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Clinical Immunology & Haematology > Adaptive Immunity (11-15) > Flashcards

Adaptive Immunity (11-15) Flashcards

1
Q

Where do pre T lymphocytes arise from?

A
  • foetal liver before birth - gamma delta (TCR less diverse)
  • bone marrow - alpha beta TCR which migrate to thymus where they complete maturation
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2
Q

Expression of which proteins are required for RAG1/2

A

Notch and GATA3

RAG1/2 are enzymes required for somatic recombination

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3
Q

Which CD proteins are present on which cells?

A

CD45 - all leukocytes
–> Leukocyte Common Antigen (LCA)

CD19-23 - B lymphocytes

CD3, CD4+ or CD8+ - T lymphocytes

used in the lab to immunophenotype cells

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4
Q

What are gamma-delta T cells?

A
  • limited variability in antigen-binding site
  • arise early in development
  • go to mucosal sites and stay there (present in tissue)
  • identify and respond to danger and damage
  • make up 5% of T cells
  • CD4-, CD8-
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5
Q

What does the commitment of developing T cells to the CD4+ or CD8+ lineage depend on?

A

Strong TCR signaling promotes the differentiation of CD4+ T cells by upregulating the expression of the transcription factor ThPOK (T-helper-inducing POZ/Krüppel-like factor) and repressing the expression of Runx3, a transcription factor critical for CD8+ T cell development

Weaker TCR signalling favours CD8+ T cell differentiation by promoting the expression of Runx3 and inhibiting ThPOK expression

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6
Q

What is the TCR complex?

A
  • surface expression of the TCR requires assembly of TCR alpha:beta with the signalling subunits of CD3
  • CD3 proteins and the zeta chain are constant, regardless of specificity of TCR
    –> required for signalling, not for antigen recongnition
    –> zeta chain predominantly in cytoplasm
  • CD3 binds TCR through charge interactions in transmembrane domains to for complex
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7
Q

What are the primary lymphoid organs?

A

aka central

  • bone marrow
  • thymus
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8
Q

What are the secondary lymphoid organs?

A

aka peripheral

  • lymph nodes
  • spleen
  • MALT, GALT
  • Peyer’s patches
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9
Q

How do effector T cells enter tissues?

A

different tissue entry dependent on adhesion molecule expression

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10
Q

What is the lymphatic system and what is in it?

A

made up of lymph nodes and lymphatic vessels

has lymphocytes, monocytes, dendritic cells

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11
Q

How do lymphocytes enter lymph nodes?

A

mature lymphocytes enter from arteries
B and T cells enter their respective zones through chemokine detection

naive lymphocytes enter through high endothelial venules (HEVs)

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12
Q

How do naive lymphocytes enter the walls of HEVs?

A

rolling
–> binding of L-selectin on lymphocyte to GlyCAM-1 and CD34 on endothelial cell

activation
–> LFA-1 (lymphocyte) is activated by CCR27 (lymphocyte) binding to CCL21 or CCL19 bound to endothelial surface

adhesion
–> activated LFA-1 binds tightly to ICAM-1

diapedesis (entry)
–> lymphocyte crosses the endothelium and enters the lymph nodes via diapedesis

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13
Q

What is the structure of the spleen?

A
  • largest secondary lymphoid organ
  • capsulated
  • entry into white pulp is via marginal sinus not HEVs
  • non-lymphoid red pulp: Removal of old, damaged and dead red blood cells along with antigens and microorganisms
  • white pulp: surrounding arterioles has T and B cell areas
  • PALs: Peri-Arterial Lymphoid Sheath (mostly T cells)
  • B cell follicles
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14
Q

What is the function of the spleen?

A
  • circulating lymphocytes delivered to marginal sinus, designed for capture of blood-borne antigens or intact microbes
  • marginal zone (MZ) rich in specialised populations of macrophages and DCs and marginal zone B cells, which do not recirculate
  • pathogens efficiently trapped in MZ by DCs and macrophages, which deliver antigen into white pulp
  • marginal zone B cells adapted to provide rapid responses to pathogens that enter marginal zone eg production of IgM antibodies
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15
Q

What cells are MHC classes I and II present on?

A

MHC-I
- all nucleated cells
- grove closed, 8-11 residues, anchor sites more specific
–> structure more specific as these present antigens from viruses and intracellular bacteria (small range)

MHC-II
- DCs, macrophages, B cells
- groove open at both ends, 10-30+ residues, anchor sites less specific

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16
Q

How are intracellular antigens presented?

A
  1. cytosolic protein digested in immunoproteasomes
  2. the peptides, 8-10 amino acids in length, are transported from the cytoplasm into the endoplasmic reticulum (ER) by the transporter associated with antigen processing (TAP) proteins. TAP forms a channel in the ER membrane through which peptides can pass. These are loaded onto newly synthesised MHC class I molecules.
  3. movement through ER, endocytosed (enclosed in vesicle), the subsequently through the GA
  4. vesicle travels to cell membrane where antigen-MHC I complex is presented to a CD8+ T cell
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17
Q

How are extracellular antigens presented?

A
  1. endocytosis of extracellular protein
  2. digestion of protein through fusion of protein containing vesicle with endosomes/lysosomes
  3. MHC class II molecules is synthesised in the ER, with a CLIP protein bound which:
    - stabilises MHC molecule
    - acts as a chaperone
    - prevent premature antigen binding
    - facilitates proper protein folding
  4. MHC class II containing vesicle fuses w antigen containing lysosome/endosome, which causes displacement of CLIP
  5. vesicle moves to the cell membrane where the antigen is presented to a CD4 T cell
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18
Q

What is MHC polymorphism?

A

MHC genes exhibit polymorphism, meaning they have multiple alleles within a population

each allele encodes for a slightly different MHC molecule, w variations in their peptide-binding grooves
–> individuals express a diverse array of MHC molecules capable of presenting a wide range of antigens to the immune system

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19
Q

What is MHC polygeny?

A
  • the MHC is encoded by a cluster of genes, and individuals inherit multiple MHC genes from each parent
  • this polygeny increases the number of different MHC molecules expressed

each MHC gene may have different alleles , and the combination of alleles inherited from each parent results in even greater diversity in the MHC molecules expressed by an individual

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20
Q

What are the differences between myeloid an plasmacytoid DCs?

A

plasmacytoid dendritic cells (pDC)
- Specialized in producing large amounts of type I interferons (IFN-α and IFN-β) in response to viral infections through Toll-like receptor (TLR) signaling.
- limited antigen presentation
- derived from pre-DC population along w monocyte derived DC subsets

myeloid dendritic cells (mDC)
- Efficient in antigen uptake, processing, and presentation to T cells, promoting adaptive immune responses.

  • Produce proinflammatory cytokines and chemokines upon activation through various stimuli, including pathogens and inflammatory signals
  • conventional DCs derived from myeloid progenitor cells
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21
Q

What receptor is crucial for DC maturation and migration?

A

CCR7

binds to CCL19 and 21 on the endothelial surface

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22
Q

What is the function of fibroblast reticular cells?

A

form a network in the T cell zones in the lymphoid tissue to enable interactions between naïve T cells and DC

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23
Q

What is the SMAC?

A

supramolecular activation cluster
– another name for the immunological synapse

  1. T cells initially binds APCs through low-affinity LFA-1 (T cell):ICAM-1 (APC) interactions
  2. subsequent binding of TCR to MHC-antigen complex signals LFA-1
  3. conformational change in LFA-1 increases affinity and prolongs cell-cell contact
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24
Q

What is WASP?

A

Wiskott-Aldrich Syndrome Protein

  • in the early phases of T-cell activation, adhesion molecules are scattered randomly across the surface
  • activation of WASP by ZAP-70 induces the actin cytoskeleton to form an immunological synapse

WASP expressed exclusively in haematopoietic stem cells

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25
Q

What is Wiskott-Aldrich Syndrome?

A

mutation in the function of WASP

  • increased tendency to bleed cause by significantly reduced no. of platelets
  • recurrent bacterial, viral and fungal infections
  • eczema of the skin
  • increased risk of developing severe autoimmune disease
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26
Q

What is required for full activation of T cells?

A

CD4+
- CD40 on DC engagement w CD40L on CD4 T cells

CD8
- 4-1BBL on activated APC binding to 4-1BB on activated CD8 T cells

27
Q

How does TCR signalling occur in the TCR cluster?

A
  • initiated by tyrosine phosphorylation at cytoplasmic regions (ITAMs)
  • One ITAMs in each of CD3 epsilon, gamma, theta chains
  • a zeta chain contains 3

– epsilon/theta heterodimer
– epsilon/that heterodimer
– zeta/zeta homodimer
–> 10 ITAMs in total

28
Q

What cytokines and receptors are important for T cell activity?

A
  • IL-2 is key for proliferation
  • CD40L important for full activation of innate cells (and class switching of Ab)
  • CTLA4 preferentially binds B7 (CD80/86) on APCs to control the response

(ordered by time after activation)

29
Q

Once activated, why do T cells no longer require co-stimulation?

A

CD4 T cells need to activate B cells and macrophages that have taken up antigen even if no co-stimulatory molecule expression

CD8 T cells must be able to recognise antigen presented on cells that do not express co-stimulatory molecules

– easier subsequent activation
– proven to act against foreign antigen

30
Q

What are the dynamics between different T cells?

A

Activated Th2 cells secrete IL-4
–> inhibits differentiation of Th1
–> inhibits development of Th17

Activated Th1 cells secrete IFN-gamma
–> inhibits proliferation of Th2
–> inhibits development of Th17

Treg cells suppress the differentiation and proliferation of Th1 and Th2 cellsthrough secretion of IL-10 and TGF beta

31
Q

How do memory T cells arise?

A

derive directly from some effector T cells

  • central memory cells express CCR7 and remain in lymphoid tissue
  • effector memory cells lack CCR7 and migrate to tissues
32
Q

How does egression of lymphocytes from lymphoid organs occur?

A

mediated by sphingosine 1 phosphate (S1P) and S1PR on T cells

33
Q

What is the function of Th1 cells?

A

intracellular bacterial infection

  1. produce IFN-gamma and CD40L which induce and activate M1 macrophages
  2. FasL induces apoptosis of bacteria-laden macrophages
  3. produces IL-2 which activates naive CD4 and CD8
  4. GM-CSF and IL-3 induces monocyte production and differentiation
34
Q

What is the function of Th2 cells?

A

helminth infection

  1. produce IL-13
    - induces weep and sweep response
    - increased intestinal cell turnover
    - activates M2 macrophages = tissue repair and increased smooth muscle contraction that enhances worm expulsion
  2. IL-5 recruits and activates eosinophils
    - produced MBP kills parasites
    - mediate ADCC
  3. IL-3 and IL-9 drive mast cell recruitment
    - produce mediators such as histamine and TNF-alpha which recruit inflammatory cells
35
Q

What is the function of Th17 cells?

A

extracellular bacterial infection

  1. Il-17 and IL-22 induce production of antimicrobial peptides by epithelial cells
  2. IL-22 increases epithelial cell turnover which impairs bacterial colonisation
  3. IL-17 induces neutrophil production in the bone marrow and recruitment
  4. CCL20 is a chemoattractant for other Th17 cells
36
Q

What are the killing mechanisms of CTLs?

A
  1. perforin/granzymes
    - perforin induces uptake of granzymes into target cell endosome and release into cytosol, activating caspases
  2. Fas/FasL
    - FasL on CTL interacts w Fas on target cel, causing it to apoptose
37
Q

What is central tolerance?

A

occurs in generative lymphoid organs during development of the immune system (embryonic/neonatal)
–> thymus - T cells
–> bone marrow - B cells

negative selection occurs
–> immature lymphocytes specific for self antigens undergo
- deletion
- receptor editing (B cells)
- differentiation into T regs (CD4 T cells)
–> lymphocytes need to recognise self but too strong of a reaction leads to these outcomes

mediated by AIRE, a TF that drives expression of self antigen in medullary thymic epithelial cells (mTECs) which are presented to immature T cells
–> mutation results in APECED
–> cannot be cured by a haematopoietic stem cell transplant as mTECs are stromal cells and not part of the haematopoietic system, also, embryogenesis has already occured to tolerance cannot be reset

38
Q

What is peripheral tolerance?

A

occurs in peripheral tissues

mature self-reactive lymphocytes that escape central tolerance are:
- rendered non-responsive (anergy)
- deleted
- suppressed by Tregs

prevents reactivity to:
- self antigens not expressed in thymus/early life
- harmless foreign antigens eg food proteins, commensals
- foetal antigens (which is semi-allogenic)

39
Q

How can infection result in autoimmunity?

A
  1. in an individual with APCs that have more tendency to present self antigens, the APC can be activated by an infection but instead present a self antigen to T cell, which gets activated due to the presence of danger signal
  2. microbial antigen is v similar to host antigen
    eg group A strep (GAS) –> rheumatic fever
40
Q

How can treatment induce anergy to prevent autoreactive T cells?

A

block B7/CD28 by using antibodies that bind to B7

41
Q

What is AICD?

A

activation-induced cell death

after effector T cells have activated other cells/killed their targets, they must be removed to avoid long term inflammation and tissue damage

Fas on activated T cells binding to FasL on another cell, killing T cell
–> T cells also express FasL, two T cells can kill each other

42
Q

What is ALPS?

A

Autoimmune Lympho-Proliferative Syndrome

occurs in patients w mutations in apoptosis pathway
- Fas, FasL, Caspase 10

causes autoimmune disease and probs inability to kill infected cells

can be cured by a haematopoietic stem cell transplant

43
Q

Where are Tregs generated?

A

in the thymus (nTregs): generated during negative selection

in the periphery: generated in the presence of TGF-beta

44
Q

What molecules do Tregs require?

A

FOXP3 for differentiation

CD25: IL-2 receptor
CTLA-4: inhibitory receptor

45
Q

How do Tregs suppress other cells?

A

CTLA-4
- blocks B7 on APC so not available for effector T cells to bind to w CD28
- removes B7 from APC
- binding to B7 sends inhibitory signals to APC -> decreased antigen presentation and cytokine production

  • production of suppressive cytokines (IL-10, TGF-beta
  • consumption of available IL-2 through CD25 binding, so T cell proliferation is reduced
46
Q

What is IPEX?

A

Immunodysregulation , Polyendocrinopathy, Enteropathy, X-linked

caused by mutations in FOXP3 gene -> loss of functional Tregs

symptoms
- enteropathy
- type-1 diabetes
- dermatitis
- other autoimmune manifestations

can be diagnosed through flow cytometry of peripheral blood cells

can be cured via haematopoietic stem cell transplant

47
Q

Why might the incidence of autoimmunity be higher in females than males?

A

sex bias

  1. X/X chromosomes - incomplete inactivation
  2. gonadal hormones
  3. pregnancy
48
Q

How can trauma cause autoimmune disease?

A

some sites are normally inaccessible to the immune system as inflammation in these sites would be risky = immunologically privileged
- physical barriers restrict entrance to lymphocytes

damage to these barriers by trauma can lead to autoimmunity
eg sympathetic autoimmune opthalmia
–> trauma to one eye results in release in sequestered antigens
–> these are carried to lymph node and activate T cells
–> effector T cells return via blood stream and encounter antigen in both eyes

49
Q

What is dysbiosis?

A

the microbiome modulates the immune system, maintaining homeostasis

disturbances in the composition of microbiota can lead to immune dysregulation and development of autoimmunity

50
Q

How can autoimmune diseases be treated?

A

monoclonal Abs - block specific steps of the immune response
eg rituximab (anti-CD20) marks B cells for phagocytosis, but eliminating that entire part of the immune system
–> used to treat rheumatoid arthritis

increase number of Tregs

tolerogenic vaccines - induce permanent tolerance to the autoantigen

51
Q

What can be measure using flow cytometry?

A
  • cell size: small angle light scattering
  • cell granularity: large angle light scattering
  • cell counting: light scatter or electrical impedence
  • cell markers/phenotype
  • nucleic acids
  • organelles
52
Q

What is forward scatter?

A

measurement of relative cell size

  • light scatter in the forward direction (along the same axis as laser light)
  • intensity of forward scatter is proportional to the size of cells
    ie the larger the cell, the more light bends around it
53
Q

What is side scatter?

A
  • light scatter to the side is detected in the side or 90 degree scatter channel (SSC)
  • the intensity of side scatter is proportional to the shape and optical homogeneity (granularity) of cells
    ie the more complex the cell (more stuff inside), the more light is scattered
54
Q

Why does a threshold need to be set in the flow cytometer?

A

RBCs and platelets are 1000x times more abundant than WBC

can tell the machine to ignore anything below a certain size
if this isn’t done, most of the work focusses on the stuff that is more abundant and become less accurate at measuring stuff you do want

55
Q

What are fluorochromes?

A

molecules or proteins that absorb light of one wavelength and emit light of a different wavelength

when hit with a laser, they are put into an excited state but it doesn’t want to be there so it emits light to come back to its ground state

can be attached to cells to cell surface proteins or carbohydrates and intracellular proteins

56
Q

What is a drawback of coloured labels?

A

light is a bell shaped curve of omission
as more things are added, the more overlap there is

fluorochromes can emit colours forward and backward into different colours, overlapping into adjacent fluorochromes

synthetic polymers “brilliant dyes”, which are same as fluorochromes but with more turns of fluorescence gives more fluorescence but in turn more overlap
–> a problem if trying to label multiple things at once

57
Q

What is sequential gating?

A

blocking the machine from detecting certain things

eg lymphocytes - have Fc receptors which bind antibodies that muddy results

eg singlet gating - not detecting things that look like cells even though they are not such as debris and small cells binding and looking like a larger cell

–> requires teaching the machine to no detetct certain things

58
Q

Summarise B cell development up to the immature B cell stage.

A
  1. interaction w stromal cells inititates B cell differentiation through IL-7 and E2A
  2. After initiating differentiation to the B cell lineage, the D-J segment of the H cain start rearranging in early pro-B cells

Once D and J have rearranged, early pro-B cells move on to the late pro-B cell stage,and V starts rearranging first on one allele.

  1. after VDJ recombination, first check occurs
    - where cells express surrogate light chain forming the pre-BCR
    - If the VDJ rearrangement in the first allele is successful, the cell moves on. If not, thesecond allele starts rearranging. If this is not successful either, the cell dies. If it issuccessful, the cell moves on to the large pre-B stage
  2. large pre-B cells perfrom allelic exclusion, proliferate, and rearrange the L chain leading to small pre-B stage
    • light chain rearrangement is checked, if successful, allelci exclusion takes place and IgM can be expressed, moving on to immature B cell stage
59
Q

How does alpha/beta TCR undergo VDJ recombination?

A

alpha chain contains V and J
beta chain contains V, D, and J

mechanisms that control recombination events are same between B and T cell
- RAG1/2: cutting at RSS
- Artemis: adding new nucleotides

summary
- RAG1 binds to RSS
- RAG2 is guided by RAG1 and cuts DNA

  • activity of RAG1/2 forms a loop structure and brings part to be joined into close proximity
  • cleavage occurs at ends of coding sequences and loop is cut out
  • artemis cleaves hairpin loops left after cleavage, which creates raggedy ends that are targeted for extension
  • TdT adds new nucleotides to join DNA strands together, which is random so new sequence for every recombination event
60
Q

After the immature B cell has formed, what happens next in B cell development?

A

B cells are tested for reactivity to self antigens, called B cell tolerance

occurs in the spleen in two stages:
1. T1 - B cells are checked for autoreactivity, if they receive a strong signal if they encounter self antigens they are deleted, B cell peripheral tolerance
2. T2 – B cells undergo positive selection, a process in which B cells with low-affinity receptors for self-antigens receive survival signals and mature into functional B cells capable of responding to foreign antigens.
– B cells also undergo receptor editing, a process in which the B cell receptor (BCR) undergoes rearrangement to change its specificity, thereby reducing the likelihood of autoreactivity

B cells move through white pulp between T1 and T2

61
Q

In what stages does the T cell develop?

A

occurs in thymus, called ‘thymocytes’
leave bone marrow and travels through blood by following chemokine signals

stages of development are defined by expression of CD molecules:
- 4 stages of double negative expression (DN1-4)
- 1 double positive stage (DP)
- then express either CD4 or CD8

after DN3 is where gamma delta T cells can arise
alpha chain recombination occurs after DN4
positive selection takes place after DP so only T cells w good receptors remain
after SP, negative selection occurs to filter out autoreactivity

62
Q

Describe positive selection in T cell development?

A

occurs during DP stage

it is the selection of cells w functional TCRs able to intercts w self MHC-peptide
only T cells able to interact w MHC and signal through their TCR are useful

a lot of the alpha chains generated by gene rearrangement will not be able to make functional TCRs, determines MHC restriction

this is done by cortical thymus epithelial cells (cTEC) present peptides to DP cells both in MHC I and II

63
Q

Describe negative selection in T cell development.

A

occurs during SP stage

deletion or modification of autoreactive CD8 and CD4 cells in thymus
recognition of cell would lead to autoimmunity
done by SP T cells interacting w:
- DCs: present self antigens from blood/lymph
- mTECs (medullary thymic epithelial cells): present self antigens from tissues areound the body, tissue restricted antigens (TRAs)

high affinity binding = apoptosis
intermediate affinity binding = Treg
low affinity binding = survival

negative selection is central mechanism for central tolerance of T cells

Clinical Immunology & Haematology (5 decks)

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