Controversies and Current Research The immune system in menopause

Controversies and Current Research The immune system in menopause and infertility Northside Hospital WomenFirst February 26, 2002 Mark Perloe, M.D., mpmd@ivf.com www.ivf.com Controversies and Current Research The immune system in menopause and infertility Immunology 101 Sex hormones and the immune system Pregnancy Recurrent pregnancy loss Infertility – Sperm Antibodies – Endometriosis – Premature Ovarian Failure Getting information Evaluating medical research Immune Cells Adaptive Immune Response Lymphocytes B-Cells – Antibody production T-Cells – Helper/inducer – Suppressor – Cytotoxic Innate Immune Response Phagocytes Macrophages Neutrophils, basophils, eosinophils, mast cells Natural Killer Cells – Activated & inactivating receptors Immune Cells Human Leukocyte Antigens HLA Cell surface molecule assists recognition of antigens by Tlymphocytes Determines individual tissue typing HLA Class I – A, B, C, G – CD8+ cytotoxic T cells HLA Class II – DP, DQ, DR – CD4+ Helper T cells T cells recognizing self-antigens undergo apoptosis in thymus Cytokines Soluble molecular mediators responsible for many of the intercellular collaborations that take place during the development of the immune response Involved in cell growth, differentiation & function Short half-life Act locally Cytokine Response Complement Soluble components of the innate immune system – Enhanced phagocytosis – Stimulates chemokines and proinflammatory cytokines – Membrane attack complex leads to cell death Triggered by: – Antigen-antibody complex – Bacterial cell walls Immune System Sexual Dimorphism Males are more susceptible to infection Androgens increase susceptibility to infection Women 2.7-fold risk to develop autoimmune disorders Autoimmune Disorders Disease Grave’s Disease IDDM Prevalence Rate/100,000 1152 192 Female-Male Ratio 8/1 1/1 Pernicious Anemia Rheumatoid Arthritis Hashimoto’s Thyroiditis 151 860 792 Not known 3/1 20/1 Systemic Lupus Erythematosus Significantly higher risk of pregnancy loss Excess loss due to second trimester loss Poor prognosis group – Severe renal insufficiency – Pre-pregnancy flare or newly diagnosed within 6 m. Higher rate of pre-eclampsia & premature delivery May worsen during pregnancy Role of Sex Steroid Hormone RA improves with pregnancy – Potential for postpartum flare – Flares during menopause Effect of pregnancy on SLE more variable Estrogen accelerates and androgens reduce SLE, Sjögrens’ syndrome & thyroiditis (rodents) Effect may vary by subject and organ Th2 pregnancy response may reduce Th1 mediated diseases & increase Th2 mediated conditions – Th1: Multiple sclerosis and rheumatoid arthritis – Th2: Systemic Lupus Erythematosus Estrogen Estrogen – – – – – Promote antibody production Alters peripheral T-cell activity ↑CD4+ cells Reduce NK cell activity Reduces vascular macrophage activity MCP-1 Inhibits bone resorption • Reduces osteoclast stimulation: IL-1, TNF-α, IL-6 Progesterone Inhibits lymphocyte activation Inhibits killer-T cell generation and activity (PIBF) Reduces macrophage proliferation & oxygen free radical generation Inhibits peripheral antibody production Promotes allograft survival Reduces Th1 cytokines Androgens Increases cytotoxic CD8+ T cells Reduces pre-B cell population in bone marrow No effect on peripheral B cells Reduce NO synthetase – Immune defense – Atherosclerosis Decreases macrophage Fc receptor Stimulates Th1 response Pregnancy Why didn’t your mother’s body reject you? – 1950 Medawar: maternal-fetal tolerance – 1991 Colbern & Main: maternal-placental tolerance Is the pregnant uterus an immune-privileged site? – Mechanical barrier to placenta • Cell traffic exists across placenta in both directions – Suppression of the maternal immune system during pregnancy • Maternal antiviral immunity not affected by pregnancy • Progesterone is immunosuppressive – Absence of polymorphic MHC class I and II molecules on the placenta (HLA-G is expressed) – Cytokine shift • Regulate immune response and control placental growth and implantation – Local immunosuppression • Cytokine FAS-FASL induces programmed cell death (apoptosis) in harmful cytotoxic T cells directed against paternally derived HLA antigens Pregnancy Loss 30-40% occult pregnancy loss 15-20% clinical pregnancy loss 1-2% recurrent pregnancy loss Prevalence Spectrum of Pregnancy Loss Pre-clinical occult pregnancy loss – Developmental failure: fertilized egg fails to divide – Failure to implant: blastocyst does not implant – Preclinical: failure after implantation Clinical loss – – – – Embryonic: loss before the 9th week of pregnancy Fetal: loss after the 9th week of pregnancy Miscarriage: loss after before the 20th week of pregnancy Stillbirth: loss after 20 weeks Recurrent pregnancy loss autoimmunity and pregnancy loss Diagnosis – Antiphospholipid antibody syndrome ACL, APS, API, APE – Anti Nuclear Antibodies ANA – Anti Thyroid Antibodies ATA Treatment – Heparin and baby aspirin – Prednisone – IViG Recurrent pregnancy loss Alloimmunity: pregnancy as an allograft Immunosuppression in pregnancy – Role of NK-cells – TH1 vs. TH2 response – HLA-G, Progesterone Blocking Factor Diagnosis – – – – Embryo toxic factor Immunophenotype and NK-cell activity Cytoxicity HLA Treatment – IViG – LIT Antiphospholipid Antibodies & Infertility There is no evidence to suggest that APA are a cause of infertility or IVF failure NK-Cells and Infertility Sperm Antibodies Causes – – – – Obstruction of sperm egress Testicular trauma Sexually transmitted diseases Polyglandular autoimmune failure Fertility impaired only when a majority of sperm are coated with antibody No prospective studies that demonstrate decreased fecundity in couples where sperm Ab are detected Present in 3-5% of infertile population Sperm Antibodies May inhibit or promote zona binding Alter sperm longevity Adverse effect on sperm-mucus interaction and sperm transport Polyclonal antibodies – May be specific to an individual – React to several different sperm proteins/locations May be present in serum but not semen Cumulative Pregnancy Rates OR….. Will I ever conceive? ICSI maximizes fertilization Endometriosis Endometriosis Endometriosis Estrogen & Natural Killer Activity Anti-Ovarian Antibodies Indications for testing – Diminished ovarian reserve – Poor response to ovulation induction What causes AOA? – Ovarian surgery – Infection – Immune system activation Treatment – Medrol therapy – Oocyte donation Internet Resources Where to find information – National Library of Medicine • Medline, PubMed – Expert Chats – Bulletin Boards & Newsgroups – Organization Websites – Mail Lists & eGroups – Other Websites Caveats & Limitations Limitations – – – – – Credentials may not evident Financial bias Self promotion Dumbing down information provided Is material current? No two cases are identical Keyboard + monitor Pelvic Exam +Ultrasound Evaluating medical literature – Press and public get access at before physicians! Clinical Study Types Experimental Studies – Randomized Control Trials (RCT) – Randomized Cross-Over Trial Observational Studies – – – – – Cohort (Incidence, Longitudinal) Case-Control Cross-Sectional (Prevalence) Case Series Case Report Evaluating Medical Studies Validity: Truth – External Validity: Can the study be generalized to the population of the reader – Internal Validity: Study is well designed. Results not due to chance, bias or confounding factors – Symmetry Principle: Groups are similar Evaluating Medical Studies Confounding: distortion of the effect of one risk factor by the presence of another Bias: Any effect from design, execution, & interpretation that shifts or influences results – Confounding bias: failure to account for the effect of one or more variables that are not distributed equally – Measurement bias: measurement methods differ between groups, lack of blinding – Sampling (selection) bias: design and execution errors in sampling – Reader/Investigator bias: human tendency to accept information that supports pre-conceived opinions and reject studies that don’t – Sponsorship bias: studies designed to support sponsors views What’s a Meta-analysis? Meta-analysis provides an overview of clinical trials Meta-analysis is a set of statistical procedures designed to accumulate experimental and correlational results across independent studies that address a related set of research questions. Meta-Analysis Variability in populations Variability in study design – Study quality – Endpoint reportage – Availability of data Variability in interventions Clinical Decision-making What is my RISK ? – of the event the treatment strives to prevent? – of the side-effect of treatment? What is my chance of RESPONDING? What is the treatment’s FEASIBILITY in my MD’s practice/setting? What are my VALUES ?