Immune System in Pregnancy - Jan 2024 Past Paper PDF

Immune system in pregnancy Alison Busby  Aims/Learning outcomes To consolidated your understanding about the normal functioning of the immune system. To be able to identify the most significant pregnancy-related changes in the functioning of the immune system and summar...

Immune system in pregnancy Alison Busby  Aims/Learning outcomes To consolidated your understanding about the normal functioning of the immune system. To be able to identify the most significant pregnancy-related changes in the functioning of the immune system and summarise the reason for these changes and their implications for childbearing women and pregnancy outcomes. To be able to explain why women who are Rh Negative may be offered donated Anti D during pregnancy and following birth.  Consider the following questions 1. List some of the physical barriers that help prevent invasion by pathogenic microbes. 2. What is meant by ‘innate’ or ‘non-specific’ immunity? 3. What is meant by ‘specific’ immunity? (Also, what is an ‘antigen’ & what is an ‘antibody’?) 4. Why does the body normally reject transplanted tissue unless the person is taking immuno-suppressant medication?  Types of 500 billion blood cells made in the bone marrow each day Natural Killer Cells (Non-specific/ innate protection) Recognise virus-infected cells and cancer cells via stress blood cells – all from these stem cells markers. Recognise own cells via protein markers) Uterine NKC trigger necessary inflammation in Mast Cells rich in histamine. endometrium allowing embryo implantation. Act as early warning system to trigger immune activity in ‘at risk’ tissues. Can trigger T helper 1 cells excessive reactions (allergy). Help Cytotoxic T cells to Also affect sleep-wake cycles. attack host cells invaded by pathogens (mostly viruses) T Helper 2 cells Help activate B lymphocytes to make antibodies Erythrocytes or RBC M Cytotoxic T cells Some become Helper T Cells Memory Cells. T Reg Th1 Th2 M Regulator or Platelets T Cells B lymph/Plasma cells release Cytotoxic T Cells antibodies into the blood. Neutrophils – most common WBC. Attach to viral infected Triggered by presence of Circulate in the blood. First responder at cells, cancer cells & antigens & Helper Th2 cells site of infection (attracted by cytokines), foreign cells. Triggered phagocytose pathogens & die – form pus by antigens presented in Regulator T Cells (Tregs) calm Basophils Role in inflammatory response, Macrophages & dendritic cells the wall of these cells. cell-mediated immunity release Histamines migrate out of the blood. Effective Kill the cell triggered by activity (interrupt +feedback Eosinophils Role in defence against phagocytes. Alert other cells. interferon. Some process) to protect own cells. parasites & worms & allergic reactions become Memory Cells  Blood & Immune responses questions 1.Which type of blood cells have no nucleus ‘hang out’ whilst they mature? and why? 9.What are macrophages are good at? 2.What do platelets do and what is another 10.Do T or B cells make and release antibodies name for them? into the blood? 3.Which WBCs arrive first at the site of tissue 11.Do T or B cells attack infect host cells? damage or infection? 12.What do T helper cells do? 4.Which sorts of WBCs contribute to the release of histamine & identify three 13.What do T regulator cells do? functions of histamines. 14.What is the difference between Non- 5.Natural killer cells (NKCs) are part of the specific and specific immunity? non-specific immune response– what are 15.Why does the body normally reject they especially good at? transplanted tissue unless the transplant is 6.Why are NKCs very important for a a close match of the person’s ‘tissue type’ successful pregnancy? and the person is taking immuno- suppressant medication to suppress their 7.What is an antibody and what is an own immune system? antigen? 8.Lymphocytes form into either T cells or B cells – where do these two sorts of cells  Why doesn’t the mother’s body reject the fetus as foreign tissue? Immune system normally attacks foreign cells & proteins Fetal tissue is different from mother’s – Each person has their own unique MHCs (major histo-compatibility complexes - antigens) If fetal tissue is used as a graft for the mother, her body rejects it So why not rejected in the uterus? Various factors contribute to this:  Summary - key immune system changes in pregnancy Body aims to maintain protection, but not reject the fetus: 1.Hormonal & physical changes increase risk of some bacterial infections 2.Innate immunity mechanisms are enhanced to increase protection 3.B-cell responses to most infective agents are enhanced 4. Responses to foreign MHCs are suppressed (to reduce rejection risk for fetal/placental tissue), but also reduces immune protection against viral infections which multiply with a person’s own cells 5. Particular immunological responses in the endometrium & placenta 6. Changes in some auto-immune disease processes during pregnancy  Innate/non-specific immunity Early ( 1-4 days) general defences against foreign antigens: – Physical barriers e.g… & Biochemical barriers e.g… – Circulating Factors/Compliment System Small plasma proteins circulate as inactive precursor e.g… Activation leads to a cascade of effects to clear foreign material & damaged cells, tiggering & enhancing… – Inflammation responses – includes… – Phagocytosis by Neutrophils & Macrophages – Lysis (breakdown) by Natural Killer Cells Alterations in non-specific/innate immunity in pregnancy White cell count increase in early preg – especially neutrophils – ?To quickly destroy stray trophoblast cells in maternal blood? Faster phagocytosis – Oestrogen makes Macrophages & Neutrophils more active At the placenta - many macrophages but some actions inhibited… – Eg Glyco-protein PZP inhibits phagocytosis & Interleukin-2 release (needed to activate T & B cells) Natural Killer Cell activity suppressed by progesterone – Especially in 2nd & 3rd Trimesters – Increases vulnerability to viral infections especially in later pregnancy – Activity at the placenta – see later  Normal Adaptive /Specific Immunity Protective responses against specific antigens Establishes an immunologic memory of those responses. Normally none-reactive to hosts own MHCs Includes 3 main responses… 1. Antibody production – against free bacteria, viruses & toxins B-lymphocytes attach to antigens, then form & release antibodies (immunoglobulins) into the plasma, assisted by T-helper cells (Th2) These B-lymphocytes replicate so more antibodies can be made Some cells become long-living ‘memory cells’ so response is much quicker when next exposed to that pathogen (Sensitisation)  Adaptive (Specific to organism) immunity 2. Cell-mediated immunity – eg destruction of cells with foreign MHCs, cancer cells & hosts own cells inhabited by intracellular microbes (viruses & certain small bacteria – eg Listeria) T-cytotoxic cells (Tc) attach to & kill virus-infected cells, assisted by T-helper cells (Th1) These are also the cells responsible for attacking transplanted tissue (so could potentially attack the fetus) Some Tc cells become memory cells - so can react quickly in future infections 3. Regulatory T-cells (T-regs) inhibit the immune responses once the invading antigens are controlled Suppress cell-mediated immunity to prevent Tc cells attacking our own tissues and causing auto-immunity problems  Alterations in adaptive / Specific immunity in pregnancy 1. Progesterone alters the balance of Th1 & Th2 cells – Fewer Th1 helper cells – so less help for cell-mediated responses ↓ – More Th2 helper cells – so more help for antibody-mediated responses ↑ – If Th-1s NOT reduced… Good protection against viruses remains but… Associated with spontaneous abortion, pre-eclampsia, pre-term labour & fetal growth restriction. 2. The number of T-regulator cells increases ↑ – Suppress tissue-rejection processes Protects the placental cells from aggressive immune responses – Suppresses cell-mediated immunity Results in decreased protection against viral infections. – Improves condition of some auto-immune diseases eg rheumatoid arthritis  Interactions of fetal tissue & maternal immune response at the placenta Normally a vigorous but ‘non-standard’ maternal immune response to fetal MHC antigens on the placental cells. – Needs a strong immune response from the mother for a healthy pregnancy (eg contributes to spiral artery re-modelling) – Fertility decreases if couple are closely related – may be because a less vigorous response to the fetal tissue is generated as is more similar to the woman's tissue?? Trophoblast cells have a unique MHC-1 antigen (HLA-G) – Blocks cytotoxic action of NK cells (see next slide) A Trophoblast enzyme breaks down amino acid TRYPOPHAN – Trypophan is essential for T-cell proliferation. – If trypophan supplied limited - T cells become T-Reg cells (calm immune reactions) Natural Killer Cells at placental site – unique & very active  Natural Killer Cells at the placental site NKCs in the blood - Normally recognise & attack viral-infected cells or foreign cells or cancer cells - which cease to display ‘self’ marker proteins NK cells gather at placental implantation site – under the influence of local prostaglandins, they act differently to NK cells in the blood – A Trophoblast MHC protein (HLA-G) blocks receptors on the NK cells that initiate lysis (cell death) (protects trophoblast cells in that area?) – Instead, NK Cells produce certain cytokines IL-8 & IL-10 which stimulate trophoblastic invasion & vascular re-modelling. Unfortunately, this also means there is less resistance to intra-cellular pathogens such as Viruses, Listeria & Toxoplasmosis Smoking alters NK cells - making them more cytotoxic to placental cells – Allows damage of placental cells & so affects placental functions  Effects of semen on the woman’s immune system Semen in the woman’s body causes release of cytokine signals to increase numbers of T-reg cells to calm rejection processes. Why? – So maternal immune system does do not usually attack sperm cells? – Does frequent exposure to partner’s semen affect immune responses? – Impact on embryo implantation in in surrogate mothers ?? – NB: Assists the transmission of sexually transmitted infections  Pre-eclampsia Associated with poor placental development due to inadequate re-modelling of spiral arteries. Remodelling depended on a vigorous but altered immune response at the placental implantation site (NK Cells) Seems to be associated with limited contact with partner’s semen e.g… – First pregnancies – New partner – Longer gap between pregnancies – Pregnancy soon after first intercourse with partner – Barrier methods of contraception  Maternal susceptibility to infection Increased maternal risk of serious viral illness especially in last trimester – Eg Viral hepatitis 10 x infection rate of non- pregnant women & worse effects – Eg Flu – delayed response, higher infection rate, more severe effects especially in 3rd trimester – Eg COVID – increased risk of severe disease Latent infections may become more severe in pregnancy – Eg Tuberculosis, Malaria, HIV (all live inside host cells) Increased immunological responses to bacteria – aid responses to increased risk of UTI (due to anatomical changes) and increased risk of bacterial chest infections (reduced secretion clearance)  Protecting the fetus from infection? Most viruses & many bacteria theoretically could cross the placenta – but few do. – Membranes & placenta – a physical barrier – Amniotic fluid - contains anti-bacterial factors, similar to human milk eg transferrin, immunoglobulins & lysozymes – Trophoblast cells secrete antimicrobial factors to inhibit infection – Trophoblast cells have many receptors for recognising & binding to specific molecular patterns associated with pathogens Fetus is susceptible to some viruses, intracellular bacteria & parasites which are able to cross the placenta – Eg CMV, Rubella, Varicella, Toxoplasmosis, Listeriosis – Infection risk is greater in later pregnancy but causes fewer damaging effects as fetal nervous system is more mature  Trans-placental passage of antibodies Neonatal immune system immature & has no memory store Gains temporary passive immunity via placenta & breastmilk – IgG antibodies cross placenta in large amounts (active transport) – Give passive immunity to whatever the mother is immune to. Transfer rate increases very significantly after 34 weeks – Pre-term infants miss out on IgG in pregnancy – SGA infants - placental dysfunction means fewer immunoglobulins (IgGs) cross over. – Breastmilk even more important for these babies as it contains large amounts of IgA – Unfortunately, Anti D antibodies can cross also the placenta  Rhesus incompatibility in pregnancy In a woman with Rh -ve blood (RBC have no D antigens) with a Rh +ve fetus… At placental separation following birth, sometimes, some fetal Rh+ve blood can enter her circulatory system. Her immune system recognises Rh+ve (D) antigens on the fetal cells as ‘foreign’ After few days, develops antibodies against the D antigen, (= Anti-D antibodies). No problem is caused for this baby as is already born! But the woman will go on to develop memory cells (sensitisation) to enable greater & faster antibody production when next exposed to D antigens eg during the next pregnancy.  Rh (Anti-D) antibodies In a future pregnancy with another Rh+ fetus, a slight exposure to fetal blood will trigger prod’n of many anti- D antibodies. These antibodies can cross the placenta and attach to the D antigens on the fetal RBC, causing cell death and consequent anaemia & jaundice Fetal jaundice cleared by the placenta into the maternal blood but shows in the neonate very soon after birth. With each maternal exposure, maternal IgG (Anti D) is made in larger amounts, causing lysis of more fetal RBCs. The more maternal Anti-D made, the worse the effects for the fetus/baby: – Mild, then severe anaemia & jaundice – Liver problems/Hydrops Fetalis – Stillbirth or neonatal death Placental separation poses the greatest risk for maternal exposure to fetal blood But can happen following miscarriage/TOP, APH, trauma eg RTA/Assault Also following amniocentesis or CVS.  Prophylactic Anti D administration 10% UK women are Rh Neg. Now unusual to see affected babies (500/yr NICE 2016) Following birth… Take cord blood to determine baby’s blood group (do NOT hold the cord in your hand) Take maternal blood to examine to see how many fetal cells are present in her blood New blood test for pregnant women could help thousands avoid unnecessary treatment | News and features | News | NICE Since 1967 at-risk women been offered Anti-D (from donated human blood) to kill any fetal RBCs in her circulation before she develops antibodies herself and so prevent primary sensitisation (formation of memory cells). If lots of fetal cells seen – she is given a larger dose Must be given within 72hs of birth to prevent sensitisation Anti D is a human blood product – limited supply & not acceptable to all. As exposure can occur at other points during the pregnancy also… Give 2 small doses @ 28 & 34wks or one bigger dose 28-30wks After any episode of bleeding in pregnancy These small doses do not appear to cause the fetus any harm – Maternal anti-D prophylaxis during pregnancy does not cause neonatal haemolysis | ADC Fetal & Neonatal Edition (bmj.com) Also, other antigens/antibodies associated with Rh factor (eg Anti E) associated with previous large transfusions – effects not usually severe.  Immune system & Labour Cervical ripening, SRM, initiation of contractions – all involve WBC activity & inflammatory processes WBC count increases during labour and immediately afterwards – returns to normal values by 4-7 days. – May help reduce risk of genital tract infection Labour & vaginal birth (but not EL C/S ) stimulate WBC formation in the fetus.  The neonate Very immature immune system (So does not attack maternal tissue??) – but exposes neonate to significant risk of infection – Compensated for by placental IgG transfer & then breastfeeding. – And allows rapid colonisation by maternal commensal bacteria Home birth, vaginal birth, skin-to-skin contact & breastfeeding facilitate colonisation of skin, mucus membranes & gut with commensal maternal flora – Takes 6-8 weeks to fully colonise – Abnormal colonisation seen with C/S, antibiotics & feeding with formula milk A healthy gut microbiome – Triggers effective development of immune system – Supports bowel flora needed to produce Vitamin K & other beneficial products – Inhibits pathogen growth – Early colonisation affects long term immunity & epigenetic effects.  Sources and other information Library books (via the unit reading list) – Tortora – Blackburn – Coad & Dunstall – Stables & Rankin Innate immunity (article) | Immune system | Khan Academy Home | British Society for Immunology Basic Information about the microbiome & epigenetics – https://www.youtube.com/watch?v=9AfBsTAQ8zs – Your Gut Microbiome: The Most Important Organ You’ve Never Heard Of | Erika Ebbel Angle | TEDxFargo - YouTube  Open Book Example Questions 1. Summarise 5 key changes in the immune system during pregnancy and explain why each is important for mothers and/or babies. (20 marks). 2. Explain the physiological process of Rhesus incompatibility. Explain why and when Rhesus negative women may be offered donated Anti D following the birth of their baby (20 marks).  MCQ Examples Which white blood cells are Maternal immunoglobulins the first phagocytes to start to cross the placenta in arrive in large numbers at larger numbers to give passive the site of an infection immunity to the fetus from: a) Basophils a) 28 weeks b) Eosinophils b) 30 weeks c) Macrophages c) 32 weeks d) Neutrophils d) 34 weeks e) Thrombocytes (platelets) e) 36 weeks