L10 Infection and Immunity Immunity through life

Overview

This lecture tracks how the immune system changes across the lifespan and how those changes affect susceptibility to infection, autoimmune disease and malignancy, and vaccine strategy. It covers neonatal immune incompetence and maternal antibody transfer, infant gut microbiota development and the paediatric vaccination schedule, the immune adaptations of pregnancy (and their complications), and immunosenescence in old age, closing with age-stratified infectious disease data that produces a U-shaped incidence curve across life.

Neonates: maternal antibody transfer

• The neonatal immune system is relatively incompetent shortly before/after birth, so transferred immunologic memory from the mother is essential for fetal, newborn and infant survival.
• Maternal antibody can protect offspring because it is a soluble product (mostly IgG, crossing the placenta; mostly IgA, via breast milk into the intestine) that acts directly, whereas maternal T cells cannot protect offspring because T cell immunity requires re-establishing cellular components in the recipient (a naive CD4 T cell interacting via TCR with a mature dendritic cell, and a B cell with surface BCR) rather than simply transferring a molecule.
• Kinetics of protection: circulating maternal (placental) neutralizing antibody in the child peaks at birth and declines to near zero by about 1 year; intestinal (breast milk) antibody in the child peaks at around 3 months and declines by about 1 year (affected by early vs late weaning); the child’s own antibody rises with vaccination to a high level by about 4 years, but without vaccination rises much more slowly and is still low by 15 years.
• Where maternal antibody is absent, the child’s own antibody response is still higher with vaccination than without, from birth to 15 years.
• Age at diagnosis of agammaglobulinaemia rises steeply from about 6 months (when maternal antibody has waned) to a few years, then plateaus near 100% cumulative diagnosis, showing maternal antibody was masking the underlying defect.
• NZ rotavirus cases (2004-5, pre-vaccine) peaked in the 6-11 and 12-17 month age bands (~110 cases each), consistent with the window after maternal antibody wanes.

Neonates: muted innate and adaptive responses

Innate:

• Mature neutrophils are present from the end of the first trimester and increase shortly before birth, but are weakly bactericidal with reduced responsiveness; pre-term infants have especially impaired neutrophil function.
• Monocytes and macrophages are immature: reduced pattern recognition receptor (PRR) expression, impaired signalling, reduced cytokine production.
• Dendritic cell numbers and function are reduced.
• Serum complement concentrations are lower; some components reach adult levels within one month.
• Net effect: increased susceptibility to bacterial and viral infection.

Adaptive:

• Mature T cells are abundant before birth, but with increased Tregs (suppressive/anti-inflammatory) and effector CD4 T cells skewed towards Th2 responses.
• B cell responses are blunted: reduced proportion of conventional B cells, increased proportion of B1 cells (spontaneous producers of low-affinity IgM with limited specificities), and reduced responsiveness to B cell help (decreased somatic hypermutation and immunoglobulin class switching).
• Net effect: increased susceptibility to bacterial and viral infection.

Infants and young children: gut microbiota

• Gut bacteria influence T cell differentiation (about 20% of all T cells reside in the gut) and shape memory B and T cell development.
• Factors that influence gut microbiota: vaginal vs caesarean delivery, breastmilk vs formula feeding, introduction of solids, geography, antibiotic exposure.
• Bacterial diversity increases and interindividual variability decreases across birth, 1 month, 6 months, 12 months and 2-3 years; gut microbiota in children under 3 fluctuates and is more impressionable to environmental factors than adult microbiota.
• Timing and nature of microbial exposure in this window can affect later disease susceptibility, including asthma, allergy and IBD.

Vaccination in infancy

• Vaccination stimulates protective immunity in the maturing immune system and shapes the immune repertoire via acquisition of immunological memory.
• NZ schedule for a baby born in 2023: 6 weeks - rotavirus (1 of 2), diphtheria/tetanus/whooping cough/polio/hep B/Hib (1 of 3), pneumococcal (1 of 3); 3 months - rotavirus (2 of 2), diphtheria/tetanus/whooping cough/polio/hep B/Hib (2 of 3), meningococcal B (1 of 3); 5 months - diphtheria/tetanus/whooping cough/polio/hep B/Hib (3 of 3), pneumococcal (2 of 3), meningococcal B (2 of 3); 12 months - MMR (1 of 2), pneumococcal (3 of 3), meningococcal B (3 of 3); 15 months - Hib booster, MMR (2 of 2), chicken pox (single dose); 4 years - diphtheria/tetanus/whooping cough/polio booster; from age 9 - HPV (2 doses, 6 months apart); from age 11 - tetanus/diphtheria/whooping cough booster.

Pregnancy: immune adaptation

• The maternal immune system changes to prevent rejection of the semi-allogeneic fetus and to protect the pregnancy.
• Local (decidual) factors: 70% of decidual leukocytes are NK cells, 20-25% macrophages, 1-2% dendritic cells; specialised decidual NK cells and DCs are essential for trophoblast invasion of the uterus and implantation.
• Systemic factors: expansion of Tregs with fetal specificity (tolerogenic), and immune modulation by progesterone.
• Net effect: increased susceptibility to infection (e.g. malaria, influenza) but remission of some autoimmune diseases during pregnancy.
• Mechanism of decidual NK support for placentation: NK cells act on stromal cells via the NKp30 receptor, releasing VEGF and PLGF that drive vascular growth toward the trophoblast; NK cells also interact via NKp44; trophoblast cells express CXCR1 and CXCR3, which bind NK-released IL-8 and IP-10 respectively, promoting trophoblast invasion toward the spiral arteries.

Pregnancy: preeclampsia and infection risk

• Preeclampsia (PE) is associated with hypertension after 20 weeks gestation, decreased renal function, and small babies; inflammation may contribute via shallow trophoblast invasion and chronic inflammation (systemically increased effector CD4 T cells, decreased Tregs), leading to hypertension and placental ischaemia.
• Healthy placentation: deep trophoblast invasion, increased NO, M2 macrophages and DCs releasing TGF-β/IL-10/HO-1, Tregs present, decreased vascular resistance, increased blood flow.
• Shallow placentation (PE): shallow trophoblast invasion, increased ROS and IFN-γ, uNK cell/Th1/Th17 cells releasing TNF/IL-6/IL-17, M1 macrophages, altered sFlt-1/VEGF/sEng balance, increased vascular resistance and permeability, decreased blood flow. > [!warning] The transcript notes the exact up/down arrow directions for some sFlt-1/VEGF/sEng/NO labels on this slide were too small to read reliably.
• Influenza and pregnancy: pregnant 18-49 year olds are more likely to be hospitalised with influenza than non-pregnant counterparts (RR 5.23, 95% CI 4.57-5.99); pandemic H1N1 influenza during pregnancy had high mortality, especially in the third trimester, likely reflecting modulated immunity plus physiological changes (increased cardiac output and oxygen consumption, decreased lung capacity and tidal volume).
• Rajasthan H1N1 pandemic (2009-10) outcomes by trimester (rural/urban deaths/discharges): 1st trimester 4 patients (rural 4 death/0 discharge; urban 0/0); 2nd trimester 18 patients (rural 7 death/8 discharge; urban 3 death/0); 3rd trimester 15 patients (rural 9 death/3 discharge; urban 3 death/0); total 37 patients (rural 20 death/11 discharge; urban 6 death/0).

Vaccination in pregnancy

• Pregnant people can be immunised with inactivated vaccines.
• WHO recommends influenza vaccination for pregnant people at any stage of pregnancy.
• Pertussis booster reduces transmission risk to the newborn; if given before 36 weeks, maternal IgG can protect the infant.

Old age: immunosenescence

• The aged immune system is less efficient at recognising and limiting infections, producing increased incidence and increased severity of infectious disease; mechanical barriers (e.g. skin) are also less protective.

B cell decline:

• Reduced function of mature B cells, including inefficient generation of memory B cells.
• Impaired B cell development: decreased numbers of early B cell progenitors and decreased expression of genes important for B cell development.
• Alterations in the size and composition of the B cell repertoire (the number of different BCRs expressed by an individual).
• Outcomes: heightened susceptibility to infection, decreased antibody responses to vaccination, increased incidence of autoimmune disorders.

T cell decline:

• Decreased number of naive T cells, driven by progressive decrease in thymic output (total T cell numbers stay roughly constant because existing naive cells are long-lived).
• Increased proportion of memory T cells and increase in Tregs.
• Accumulation of CD8 T cells with a limited TCR repertoire, associated with CMV seropositivity.
• Thymus weight rises sharply to a peak around puberty/early adulthood then declines with age, with the proportion of fat tissue increasing and cortex/medulla proportion shrinking (visible on cross-section at newborn, 17 years, and 50 years, with progressive replacement of cortex/medulla by fat).
• Thymic output declines 10-100 fold from young adulthood to older adulthood. Comparing young vs older adults: TCR repertoire “richness” declines 2-5 fold for both CD4+ and CD8+ T cells; “compartment size” declines for CD8+ T cells; “clonality” increases moderately for CD4+ T cells and greatly for CD8+ T cells. Homeostatic T cell proliferation feeds both CD4+ and CD8+ compartments and is stable over most of adult life.
• Possible link between age-related T cell decline and cancer; helper T cell decline also impairs the ability of B cells to produce antibody. Both all-malignancy incidence (UK 2004) and breast cancer incidence (Australia 2010) rise steeply from around age 35-44/40-49 onward.

Vaccination in older adults

• Shingles (herpes zoster): reactivation of varicella zoster virus (VZV), presenting as a rash with acute pain; complications include postherpetic neuralgia, vision loss, hearing loss, pneumonia, and secondary bacterial infection.
• Risk of zoster rises with age (rate per 1,000 person-years): 0-14y 1.1; 15-29y 1.4; 30-39y 2.0; 40-49y 2.9; 50-59y 4.6; 60-69y 6.9; 70-79y 9.5; 80+y 10.9 - risk and severity increase markedly after age 50 due to age-related decline in immunity.
• Zostavax is licensed for adults aged 50 to under 81, regardless of recalled chickenpox history; it is a live vaccine, so it is contraindicated in the immunosuppressed, and vaccine efficacy falls with age: 50-59y 70%, 60-69y 64%, 70-79y 41%, 80+y 18%; protection lasts approximately 5-8 years.
• Influenza: older adults are at greater risk of severe infection or complications; NZ has funded seasonal influenza vaccine for those 65+ since 1997, but NZ DHB staff vaccine coverage was low (58% in 2013). Influenza hospitalisation rate (per 100,000, Auckland/Counties Manukau, 2013) is highest in infants (<1y, ~205) then falls before rising again with age: 50-64y ~37, 65-79y ~87, 80+y ~120.

Infectious disease incidence and age

• Multiple datasets show a U-shaped (or partially U-shaped) incidence/mortality curve by age, high in early life, low in mid-life, rising again in older age: invasive pneumococcal disease (England and Wales, and Hong Kong), meningitis (Australia, urban), and community-acquired pneumonia (Finland) all peak in infancy/early childhood, fall to a low point in adolescence/young adulthood, then rise again from about age 60-75 onward.
• Tuberculosis mortality (per 100,000) shows a different, bimodal pattern by TB type: disseminated TB mortality is highest in infancy (0-1y ~55, 1-2y ~45) and falls to near zero by age 16-20; pulmonary TB mortality is low in youth, rises from age 16-20 (~5) through 21-50 (~35-38), peaks around 51-70 (~40-48), then declines over age 70 (~23).
• COVID-19 deaths in NZ (from Sept 2022) rise steeply with age and total 2,084: 0-59y 90 deaths, 60-69y 141, 70-79y 383, 80-89y 799, 90+y 671 (by ethnicity: Māori 184, Pacific Peoples 101, Asian 89, European or Other 1,705 total).

Summary: strength of immune response across life

• Maternal antibody is high near birth and declines rapidly to near zero by about 1 year.
• B cell/innate responses, Th2 responses and Th1 responses each rise through infancy, plateau through adulthood (roughly 20-60 years), then decline from about 70-90 years; Th2 tracks slightly above and Th1 slightly below the B/innate curve.
• Treg activity is relatively stable across life.
• The immune response during pregnancy is shown as a low, flat curve throughout life, with an open question (marked ”?”) about additional immune modulation of Th2/Th1 during the reproductive-age pregnancy window (roughly 18-33 years). > [!warning] The transcript notes the pregnancy-related dashed bumps and ”?” annotation on this slide were too small to read the precise meaning or values.

Self-test

1. Explain why maternal antibody can protect an infant but maternal T cells cannot.
2. Describe how circulating (placental) and intestinal (breast milk) maternal antibody levels in the child change over the first year of life, and how the child’s own antibody level differs with and without vaccination by age 4 and by age 15.
3. List the three main features of the neonatal innate immune system that are muted compared with adults, with one distinguishing detail of each.
4. List the two main features of the neonatal adaptive immune system that are muted compared with adults, with one distinguishing detail of each.
5. What proportion of decidual leukocytes are NK cells, and what is their role in trophoblast invasion?
6. Describe the mechanism by which decidual NK cells promote trophoblast invasion and vascular growth towards the spiral arteries.
7. Distinguish the immune features of healthy placentation from those of shallow placentation associated with preeclampsia.
8. A pregnant woman in her third trimester develops severe influenza requiring hospitalisation. Explain, using immune and physiological changes of pregnancy, why she is at elevated risk compared with a non-pregnant woman of the same age.
9. What vaccination advice applies to pregnant people regarding vaccine type, influenza, and pertussis timing?
10. Describe the changes in B cell function and development that occur with ageing, and their clinical outcomes.
11. Describe the changes in T cell numbers, thymic output and TCR repertoire that occur with ageing.
12. Distinguish Zostavax eligibility, contraindication, and how its efficacy and duration of protection change with age.
13. Describe the general shape of infectious disease incidence across the lifespan for conditions such as invasive pneumococcal disease, meningitis and community-acquired pneumonia, and explain what happens at both ends of the age range.
14. Distinguish the age pattern of disseminated TB mortality from that of pulmonary TB mortality.
15. Using the lecture’s life-course summary graph, describe how maternal antibody, B cell/innate immunity, Th1/Th2 responses and Treg activity each change from birth to old age, and identify what remains an open question about immunity during pregnancy.

Answers

Reveal answers

1. Maternal antibody (IgG via placenta, IgA via breast milk) is a soluble molecule that can act directly in the infant once transferred. Maternal T cell immunity depends on cellular interactions (a naive CD4 T cell engaging a mature dendritic cell via TCR, and a B cell with surface BCR) that would need to be re-established in the infant’s own body, so simply transferring maternal T cells cannot confer protection.
2. Circulating (placental) maternal antibody in the child peaks at birth and declines to near zero by about 1 year. Intestinal (breast milk) antibody peaks at around 3 months and also declines by about 1 year. With vaccination, the child’s own antibody reaches a high level by about age 4; without vaccination it rises much more slowly and is still low by age 15.
3. Neutrophils: present from end of first trimester but weakly bactericidal with reduced responsiveness (worse in preterm infants). Monocytes/macrophages: immature, with reduced PRR expression, impaired signalling and reduced cytokine output. Dendritic cells: reduced numbers and function. (Complement is also lower, reaching adult levels for some components within one month.)
4. T cells: abundant before birth but skewed with increased Tregs and Th2-biased effector CD4 responses. B cells: reduced proportion of conventional B cells, increased B1 cells (low-affinity IgM), and reduced somatic hypermutation/class switching due to poor B cell help.
5. About 70% of decidual leukocytes are NK cells; specialised decidual NK cells (with macrophages and DCs) are essential for trophoblast invasion of the uterus and implantation.
6. Decidual NK cells act on stromal cells via NKp30, releasing VEGF and PLGF that drive vascular growth toward the trophoblast, and interact via NKp44. Trophoblast cells express CXCR1 and CXCR3, which bind NK-released IL-8 and IP-10 respectively, promoting trophoblast invasion toward the spiral arteries.
7. Healthy placentation: deep trophoblast invasion, increased NO, tolerogenic M2 macrophages/DCs releasing TGF-β/IL-10/HO-1, Tregs present, decreased vascular resistance, increased blood flow. Shallow (preeclamptic) placentation: shallow invasion, increased ROS/IFN-γ, inflammatory uNK/Th1/Th17 cells releasing TNF/IL-6/IL-17, M1 macrophages, altered sFlt-1/VEGF/sEng balance, increased vascular resistance/permeability, decreased blood flow.
8. Pregnancy modulates immunity (systemic tolerogenic shifts, e.g. Treg expansion) which may impair antiviral defence, and pregnancy also causes physiological changes (increased cardiac output and oxygen consumption, decreased lung capacity and tidal volume) that reduce respiratory reserve; together these raise the risk of severe/fatal influenza, especially in the third trimester (matching the transcript’s H1N1 data showing high mortality in that trimester).
9. Pregnant people can receive inactivated vaccines. WHO recommends influenza vaccination at any stage of pregnancy. Pertussis booster given before 36 weeks allows maternal IgG to cross and protect the newborn, reducing transmission risk.
10. Ageing reduces mature B cell function (inefficient memory B cell generation) and impairs B cell development (fewer early progenitors, reduced expression of developmental genes), altering the size/composition of the B cell repertoire. Outcomes: greater infection susceptibility, poorer antibody responses to vaccination, and more autoimmune disease.
11. Naive T cell numbers fall due to progressively declining thymic output (10-100 fold from young to older adulthood), though total T cell numbers stay roughly constant because existing naive cells are long-lived. Memory T cells and Tregs increase proportionally. TCR repertoire richness falls 2-5 fold for CD4+ and CD8+ cells, CD8+ compartment size declines, and clonality increases (more for CD8+ than CD4+), with accumulation of CD8 T cells of limited TCR repertoire linked to CMV seropositivity.
12. Zostavax is licensed for ages 50 to under 81 regardless of chickenpox history, but is contraindicated in the immunosuppressed because it is a live vaccine. Efficacy falls with age (70% at 50-59y, 64% at 60-69y, 41% at 70-79y, 18% at 80+y), and protection lasts only about 5-8 years.
13. These diseases show a U-shaped pattern: incidence/mortality is high in infancy/early childhood (immature immune system), falls to a low point in adolescence/young adulthood, then rises again from around age 60-75 onward as immunosenescence sets in.
14. Disseminated TB mortality is concentrated in infancy (highest at 0-1y and 1-2y) and falls to near zero by age 16-20, reflecting neonatal/infant immune immaturity. Pulmonary TB mortality is low in youth but rises through adulthood (age 16-50), peaks around 51-70, then declines after 70.
15. Maternal antibody is high at birth and declines rapidly to near zero by about 1 year. B cell/innate immunity and Th1/Th2 responses all rise through infancy, plateau through adulthood (roughly 20-60 years), and decline from about 70-90 years, with Th2 tracking slightly above and Th1 slightly below the B/innate curve. Treg activity stays relatively stable across life. The pregnancy curve is low and flat throughout life, but the lecture flags an open question about extra Th1/Th2 modulation specifically during the reproductive-age pregnancy window (about 18-33 years).