S4: Development of the Immune System

Question 1

Is the immune system fully functional at birth?

Answer 1

As with many other systems, the immune system is not fully functional at birth. The act of being born, moving from the sterile environment of the womb to the wider world, exposes babies to a whole range of pathogens that they have never encountered and have no protection against.

Question 2

Why is the immune response in early life dampened (supressed) compared to children and particularly adults?

Answer 2

• It is due to the immunosupressive environment of the womb, this is because we don’t want the mother and child to react to each other.
• May also be an adaptation to the exposure to large amounts of new antigens in early life. Immune responses are carefully regulated to ensure appropriate levels of immune responses but avoiding inflammatory responses to harmless or benign antigens. Since there are more new antigens in early life, it may be that the response is skewed to suppression.

Question 3

What is the consequence of a dampened immune system at birth?

Answer 3

• The reduction in immune responses leads to increased susceptibility to pathogens and to reduced responses to vaccines. The peak age of serious bacterial infections is <5 years of age. For example, the highest rate of meningitis of any age group is in newborns. Also, we cannot vaccinate from birth (with some exceptions) and vaccination starts from 2 months of age and requires multiple doses.
• The altered function of the neonatal immune response may also influence the development of asthma and allergy in later life.

Question 4

What age group does the bacterial infection group B streptococcus affect primarily?

Answer 4

Bacterial infection of group B streptococcus- number of cases occur mostly on day one of life showing how weak the newborn immune system is.

Question 5

What age group does the bacterial infection invasive pneumococcal affect primarily?

Answer 5

Invasive pneumococcal mostly causes pneumonia, septisemia and meningitis. They most affect children under 1 years of age. As people get older they become susceptible to this disease again (immunosenescence (waning immune system in age)).

Question 6

What can the immune system be divided into?

Answer 6

1. Non antigen specific (innate).

2. Antigen specific (adaptive).

Question 7

Describe the non antigen specific immune system (innate)

Answer 7

The non-antigen specific immune system is less sophisticated and more primitive, however it is rapid and uses generic anti-bacterial/anti-viral mechanisms. It responds in the same way to repeated infections and has limited recognition capacity. You are also born with it, which is why it is called innate.

• It includes barriers such as the skin and mucosal surfaces e.g. gut mucosa.
• The cellular component of neutrophils, monocytes and macrophages that phagocytose pathogens.
• There are also the soluble components like complement and cytokines, remember these are non-specific and non-selective.

Question 8

Describe the antigen specific immune system (adaptive)

Answer 8

The antigen-specific (adaptive) immune system is more sophisticated and has the ability to respond to a specific antigen and is extremely specific (can recognise over 107 structures). It is delayed in onset but also has a memory resulting in a more rapid and enhanced response on second exposure to the antigen.
- The antigen-specific immune system is broken down into two parts, humoral (B-lymphocytes through antibodies) and cell-mediated immunity (T-lymphocytes).

Question 9

How are the innate and adaptive immune systems connected? Describe the process when they encounter a pathogen

Answer 9

The innate immune system connects into the adaptive immune system by APCs, that will present the antigen on its surface to immature T-helper cells.

• When the infant is infected by a pathogen, that organism is recognised as being a pathogen because of PAMPs on its surface. These are pathogen associated molecular patterns and are highly conserved and required for the pathogen to function.
• The PAMPs are recognised by receptors on leucocytes, for example above the toll-like receptor.
• On recognition of the PAMP, the macrophage can trigger an innate immune response by starting to phagocytose the pathogen and release cytokines/chemokines to attract more immune cells.
• The dendritic cell can also phagocytose the pathogen and act as an antigen-presenting cell and thus activate the adaptive immune response which is specific to that pathogen/antigen.

Question 10

List primary lymphoid organs

Answer 10

Thymus

Bone Marrow

Question 11

List secondary lymphoid organs

Answer 11

Spleen
Lymph nodes
Tonsils
Adenoids

Question 12

Describe anatomy of the immune system

Answer 12

• Thymus is the glandular organ near the heart. It is where the T cells develop and learn their job.
• Bone marrow which is blood producing tissue located inside certain bones. Blood stem cells from bone marrow give rise to all of the different types of blood cells.
• Spleen serves as a filter for blood. It removes old and damaged red blood cells and removes infectious agents and uses them to activate cells called lymphocytes.
• Lymph nodes are small organs that filter out dead cells, antigens and other ‘stuff’ to present to lymphocytes.
• Lymphatic vessels collect fluid (lymph) that has ‘leaked; out from blood into the tissues and returns it to the circulation.

Question 13

Describe development of immune system in human foetus

Answer 13

• Mesoblastic phase: Predominance of morphologically recognisable haematopoietic cells are seen in the yolk sac, primitive nucleated erythrocyte as early as 18 days of gestation (first stage of development of immunity).
• · Hepatic phase begins at 6 – 8 wk of gestation and continues until shortly before birth.
• Splenic phase transiently precedes the myeloid phase.
• Myeloid phase initiates in marrow cavities at 10 – 12 weeks of gestation and by 20 weeks (half way through pregnancy) is the major site of blood cell formation in bone marrow

Question 14

Describe development of T cells in antigen specific immune system

Answer 14

• T cells migrate from bone marrow to the THYMUS where gene rearrangements and maturation occur to develop T cells.
• Each T cell undergoes gene rearrangements to produce a unique antigen receptor on cell surface.
• Mature T cells leave thymus and re-circulate through secondary lymphoid tissues.

Question 15

Describe development of thymus in antigen specific immune system

Answer 15

• Derived from the III (3) rd pharyngeal pouch.
• Thymic epithelium and medulla.
• At 8w gestation, there is colonization of the thymus by HSC (thymus begins developing).
• By 20w the thymus is developed.
• 16-20w T cells emigrate to the periphery (mature T cells are developed).

Question 16

What determines the type of T cell developed?

Answer 16

Largely determined by what cytokines influence their development.

Question 17

Describe development of B cells in antigen specific immune system

Answer 17

• Bone marrow production of B cells from primitive stem cells.
• There is migration to secondary lymphoid organs e.g. spleen, lymph nodes.
• Each B cell expresses immunoglobulin on its surface of single antigenic specificity.
• Ongoing gene rearrangements results in immature B cells with diverse repertoire of surface Ig molecules ready for selective events driven by antigen binding. They undergo selection based on exposure to which antigen.

Question 18

Describe a newborns active immune system

Answer 18

Newborns are deficient in their own generated specific antibodies (due to limited exposure to antigens so limited production of B cells to produce antibodies).
This is partly alleviated by:
- Trans-placental active transfer of materal IgG antibody. So newborn has higher levels of antibodies than bother when born. However, these antibodies have an half life of one month, so there is half level of antibody present at one month (it wanes).
- Secretory IgA in breast milk inhibits adherence of bacteria to mucosal surfaces.

Question 19

Describe development of serum immunoglobulin levels graph (Y axis is % of adult levels, X is the age in months).

Answer 19

• It can be seen at the birth the IgG levels are very high, 120% of the adult level. This is because it is maternally derived via placental transfer! By 3 months later the trough is reached and it is at its lowest. IgG maximum transfer occurs during the last trimester of pregnancy.
• Eventually child produces its own IgG but in the meantime it has lower levels during childhood which explains increased infection during that period. It is until about 5 years of age where IgG levels reach that of an adult and adult pattern is developed.
• IgG production increases with IgG1+3 before IgG2+4. IgG1+3 is the major transfer through the placenta.This is mportant as certain subclasses of Ig are important for certain subtypes of infection, so children remain susceptive to some infection.
• Throughout childhood there is active production of antibodies in response to antigens.
• IgA takes a lot longer to increase its levels and is the last of Ig to acheive adult levels.
• Ig A and IgM develop slowly throughout childhood, its only IgG that is transferred from mother to foetus during gestation and there is no transfer of IgA and IgM from mother to baby through placenta.

Question 20

Describe development of non antigen specific immune system

Answer 20

• Skin of newborn is extremely thin and liable to break down (weaker physical immune barrier).
• Cellular components (monocytes, neutrophils, macrophages). - Neutrophil levels in newborn can be higher than adults. However, their affinity to replace the neurotrophils is limited so even during infection, the high neutrophil number are depleted.
• Granulocytes from 31 weeks GA. There is a higher number than adults but less effective as motility and transendothelial migration is reduced. Adherance and phagocytosis is similar to adult.
• Soluble components include complement which is a series of serum proteins that function as an enzymatic cascade. Until 6-18 months of age concentration of most complement is lower than in adults and there is decreased function in children. Soluble components also include cytokines. There is decreased TNF and IL6, also decreased IL12 produced by dendritic cells.

Question 21

Why do infants have developmental immunodeficiency?

Answer 21

Immunodeficiency means that the newborn has an suppressed immune system and it is developmental as it is part of a process over time. Over time, the infants immune system will develop into a competent one and will no longer by immunosupressed.

Question 22

Factors of immunodeficiency

Answer 22

• Reduced quantity of components.
• Reduced function of components.
• Reduced physicochemical barriers.
• Deficiency of specific immune responses.

Question 23

Describe net effect of developmental immunideficiency

Answer 23

Increased susceptibility to bacterial infections eg. group B streptococcus:
- qualitative + quantitative antibody deficiency,
- deficiency of complement.
- decreased number of phagocytic cells at the site of infection.
Increased susceptibility to severe viral infections compared to adults eg. herpes simplex virus where severe and overwhelming HPV is highest in first year of life:
- antibody deficiency.
deficiency NK cell activity.
- decreased cytokine production.
- decreased activity macrophages.
- decreased T cell cytotoxicity.

Question 24

Describe how we protect newborn infants due to their immunodeficiency

Answer 24

• Early treatment with antibiotics/antivirals/
• Limit exposure to infection e.g. handwashing.
• Avoiding unnecessary medical procedures e.g. cannula breaches the skin which is part of the immune system.
• Encourage breast feeding (transfer of IgA + contains range of other factors that supplement immune system).
• Maternal vaccination during gestation (these increase antibodies in the mother, which is natural immunisation for infant as they can be passively passed across through placenta) e.g. Tetanus (neonatal tetanus is prevented by vaccinating mother), pertussis, RSV, GBS.
• Timely infant vaccination.

Question 25

How does maternal vaccination affect infant?

Answer 25

• The concept behind maternal vaccination is that vaccinating women during pregnancy will induce an immune response whereby there will then be an increase in maternal antibodies and thus increase in IgG crossing the placenta to the infant.
  Thus it provides specific protection from birth until infant vaccinations are complete or the period of high risk of disease has passed.
• An example of where this is being used is neonatal tetanus that has high mortality and morbidity. Tetanus vaccination has been used to prevent neonatal tetanus.
  Pregnant women are also advised to be vaccinated against influenza at any stage of pregnancy.

Question 26

How does breast milk protect infants?

Answer 26

Protective factors in breast milk:

• IgA: protects against bacterial & viral infections.
• Cells: macrophages, neutrophils, lymphocytes.
• Complement components: opsonisation.
• Lysozyme: attacks bacterial cell walls.
• Lactoperoxidase: antistreptococcal agent.
• Lactoferrin: inhibits growth of bacteria.

Question 27

Describe when vaccinations are given protect infant

Answer 27

The ideal vaccine would be given as one dose, orally & at birth to provide early protection & ensure high coverage.

• However, we don’t do this due to the interference of infant antibody responses by maternal antibodies eg. measles vaccine (maternal antibodies as well as protecting infant, can interfere with vaccines to infant so need to give later on when maternal antibodies are depleted). Also there can be, poor immune responses in the newborn infant even more so if premature.
• Remember pre term infants are extremely susceptible to infection(even more so than term infants) and so preterm infants respond more poorly to vaccines than term babies.

Question 28

Describe the UK infant vaccine schedule

Answer 28

• BCG at birth (1 dose) –> for TB. This can be given before 2 months because it relies on cellular immunity to protect infant so it is an exception and is given as early as possible. Cellular immune system is not as immunosuppressed as humoral immune system in infants compared to adults.
• From 2 months of age:
• Diphtheria / tetanus / pertussis / Haemophilus influenzae type b polio vaccine need 3 doses: 2, 3, 4 mo of age. Note the multple dsoes and still needs a booster dose later on in life.
• Streptococcus pneumoniae and rotavirus at 2 and 4 mo.
• Neisseria meningitidis B vaccines at at 2 and 4 mo. Booster doses at 12 months of age: Hib/Men C & PCV & MenB.
• 1st MMR dose at 12 months of age.