Immunology of Recurrent Pregnancy Loss Ed Moticka, Ph.D. emoticka@atsu.edu "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."

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

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.

IMMUNO TRIVIA TIME!!

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

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

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

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

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

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

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

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

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

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

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

FASEB J. 2005, 19: 681-693

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

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

FASEB J. 2005, 19: 681-693 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)

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.

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

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

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

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

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

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.

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

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

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

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

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

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.