-8TLR

d stromal cell

Trophoblasts

Amniotic epithelial cells

Neutrophils

IL-17 (T Cell)

IL-22 ( lymphoid cell)

G-CSF

Ascending bacterial infection from cervix.

Cause Pre term birth

Neutrophils are recruited

Decidua

IL-15 NK CELL

CSF Macrophage

Chemokine silencing Th1/ CTL

Decidua resisted homing of Th1and CTLs

Artificial decidual reaction

Restrict immune cells (T cell, DC, B cell )

Specialisation of leucocytes (NK, macrophage)

dNK cell accumulation

T cell exclusion as true decidua

loss of macrophage and DCdensity

PERSPECTIVE VIEW

Trophoblast - d NK cell interaction is essential for success of pregnancy

Threat in reproductive success is due to pro inflammatory molecules of macrophages (IL-6, TNF- α )

Decidual macrophage exposure to CSF-1 is a major

mechanism for local monocyte recruitment & constant at gestation.

Paucity of DCs limit adaptive T cell responses & minimizing immunogenic responses to fetal/placental antigens

Impaired activation of Immune cells lead to pregnancy complications ( Preeclampsia, IUGR, Abortion)

Decidua is GROUND ZERO for avoiding immunological assault & during infection.

CONCLUSION

Erlebacher,A.2013. Annu. Rev. Immunol. 31:387–411

Manaster I, Mandelboim O. 2010. The unique properties of uterine NK cells. Am. J. Reprod. Immunol.63:434–44

Medawar PB. 1953. Some immunological and endocrinologicalproblems raised by the evolution of viviparity in vertebrates. Symp. Soc. Exp. Biol. 7:320–38

Moffett A, Loke C. 2006. Immunology of placentation in eutherian mammals. Nat. Rev. Immunol. 6:584–94

Romero R, Espinoza J, Kusanovic JP, Gotsch F, Hassan S, et al. 2006. The preterm parturition syndrome.Br. J. Obstet. Gynaecol. 113(Suppl. 3):17–42

Stewart IJ, Mitchell BS. 1991. The distribution of uterine macrophages in virgin and early pregnantmice. J. Anat. 179:183–96

Trundley A, Moffett A. 2004. Human uterine leukocytes and pregnancy. Tissue Antigens 63:1–12

REFERENCES