50. Development of Lymphocytes Flashcards
Examples of lymphocyte deficiency/ defect syndromes
Primary / Secondary
B Cells
- Congenital agammaglobulinaemia (lose immunoglobulins)
- Common variable immunodeficiency (CVID)
- Novel biologics – Rituximab
T Cells
- Severe Combined Immunodeficiency (SCID)
- DiGeorge syndrome (thymus doesn’t work properly)
- Acquired – HIV/ Chemotherapy/ Novel biologics
What is a Lymphocyte?
They are defined in many different ways
•Role – cornerstone of adaptive immunity
•Morphology:
- White cell; small, large nucleus
•Lineage:
- e.g. T and B cells
•Function: what they do
- e.g. Helper/ Cytotoxic/ Regulatory
•Phenotype: what surface markers they express
- Usually functional receptors – not just there for our convenience!
•Specificity
- What target – What Ab they produce or epitope they recognise (TCR)
•Type of receptor
- Ig class for B cell/ αβ vs γδ for T cells
•Differentiation
immature/ mature/ senescent
•By what they produce
- TH1 (IL-2, IFN-γ); TH2 (IL-4, IL-5, IlL-6, IL-10)
What are the key features of adaptive immunity?
- Specificity – picks up on what you’ve seen before
* Memory – has a quicker and bigger secondary response
Expand on clonal selection
•Basic tenet – once cell/ one specificity
•For B cells – one cell, one Ig
- May class switch but always same basic Ig
- May undergo affinity maturation
•For T cells – one cell, one T cell receptor – TCR
•Selection (when antigen is recognised for Ab) and expansion of that clone
•Retention in ‘memory’ of clonal progeny
- Continues production of antibody (B cells)
- More rapid specific secondary responses (B and T cells)
What are the defining features of specific receptor of lymphocyte?
- Light chain
- Heavy chain
- Transmembrane region
- Antigen-binding site ~ consists on alpha and beta chain, constant and variable regions
Four basic approaches when predicting the opposition.
2 – Their presence is associated with damage
#1 – it looks like a bad guy Generic recognisable features – e.g. TLR, PAMPs, etc.
The Danger Hypothesis (not only presence of pathogen, but also damage needed for action to take place)
Damage-associated molecular pattern molecules (DAMP)
#3 – I’ve seen this before, and last time it was a bad guys - Basis of the adaptive immune system (memory)
#4 – it’s not me – it shouldn’t be there - Autoimmunity
How does the immune system set up a system to recognise things it has not seen yet?
and what problems might this generate?
The ‘massive array of possibilities’ approach
- Over- and under-assiduous recognition
- Self recognition
- Cancer cells are still “self”, still expressed MHC, etc. ~ Express cancer-specific immune targets
Describe the steps involved in thymic selection.
1) Positive selection in the thymus - Must bind MHC
2) Negative selection - Must not bind self peptides
- We end up with (theoretically) are T cells that are sufficiently good at binding to MHC to recognise organisms, but they don’t recognise self-MHC, so will not cause an autoimmune disease.
- From these cell, you set up an array called naïve cells (those that haven’t chosen to be CD4 or CD8 yet) ~ these recirculate (primarily from blood to lymph nodes)
Describe the steps involved in B cell repertoire selection
•Positive selection
- identifies immature B cells with completed antigen receptor gene rearrangement
- Functional membrane Ig molecules (BCR) provide survival signals
•Receptor editing
- If high avidity self-recognition - receptor editing changes BCR specificity
- Reactivation of RAG genes produces new Ig light chain
- If still reactive, rearranges λ light chains
•Negative selection
- If still auto-reactive, immature B cells with high-affinity self-recognition die by apoptosis in bone marrow or spleen
•Once the transition is made to the IgM+ IgD+ mature B cell stage, antigen recognition leads to proliferation and differentiation
DOUBLE CHECK THIS. How can we tell how long naive cells survive?
•We give patients labelled glucose with deuterium in it (it is a non-radioactive isotope of hydrogen). It is recognisable in a mass spectrometer.
- Follow-up blood samples
- FACS extraction/digestion
- GCMS analysis for D2.
- Results showed that there were very slow turnover in peripheral blood (flat lines in the result)
- When a naïve cell is activated, it goes through ‘gene-switch-on’ events that turn it into a proliferating cell. It then starts going down a series of cascade, where amplification also takes place.
What are TEMs, TCMs, Tregs?
•TEM: Effector Memory Cells
- Short-lived population
- Continually replenished
- Doubling time about 15 days
•TCM: Central Memory Cells
- Turnover at a significant rate
- Doubling time is about 48 days
•Treg: Regulatory T cells
- short-lived population – not like ‘M’
- Needs continual replenishment
- ? Some originate from CD25 – memory T cells
Concepts of immunological memory
- Accrued cumulatively over time
- ‘stored’ for future use
- Readily available when required
- Dynamic process
Describe B cell development
Activated B cells transform into Plasma cells
- “Antibody factories”
- also produce CD27+ memory B cells
The anatomy of lymphocytes
•Organised mainly into Lymph Nodes
- Architecture optimised to facilitate cellular interaction
•Key role of Spleen in antibody generation
- Splenectomy increases the risk of infection
- Especially pneumococcal infection – recommend vaccination
Immune senescence
•Lymphocyte function deteriorates with age
- Both age of the cell and age of the individual
- Telomere shortening
- Change in functional attributes (cells don’t respond as quickly)
- Accumulation of CD57+ cells
- CMV infection a key driver of immune senescence
