Immunological Principles Relevant for

IMID and Pregnancy

Pr Vincent GEENEN
Research Director FSR-NFSR
ULg Centre of Immunology (CIL), Laboratory of Immunoendocrinology & Embryology
Institute of Pathology CHU-B23
Liege-Sart Tilman

Centre d’Immunologie
Immunological Principles Relevant for IMID and
Pregnancy

1.Sex differences in autoimmune and inflammatory disorders.

2.Immunology of pregnancy.

3.Current principles of feto-maternal tolerance.

4.Placental transfer of immunoglobulins.

Sex differences in autoimmune and inflammatory
diseases

Testosterone (T): Negative immunomodulation

Estrogen (E): Low  Th1 polarisation
High  Th2 polarisation
Progesterone (P): Negative immunomodulation
Prolactin (PRL): Positive immunomodulation

C. Whitacre Nature Immunology 2001 2: 777

Immunology of pregnancy

Immune system component Alteration with pregnancy

Thymus Involution
T and B cell number and subsets No change
H-Y specific T cell 
T-cell function No change or 
NK-cell function 
Ab-dependent cellular cytotoxicity No change
Response to vaccines No change
Immunology of pregnancy

High progesterone
/estrogen (P/E) ratio

C. Whitacre Science 199 283:1277

Immunology of pregnancy
• Deletion of leukemia inhibitory factor (LIF)
Sterility by defective embryo implantation

• Deletion of granulocyte-macrophage colony stimulatory factor (GM-CSF)

Poor placental development, fetal growth delay or fetal loss

• Deletion of macrophage colony stimulatory factor (M-CSF or CSF-1)

 Low pregnancy rate, small litter size.

• Interleukin-10 or Interferon- treatment corrects spontaneous foetal loss in the

murine CBA x DBA/2 model.

Immunomodulation by progesterone

Progesterone (P)  activation-induced deaminase (AID),  Ig diversity.

 anti-viral TLR-7 and TLR-9 mediated IFN- production.

 Th1 development but  differentiation of IL-10+ Th2 cells.

 macrophage, DC and NK cell activity.

 thymus involution and  early T-cell lymphopoiesis.

Immunology of pregnancy:
Role of progesterone in thymus involution

T.A. Tibbetts et al Proc Natl Acad Sci USA 1999 96:12021

The post partum is critical for some autoimmune
and inflammatory diseases

C. Confavreux et al. New Engl J Med 1998 339:285

The Immunological Paradox of Pregnancy

« How does the pregnant mother continue to nourish within herself for many
weeks or months a foetus that is antigenically a foreign body? »

Sir Peter Medawar, 1953

Main types of surface HLA molecules

HLA-DP HLA-DR HLA-B HLA-C HLA-A

HLA-DQ
The two HLA haplotypes are co-expressed
(codominance)
Children differ from their mother for their paternally
inherited HLA alleles
The foeto-maternal interface

A. Moffett & C. Loke Nature Reviews Immunology 2006 6:584

No expression of HLA-A, B and of HLA class II by
trophoblast

trophoblast
Expression of HLA-E and HLA-G

trophoblast
... which bind to NK inhibitory receptors

NK cells

trophoblast
Indoleamine 2,3-dioxygenase (IDO)

local
trophoblast cell tryptophan
depletion

IDO
N-formyl-kynurenine
paralyzed
lymphocyte
(reversible)
Regulatory T cells (Treg)

S. Sakagushi Nature Immunology 2005 6:345

Foeto-maternal tolerance:
Summary of local immunosuppressive pathways
The embryo plays an active role in implantation,
maternal tolerance and placentation

Endocrine ( P) and immune

effects in maternal blood

hCG

Implantation LH/hCG-R
Decidualization LIF  
LIF
LIF
Tissue
remodelling
IL-6  
IL-6
IL-6
Tolerance VEGF 
Angiogenesis
M. Tsampalas et al. Journal Reproductive Immunology 2010, in press.
hCG attracts Tregs into the foeto-maternal interface
during early human pregnancy

A. Schumacher et al. Journal of Immunology 2009 182:5488

Placental transfer of antibodies
Fetal erythroblastosis

Neonatal Graves-Basedow’s disease

Decrease of maternal serum IgG concentration
during pregnancy

A. Malek et al. Am J Reprod Immunol 1996 36:248.

Increase of fetal serum IgG concentration during
pregnancy

Serum IgG is detectable in

the foetus as early as 13
weeks of gestation, and its
concentration increases
steadily until birth.
A. Malek et al. Am J Reprod Immunol 1996 36:248
At birth, a child has more serum IgG than its mother

maternal IgG

fetal IgG

A. Malek et al. Am J Reprod Immunol 1996 36:248

IgG transcytosis by FcRn in the syncitiotrophoblast

transcytosis

FcRn
Structure of FcRn

- FcRn is a heterodimer  chain / 2-microglobulin

- 2 FcRn bind 1 IgG

- FcRn binds only IgG (not IgM, IgA, IgE)
- FcRn binds IgG1>4>3>2
- FcRn also binds albumin, at another site than IgG
Consequences of TNF blockade during foetal
development

Injection of anti-TNF in pregnant mice

 Severe but transient growth retardation (± 35%).
 Normal growth hormone blood levels.
 Decrease of IGF-1 blood levels (± 50%).
 Marked atrophy of thymus, spleen and lymph nodes.
Phenotype of TNF-/- mice

 No change in sex ratio, litter size, and weight gain after birth.
 No difference in lymphocyte, granulocyte, or monocyte populations.
 Depression of response to T-cell dependent Ag immunization.
 Highly susceptible to Candida albicans infection.
 Normal LPS-induced cytokine response (except CSF activity).
Effects of anti-TNF mAb during pregnancy and
lactation on the macaque immune system

 No effect upon T and B cell populations.

 No impairment of immune response to antigen challenge (KLH, TTX).
 No significant change in delayed type hypersensitivity responses to ID TTX.

P.L. Martin et al. Am J Reprod Immunol 2007 58:138

General conclusions
• Female prevalence of many auto-inflammatory diseases: Opposite
immunomodulative effects of testosterone and estrogens (E).
• High P/E ratio and hCG blood levels in pregnancy (1 trim.):
Negative immunomodulation.
• Foeto-maternal tolerance: Local
immuno-suppressive pathways.
• New paracrine actions for embryonic hCG in implantation, fetal
tolerance, and placental angiogenesis.
• After the 20th week of pregnancy: Active
transcytosis of IgG through placenta.