Development of the immune system

Question 1

Why is the immune response in early life dampened compared to adults?

Answer 1

• Due to immunosuppresive environment of the womb
• Adapted to the new antigens in early life - response skewed to suppression

Question 2

The reduction in immune responses leads to increased susceptibility to pathogens + to reduced responses to vaccines. What evidence shows this?

Answer 2

• Peak age of serious bacterial infections is <5yo
• Highest rate of meningitis of any age group is in newborns

Question 3

The altered function of the neonatal immune response may also influence the development of what conditions in later life?

Answer 3

Asthma and allergy

Question 4

Key components of the immune system are the non-antigen specific and the antigen-specific systems. Describe key features of the non-antigen specific immune system

Answer 4

• Less sophisticated, more primitive components
• Barriers: skin + mucosa
• Cells: neutrophils, monocytes, macrophages
• Soluble components: complement, cytokines

Question 5

Describe the antigen-specific part of the immune system

Answer 5

• More sophisticated
• Respond to specific antigens
• Commited to immune memory
• Rapid enhanced responses on subsequent exposure to antigen
• T + B lymphocytes

Question 6

What are the primary lymphoid organs?

Answer 6

• Thymus
• Bone marrow

Question 7

What are the secondary lymphoid organs?

Answer 7

• Spleen
• Lymph nodes
• Tonsils
• Peyer’s Patches
• Bronchus

Question 8

What is the thymus?

Answer 8

• Glandular organ near the heart
• T cells learn their job here

Question 9

What is bone marrow?

Answer 9

• Blood-producing tissue located inside certain bones
• Blood stem cells give rise to all of the diff types of blood cells

Question 10

What is the role of the spleen?

Answer 10

• Serves as a filter for the blood
  
  • removes old + damaged RBCs
  • removes infectious agents + uses them to activate cells called lymphocytes

Question 11

What are lymph nodes?

Answer 11

Small organs that filter out dead cells, antigens + other “stuff” to present to lymphocytes

Question 12

What do lymphatic vessels do?

Answer 12

Collect fluid (lymph) that has “leaked” out from the blood into the tissues + returns into circulation

Question 13

What are the 4 stages of development of immunity in a human fetus?

Answer 13

1. Mesoblastic: 18 days -> 10 weeks
2. Hepatic: 6-8 weeks -> birth
3. Splenic
4. Myeloid: 10-12wks -> 20wks gestation

Question 14

Which immunity development stage is responsbile for the major site of blood cell formation?

Answer 14

• Myeloid

Question 15

In regards to development of immune responsiveness in human fetus, what developments occur from 4 to 11 weeks of gestation?

Answer 15

• 4 - macrophages in yolk sac
• 5 - complement synthesis detectable
• 6 - Natural Killer cells present in liver
• 6-7 - thymic epithelium develops
• 7 - lymphocytes + macrophages in blood
• 7-9 - lymphocytes in thymus
• 11 - serum IgM detectable in infection + mitogen responsiveness of thymocytes

Question 16

In regards to development of immune responsiveness in human fetus, what developments occur from 12 to 20 weeks of gestation?

Answer 16

• 12-14 - neutrophils in blood
• 13 - B cells in bone marrow
• 14 - mitogen responsiveness of peripheral lymphocytes
• 17 - IgG in serum - infection only
• 20 - alloreactivity detectable

Question 17

Describe how the T cells develop

Answer 17

• T cells migrate from bone marrow -> THYMUS
• Gene rearrangements + maturation occur
• Each T cell undergoes gene rearrangements to prod a unique antigen receptor on cell surface
• Mature T cells leave thymus + re-circulate through secondary lymphoid tissues

Question 18

What is the thymus derived from?

Answer 18

3rd pharyngeal pouch

Question 19

What is the thymus composed of and how does it develop?

Answer 19

• Thymic epithelium + medulla
• @ GA 8w - colonization of the thymus by HSC (haemopoetic stem cells)
• @ GA 20w - thymus is developed
• @ GA 16-20w - T cells emigrate to periphery

Question 20

The other part of the antigen-specific immune system is B cells - describe the development of B cells

Answer 20

• Bone marrow produces B cells from primitive stem cells
• Migration to secondary lymphoid organs eg. spleen, lymph nodes
• Each B cell expresses immunoglobulin on its surface - of single antigenic specificty
• Ongoing gene rearrangements results in immature B cells with diverse repertoire of surface Ig molecules ready for selective events driven by antigen binding -> develop memory B cells for faster, more specific response

Question 21

Why will a baby be born with a lot of IgG antibody and how does this level change throughout life?

Answer 21

Newborns are deficient in their own-generated specific antibodies. This is partly alleviated by trans-placental active transfer of maternal IgG antibody.

These IgG antibodies will be broken down and metabolised by around 3 months of age, so will be at its lowest then but IgG begins to increase slowly after that. Reaches adult levels around 5 years of age.

Question 22

There are different classes of IgG - which ones are transferred first across the placenta?

Answer 22

IgG1 and IgG3 before IgG2+4

Question 23

In terms of development of the non-antigen specific immune system, when are granulocytes present from and what are they like comp to adults?

Answer 23

• From 31w GA
• High number but less effective: motility + transendothelial migration reduced
• Adherence + phagocytosis similar to adult

Question 24

Describe the development of complement proteins

Answer 24

• Series of serum proteins that function as enzymatic cascade
• Until 6-18 months of age conc of most C’ lower than in adults
• Reduced function in children

Question 25

How are cytokines different in newborn infants?

Answer 25

* Reduced TNF and IL6 * Reduced IL12 produced by dendritic cells

Question 26

What 4 things contribute to developmenal immunodeficiency, within the newborn?

Answer 26

* reduced quantity of components * reduced function of components * reduced physicochemical barriers * deficiency of specific immune responses

Question 27

Why is there increased susceptibility to **bacterial infections** in the newborn?

Answer 27

* Eg. group B streptococcus * Qualitative + quantitative **antibody** deficiency * Deficiency of **complement** * Decreased number of **phagocytic** cells at site of infection

Question 28

Why is there increased susceptibility to severe **viral infections** in the newborn?

Answer 28

* Eg. herpes simplex virus * **antibody** deficiency * deficiency in **NK cell** activity * reduced **cytokine** production * reduced activity **macrophages** * reduced **T cell** cytotoxicity

Question 29

How can we protect newborn infants?

Answer 29

* **Early treatment** with antibiotics/antivirals * **Limit exposure** to infection eg. handwashing, avoiding unnecessary procedures * Encourage **breast feeding** * _Maternal_ **vaccination** - tetanus, pertussis, RSV, GBS * Timely _infant_ **vaccination**

Question 30

What are the protective components of breast milk and what do they do?

Answer 30

* **IgA** - protects against bacterial + viral infections * **Cells** - macrophages, neutrophils, lymphocytes * **Complement** - opsonisation * **Lysozymes** - attack bacterial cell walls * **Lactoperoxidase** - antistreptococcal agent * **Lactoferrin** - inhibits growth of bacteria

Question 31

The ideal vaccine to protect infants would be given as one dose, orally and at birth to provide early protection + ensure high coverage. Why is this not possible?

Answer 31

* Interference of infant antibody responses by maternal antibodies eg. measles vaccines * Poor immune responses in the newborn infant, even more so if premature.. So wait till they're older when their responses will be bigger and adequate and give them smaller doses multiple times.

Question 32

Whereas most vaccines have no effect at birth, what is the exception to this rule and why is this?

Answer 32

* BCG given at birth * Giving BCG at birth does protect most infants against severe forms of TBas it **doesn’t require an antibody production**, BCG works by generating **cellular T cell immunity**, not B cell antibody immunity. T cells function better in newborns than B cells, which is shown by the BCG vaccine.

Question 33

Which vaccines are given from 2 months of age?

Answer 33

* Diptheria / tetanus / pertussis / Haemophilus influenzae type b polio vaccine need 3 doses: 2,3,4 months of age * Booster doses at 12 months of age * Hib/Men C + PCV + MenB * 1st MMR dose at 12 months

Question 34

What are T lymphocyte levels like in newborn infants?

Answer 34

* No transfer of maternal T cell specific immunity * Inc number compared with adult * Normal response to mitogen stimulation * Decreased response to antigen stimulation * Poor helper function to B cells * Decreased cytokine production

Question 35

What occurs, in terms of immunity, in IUGR?

Answer 35

* Poorer T-cell function * Smaller thymus * Reduced number of T cells * Reduced proliferation