Hypersensitivity and rhesus disease
Hypersensitivity reactions; rhesus isoimmunisation and haemolytic disease of the newborn
Hypersensitivity is immune-mediated tissue damage, classified into four types by the effector and the antigen. Haemolytic disease of the fetus and newborn is the obstetric model of type II hypersensitivity: maternal IgG crosses the placenta and destroys fetal red cells. CPSP asks which disease belongs to which type, why the first baby is usually spared, and how the tests and anti-D work.
The four types of hypersensitivity
| Type | Mechanism | Timing | Examples |
|---|---|---|---|
| I Immediate | Allergen cross-links IgE on mast cells (FcεRI): histamine, tryptase, leukotrienes | Minutes | Anaphylaxis, bee sting, latex allergy, asthma, hay fever |
| II Cytotoxic | IgG or IgM against an antigen fixed on a cell or tissue: complement, phagocytosis, ADCC, or receptor blocking/stimulation | Hours to days | HDN, transfusion reactions, autoimmune haemolytic anaemia, Goodpasture (linear GBM deposits), myasthenia gravis, Graves disease, pemphigus, alloimmune thrombocytopenia |
| III Immune complex | IgG with a soluble antigen forms complexes that lodge in vessels and glomeruli, fixing complement and drawing neutrophils | Hours to weeks | SLE, serum sickness (fever, rash, joint pain 1–2 weeks after antiserum or some vaccines), post-streptococcal glomerulonephritis, Arthus reaction, acute farmer's lung |
| IV Delayed, cell-mediated | Sensitised T cells: Th1 cells activate macrophages, or cytotoxic T cells kill; no antibody | 48–72 hours | Tuberculin (Mantoux) test, TB granulomas, contact dermatitis, transplant rejection, berylliosis, Hashimoto thyroiditis (with antibody), chronic hypersensitivity pneumonitis |
- Types II and III both use IgG and complement; the difference is whether the antigen is fixed (II) or soluble (III).
- Contact dermatitis (e.g. to a wound dressing): a hapten binds skin proteins, Langerhans cells present it, and memory T cells cause a vesicular rash after 24–72 hours in the exact shape of the contact.
- Hypersensitivity pneumonitis (farmer's lung, bird fancier's lung, bagassosis from mouldy sugarcane): fever and cough 4–8 hours after exposure (type III), with poorly formed granulomas and fibrosis on chronic exposure (type IV); no IgE or eosinophils.
- Anergy: a negative tuberculin test in advanced HIV reflects loss of CD4 Th1 cells, not absence of TB.
Rhesus antigens and sensitisation
- The Rh genes lie on chromosome 1. Rh D-negative people usually have a deletion of both RHD genes; there is no 'd antigen'. A D-positive father may be heterozygous, so only half his children are D-positive.
- Anti-D is never naturally occurring; it needs exposure to D-positive red cells by pregnancy (fetomaternal haemorrhage) or transfusion, so a first pregnancy can be affected if the woman was transfused earlier.
- Why the first baby is spared: the large fetomaternal bleed occurs mainly at delivery; the primary response is slow and mostly IgM, which does not cross the placenta. In the next D-positive pregnancy a small bleed triggers a rapid IgG secondary response; IgG crosses the placenta via neonatal Fc receptors.
- ABO protection: if mother is group O and baby A or B, her natural anti-A or anti-B (IgM) destroys fetal cells before D is presented, partly protecting against Rh sensitisation; anti-D must still be given.
How haemolytic disease develops
- Maternal IgG anti-D coats fetal red cells, which are removed by splenic macrophages (extravascular haemolysis), a type II reaction.
| Stage | Consequence |
|---|---|
| Anaemia | Erythropoietin rises; extramedullary haematopoiesis in liver and spleen; nucleated red cells (erythroblastosis) and reticulocytes in blood |
| Liver occupied by haematopoiesis | Low albumin production |
| Severe anaemia (Hb about 4–5 g/dL) | High-output heart failure with ascites, effusions and skin oedema: hydrops fetalis |
| Bilirubin before birth | Unconjugated bilirubin crosses to the mother and is cleared by her liver, so cord bilirubin is modest |
| Bilirubin after birth | Immature neonatal UGT: jaundice within 24 hours, risk of kernicterus |
- Anti-Kell antibodies also attack erythroid progenitors, suppressing production: severe anaemia with few reticulocytes and little bilirubin.
- Non-immune hydrops has other causes, e.g. parvovirus B19, which uses the P antigen to infect erythroid progenitors.
- Fetal and neonatal alloimmune thrombocytopenia (maternal antibody against paternal HPA-1a) often affects the first pregnancy and causes intracranial bleeding.
Tests and monitoring
| Test | What it detects | Used on |
|---|---|---|
| Indirect antiglobulin (Coombs) test | Unbound antibody in serum, using reagent red cells | Mother's serum at booking; crossmatch |
| Direct antiglobulin test | Antibody already on red cells | Baby's cord blood in HDN; AIHA |
| Kleihauer test | Fetal cells in maternal blood (HbF resists acid elution) | Mother, to size the bleed and anti-D dose |
| Circulating fetal DNA | RHD sequences of placental origin in maternal plasma | Mother, to genotype the fetus without invasive testing |
| Middle cerebral artery Doppler | Raised peak systolic velocity (over 1.5 MoM) from low viscosity and high output | Fetus, to detect anaemia |
- Invasive tests are avoided in sensitised women because they can boost the antibody response.
- Intrauterine transfusion uses group O D-negative, CMV-negative, irradiated red cells (irradiation prevents graft-versus-host disease) crossmatched against maternal serum.
- A low, falling anti-D titre weeks after routine prophylaxis is passive anti-D, not sensitisation.
Prevention
- Anti-D immunoglobulin removes fetal D-positive cells before a primary response begins; it cannot help a woman already sensitised. If the baby is D-negative, no anti-D is needed.
Remember Fixed antigen means type II; soluble antigen in complexes means type III; no antibody at all means type IV.
Exam trap Haemolytic disease of the newborn is type II, not type III, even though antibodies circulate.
Exam trap Use the indirect test on the mother's serum and the direct test on the baby's red cells.
Test yourself on this topic
5 of the 32 questions in our bank on this topic. Choose an answer to see why every option is right or wrong.
A baby born to an alloimmunised Rh-negative mother is pale, with a large liver and spleen. The blood film shows many nucleated red cells. Why are these cells in the circulation?
Answer: Haematopoiesis outside the marrow releases them
Haemolysis and anaemia drive a strong erythropoietin response. Red cell production expands beyond the bone marrow into the liver and spleen, which enlarge, and these sites release immature, nucleated erythroblasts into the blood. This finding gives the condition its older name, erythroblastosis fetalis. A high reticulocyte count is part of the same response.
Erythroblastosis fetalis
- Anaemia drives erythropoietin
- Extramedullary haematopoiesis in liver and spleen
- Nucleated red cells in blood
- Hepatosplenomegaly, high reticulocytes
Remember Erythroblasts in the blood: marrow overflow from haemolysis.
Exam trap Nucleated red cells are a response to haemolysis, not a sign of maternal cell transfer.
Why the other options are wrong
- Maternal anti-D removes red cell nuclei slowly Antibody coats red cells; it does not affect nuclear extrusion.
- The spleen fails to filter fetal cells The spleen is active and enlarged, removing coated cells.
- They are maternal cells crossing the placenta Maternal red cells do not cross in large numbers.
- Vitamin B12 deficiency blocks maturation Megaloblastic anaemia is not the cause in haemolytic disease.
A theatre nurse with previous hand urticaria from gloves becomes breathless, wheezy and hypotensive within minutes of putting on latex gloves during a caesarean section. Which cell, already coated with antibody, releases the mediators?
Answer: Mast cell with bound IgE
Latex allergy is a type I hypersensitivity. On first exposure, latex proteins induce IgE, which binds high-affinity FcεRI receptors on mast cells and basophils. On re-exposure, the antigen cross-links adjacent IgE molecules and triggers immediate degranulation of histamine, tryptase and newly formed leukotrienes and prostaglandins. These cause bronchospasm, vasodilatation and capillary leak within minutes.
Type I hypersensitivity
- Prior sensitisation makes IgE
- IgE on mast cell FcεRI
- Antigen cross-links IgE
- Histamine, tryptase within minutes
Remember Minutes after exposure: think IgE and mast cells.
Exam trap Type I needs a previous exposure, even if the person was unaware of it.
Why the other options are wrong
- Neutrophil with bound IgG Neutrophils are recruited later, not the trigger.
- Cytotoxic CD8 T cell Type IV effector cells, acting over days.
- Macrophage with bound IgM Macrophages do not bind IgM to trigger anaphylaxis.
- Natural killer cell with bound IgG NK cells mediate antibody-dependent cytotoxicity, not anaphylaxis.
A pregnant woman with untreated HIV and a CD4 count of 90 cells/µL has sputum-positive tuberculosis, yet her tuberculin skin test shows no induration at 72 hours. What explains the negative test?
Answer: Loss of CD4 T-helper cells
The tuberculin reaction is a type IV hypersensitivity response. Memory CD4 Th1 cells recognise mycobacterial antigens, release interferon-gamma and recruit macrophages, producing induration at 48–72 hours. With profound CD4 depletion, this response cannot be mounted, so the test is falsely negative (anergy). Pregnancy itself does not usually abolish a tuberculin reaction.
Negative Mantoux in HIV
- Tuberculin test = type IV
- Needs CD4 Th1 memory cells
- Low CD4: anergy
- False negative despite active TB
Remember No CD4 cells, no delayed hypersensitivity.
Exam trap A negative tuberculin test never excludes TB in an immunosuppressed patient.
Why the other options are wrong
- Absence of IgE on mast cells IgE has no role in the tuberculin reaction.
- Low serum complement levels Complement is not required for type IV responses.
- Blocking IgG against tuberculin Antibodies do not block delayed-type hypersensitivity.
- Pregnancy-induced IgM deficiency Not a recognised entity, and IgM is not involved.
A woman whose 5-year-old has a 'slapped cheek' rash develops arthralgia. At 22 weeks her fetus has hydrops with severe anaemia, though her antibody screen is negative. Which cells does the virus target?
Answer: Erythroid progenitors bearing P antigen
Parvovirus B19 uses the P antigen (globoside) to enter erythroid progenitor cells, where it replicates and kills them. The fetus has a short red cell lifespan and a rapidly expanding red cell mass, so arrest of erythropoiesis causes severe anaemia, high-output heart failure and hydrops. Viral myocarditis can add to the failure. A negative antibody screen excludes alloimmune causes, making this non-immune hydrops.
Parvovirus B19 in pregnancy
- Uses P antigen (globoside)
- Kills erythroid progenitors
- Fetal anaemia, non-immune hydrops
- May cause myocarditis too
Remember Slapped cheek at home, hydrops in utero: parvovirus.
Exam trap Do not assume all fetal anaemia with hydrops is alloimmune; check the antibody screen.
Why the other options are wrong
- Mature red cells bearing D antigen D antigen is the target of anti-D, not of parvovirus.
- Fetal hepatocytes making albumin Not the main target of the virus.
- Placental syncytiotrophoblast The virus does not cause hydrops by attacking the placenta.
- Fetal splenic macrophages Not the cell the virus uses to enter.
A healthy primigravida with a normal platelet count delivers a term baby with widespread petechiae and a platelet count of 12 × 10⁹/L. Cranial ultrasound shows an intraventricular bleed. What is the most likely cause?
Answer: Maternal alloantibody against fetal HPA-1a
In neonatal alloimmune thrombocytopenia, the mother lacks a platelet antigen, most often HPA-1a, inherited by the fetus from the father. Maternal IgG against it crosses the placenta and destroys fetal platelets, while her own platelets stay normal. Unlike Rh disease, a first pregnancy is commonly affected, because fetal platelet antigens are present early and sensitisation can occur during pregnancy. Intracranial haemorrhage, sometimes before birth, is the main danger.
Alloimmune thrombocytopenia
- Mother HPA-1a negative
- IgG against paternal platelet antigen
- Mother's platelets normal
- First pregnancy often affected
Remember Normal mother, very low platelets in baby: alloimmune.
Exam trap Do not assume, as with Rh disease, that a first baby is protected.
Why the other options are wrong
- Maternal autoantibody against her own platelets Maternal ITP would usually lower the mother's count too.
- Maternal IgG anti-D against fetal cells Anti-D targets red cells, not platelets.
- Congenital absence of fetal megakaryocytes Rare and usually linked with limb defects, not this picture.
- Fetal consumption from disseminated coagulation A well term baby has no trigger for DIC.
Where this sits in the CPSP syllabus
- Obstetrics & Gynaecology, Paper 2: General pathology in obstetrics, Hypersensitivity reactions; rhesus isoimmunisation and haemolytic disease of the newborn