1. Immunology of Recurrent Pregnancy Loss
Ed Moticka, Ph.D.
"THE COPYRIGHTED MATERIALS AVAILABLE IN THIS POWERPOINT ARE FOR EDUCATIONAL USE ONLY. ONE COPY PER STUDENT IS PERMITTED FOR EDUCATIONAL PURPOSES. REDISTRIBUTION IS NOT PERMITTED."

2. A
Pregnancy Loss B
Spontaneous C
Recurrent D
Uterine Factors E
Medical Conditions F
Endocrine G
Autoimmune H
Chronic Illness I
Genetic /
Environmental J
Psychological K
Therapeutic Abortion

3. Learning Objectives
Describe the immunologic relationship between fetus and mother and list the mechanisms involved in inhibiting anti-fetal responses.
Describe the immunologic responses most often responsible for recurrent pregnancy loss.
List the mechanisms which explain the etiology and pathophysiology of the anti-phospholipid syndrome.

4. IMMUNO TRIVIA TIME!!

5. Antibody is synthesized and secreted by B lymphocytes CD4+ T lymphocytes CD8+ T lymphocytes dendritic cells macrophages

6. Antibody is synthesized and secreted by B lymphocytes CD4+ T lymphocytes CD8+ T lymphocytes dendritic cells macrophages

7. HLA molecules are coded for by genes in the MHC false true

8. HLA molecules are coded for by genes in the MHC false true HLA = human leukocyte associated MHC = major histocompatibility complex

9. CD4+ T lymphocytes recognize foreign antigen presented by antigen presenting cells expressing class I HLA molecules class II HLA molecules class III HLA molecules

10. CD4+ T lymphocytes recognize foreign antigen presented by antigen presenting cells expressing class I HLA molecules class II HLA molecules class III HLA molecules Remember the rule of 8: 4x2=8 and 8x1=8

11. HLA class II molecules are expressed on all somatic cells antigen presenting cells CD8+ T lymphocytes CD4+ T lymphocytes neutrophils

12. HLA class II molecules are expressed on all somatic cells antigen presenting cells CD8+ T lymphocytes CD4+ T lymphocytes neutrophils Remember all somatic cells (including APCs) express HLA class I molecules

13. HLA class I molecules include
HLA-A, HLA-B and HLA-C
HLA-Dr, HLA-Dp, HLA-Dq

14. HLA class I molecules include
HLA-A, HLA-B and HLA-C
HLA-Dr, HLA-Dp, HLA-Dq

16. Fetus as an Allograft
Mothers and their fetuses are always genetically different
50% of fetal genes and proteins are paternal
Developing fetus (and the placenta) express HLA molecules that differ from the mother’s
Mechanisms exist to inhibit rejection
Mechanical barrier
Lack of HLA II antigen expression on trophoblast
Expression of unique HLA I molecules
Suppression of maternal response
Local immune suppression

17. FASEB J. 2005, 19:

18. Mechanical Barrier
No direct mingling of fetal and maternal blood supply
Pregnant uterus a site primarily of innate immunity
NK cells
Dendritic cells
T regulatory cells
Few specific T and B lymphocytes

19. HLA Expression Trophoblast cells express no class II HLA
Trophoblast expresses HLA-G, a unique class I HLA molecule characterized by:
Low polymorphism
Inhibitory signals to leukocytes locally
Soluble form of HLA-G induces tolerance systemically
Induces secretion TGF-β and IL-10

20. FASEB J. 2005, 19:
ILT=immunoglobulin-like transcript receptor - binding of HLA-G to these receptors transduces an inhibitory or apoptotic signal to the cell
KIR=killer inhibitory receptor (on NK lymphocytes)

21. Suppression/Deviation of Maternal Immune Response
Progesterone secreted by the placenta
Cytokines/suppressive proteins
Fas-ligand
IL-10
TGF-β
Increased number of Treg cells
Conclusion – several mechanisms exist to protect the semi-allogenic fetus from being rejected by the maternal immune response.

22. Not all pregnancies are successful and in some instances pregnancy loss can be attributed to an immune response.

23. Immunologic Mechanisms of Pregnancy Loss
20 – 50% of all spontaneous pregnancy loss can be attributed to immunologic causes
Autoimmunity
Immune mediated thrombophilias
Anti-phospholipid syndrome
Alloimmunity
Immunologic differences between individuals

24. Thrombophilia – the tendency to thrombosis
Both inherited and acquired forms exist
Acquired forms due to auto-antibodies
Immune system recognizes cell membrane phospholipids as foreign and synthesizes auto-antibodies specific for them
20 different antibodies have been identified
Lupus anticoagulant and anticardiolipin are clinically significant
Presence of these antibodies have adverse effect on implantation, trophoblast function and differentiation, and placental vasculopathy

25. Anti-phospholipid Syndrome
Autoimmune disease affecting clotting system resulting in blood clots in both arteries and veins
Diagnosis requires:
Clinical event (thrombosis; pregnancy loss)
Presence of anti-phospholipid antibodies
Anti-β2 glycoprotein I
Lupus anticoagulant
Anticardiolipin
IgG or IgM (but not IgA)
Detected twice at a 6 week interval

26. Etiology of APS Antibodies
Epstein-Barr virus
HIV
HTLV-1
Parvovirus B19
Varicella
Cytomegalovirus
Adenovirus
Origin of auto-antibodies – molecular mimicry resulting from an environmental source
Viral or bacterial antigens

27. Molecular Mimicry
Molecular Mimicry
Foreign antigens that are structurally similar to self-peptides react with lymphocytes. B cell binding will lead to presentation to T cells via MHC, which leads to T cell activation. Activation of T helper cells can stimulate CD8 cytotoxic T cells and B cells.

28. Mechanisms of aPL Antibody Induced Thrombosis
Endothelial cell – aPL antibody interaction
Endothelial cell damage or activation
Increased monocyte adhesion
Increased tissue factor expression
Platelet – aPL antibody interaction
Platelet activation
Stimulation of thromboxane production

31. Pathogenesis
Endothelial cells, platelets or trophoblast are activated (trauma; infection)
Phosphatidylserine migrates to surface of activated cells
β2GP I binds to phosphatidylserine
Anti-phospholipid binds β2GP I
Complement system activated
Platelets aggregate, thrombosis initiated

32. Mechanism of Pregnancy Loss
Spiral artery vasculopathy
Infarction and thrombosis of placental and decidual vessels
Neutrophils activated through C5a receptor
Inflammation initiated
APS patients may develop severe pre-eclampsia and HELLP syndrome

33. Anti-Nuclear Antibodies
15% of women with recurrent pregnancy losses have ANA but no association has been proven
Women with SLE
Auto-antibodies include lupus anti-coagulant and anti-cardiolipin
Increased risk of miscarriage
Increased risk of preterm delivery and IUGR
Increased risk of flares

34. Alloimmunity and Pregnancy
Female becomes sensitized to paternal antigens (sperm)
Mother becomes sensitized to fetal antigens (Rh isoimmunization)
Pregnancy upsets balance of normal ratio of lymphocyte populations

35. Take Home Message
Every human fetus expresses antigens that are foreign and potentially immunogenic
Mechanisms exist which inhibit the normal maternal immune response against these foreign antigens
Immunologic causes are implicated in 20-50% of all pregnancy losses. Relevant immune responses can be either autoimmune or alloimmune in nature.