Development of the immune system Flashcards
Why is the immune response in early life dampened compared to adults?
- Due to immunosuppresive environment of the womb
- Adapted to the new antigens in early life - response skewed to suppression
The reduction in immune responses leads to increased susceptibility to pathogens + to reduced responses to vaccines. What evidence shows this?
- Peak age of serious bacterial infections is <5yo
- Highest rate of meningitis of any age group is in newborns
The altered function of the neonatal immune response may also influence the development of what conditions in later life?
Asthma and allergy
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
- Less sophisticated, more primitive components
- Barriers: skin + mucosa
- Cells: neutrophils, monocytes, macrophages
- Soluble components: complement, cytokines
Describe the antigen-specific part of the immune system
- More sophisticated
- Respond to specific antigens
- Commited to immune memory
- Rapid enhanced responses on subsequent exposure to antigen
- T + B lymphocytes
What are the primary lymphoid organs?
- Thymus
- Bone marrow
What are the secondary lymphoid organs?
- Spleen
- Lymph nodes
- Tonsils
- Peyer’s Patches
- Bronchus
What is the thymus?
- Glandular organ near the heart
- T cells learn their job here
What is bone marrow?
- Blood-producing tissue located inside certain bones
- Blood stem cells give rise to all of the diff types of blood cells
What is the role of the spleen?
- Serves as a filter for the blood
- removes old + damaged RBCs
- removes infectious agents + uses them to activate cells called lymphocytes
What are lymph nodes?
Small organs that filter out dead cells, antigens + other “stuff” to present to lymphocytes
What do lymphatic vessels do?
Collect fluid (lymph) that has “leaked” out from the blood into the tissues + returns into circulation
What are the 4 stages of development of immunity in a human fetus?
- Mesoblastic: 18 days -> 10 weeks
- Hepatic: 6-8 weeks -> birth
- Splenic
- Myeloid: 10-12wks -> 20wks gestation
Which immunity development stage is responsbile for the major site of blood cell formation?
- Myeloid
In regards to development of immune responsiveness in human fetus, what developments occur from 4 to 11 weeks of gestation?
- 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
In regards to development of immune responsiveness in human fetus, what developments occur from 12 to 20 weeks of gestation?
- 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
Describe how the T cells develop
- 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
What is the thymus derived from?
3rd pharyngeal pouch
What is the thymus composed of and how does it develop?
- 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
The other part of the antigen-specific immune system is B cells - describe the development of B cells
- 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
Why will a baby be born with a lot of IgG antibody and how does this level change throughout life?
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.
There are different classes of IgG - which ones are transferred first across the placenta?
IgG1 and IgG3 before IgG2+4
In terms of development of the non-antigen specific immune system, when are granulocytes present from and what are they like comp to adults?
- From 31w GA
- High number but less effective: motility + transendothelial migration reduced
- Adherence + phagocytosis similar to adult
Describe the development of complement proteins
- 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
How are cytokines different in newborn infants?
- Reduced TNF and IL6
- Reduced IL12 produced by dendritic cells
What 4 things contribute to developmenal immunodeficiency, within the newborn?
- reduced quantity of components
- reduced function of components
- reduced physicochemical barriers
- deficiency of specific immune responses
Why is there increased susceptibility to bacterial infections in the newborn?
- Eg. group B streptococcus
- Qualitative + quantitative antibody deficiency
- Deficiency of complement
- Decreased number of phagocytic cells at site of infection
Why is there increased susceptibility to severe viral infections in the newborn?
- Eg. herpes simplex virus
- antibody deficiency
- deficiency in NK cell activity
- reduced cytokine production
- reduced activity macrophages
- reduced T cell cytotoxicity
How can we protect newborn infants?
- 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
What are the protective components of breast milk and what do they do?
- 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
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?
- 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.
Whereas most vaccines have no effect at birth, what is the exception to this rule and why is this?
- 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.
Which vaccines are given from 2 months of age?
- 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
What are T lymphocyte levels like in newborn infants?
- 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
What occurs, in terms of immunity, in IUGR?
- Poorer T-cell function
- Smaller thymus
- Reduced number of T cells
- Reduced proliferation
