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BMED2404 > Immunology > Flashcards

Immunology Flashcards

1
Q
  1. Correlate the structure of TCRs to their function.
A

T Cell Receptors are heterodimers, consisting of either alpha & beta chains, or less commonly gamma & delta chains. Chains are embedded in the cell membrane in a ‘Transmembrane Region’.
Each chain consists of a VARIABLE DOMAIN (Ig domains with disulphide bonds), for ANTIGEN RECOGNITION. This differs between clones and accounts for the ability of the adaptive immune system to recognise nearly any antigen it encounters and thus launch its immune response.
Each chain also possesses a more proximal (to the cell membrane) CONSTANT DOMAIN, which functions in STRUCTURAL INTEGRITY. This Ig domain is CONSERVED between clones.

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2
Q
  1. Describe the STRUCTURE of BCRs.
A

Many things in common bw T-& BCRs.

VARIABLE DOMAINS:

  • involved in Ag recognition
  • vary bw BC clones

CONSTANT DOMAINS:

  • involved in effector functions
  • relatively conserved bw clones
  • can change/switch
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3
Q
  1. What constitutes “Humoral Immunity?”
A

B CELL Lymphocytes

  • Antibodies (in serum)
  • Cytokines, chemokines
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4
Q
  1. Antibody-Antigen Interactions:

How does the HINGE give flexibility?

A

Allows variable regions to come closer together / further apart to bind epitopes that are either close together or far apart on an antigen.

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5
Q
  1. How do we create the diversity of TCR & BCR repertoire?
A
  • Each lymphocyte has only 1 receptor w 1 specificity. TC repertoire ~1 billion cells, but not enough DNA for 10^9 germline genes.

Diversity is generated through VDJ recombination: rather than having a specific gene, we have gene SEGMENTS that come together in random pieces/combinations.

Transcription, splicing and assembly leads to the vast repertoire of receptors of TCs.

(more details in #23)

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6
Q
  1. Describe MHC molecules and how the classes differ from each other.
A

MHC = ‘Major Histocompatibility’. MHC molecules are involved in TC Ag recognition, that is, TCs can only ‘see’ their respective peptide Ag’s when they are presented on MHC molecules (they don’t ‘see’ free-floating Ag’s like BCs). They are of 2 types.

Class I involved with intracellular pathogens & CD8 cytotoxic TCs. The molecule consists of a main alpha chain which forms a closed peptide binding cleft (alpha1 & alpha2 polymorphic residues) which accommodates small peptides .

Class II involved with EXTRAcellular pathogens & CD4 helper TCs. The molecule consists of an alpha AND a beta chain which form an OPEN peptide binding cleft (alpha1 & beta1 polymorphic residues) which accommodates LARGER peptides (10-22 a.a’s).

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7
Q
  1. Antibody-Antigen Interactions:

What defines the basis of which epitopes of protein antigens may be recognised?

A
  1. the sequence of a stretch of a.a’s - LINEAR epitopes

2. the 3D shape of the protein antigen - CONFORMATIONAL epitope

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8
Q
  1. Explain TC Signalling
A

TCR-CD3 Complexes are constitutively expressed to allow for TC identification.

  • Complex is required for TCR surface expression
  • CD3 gamma, delta and epsilon chains have a single extracellular Ig domain, whilst the zeta chain is mainly intracellular
  • CD3 chains have ITAM motifs (Immunoreceptor Tyrosine-based Activation Motif)
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9
Q
  1. Why is Co-stimulation so important?
A
  • Resting APCs unable to activate naïve TCs
  • TCs that recognise ag WITHOUT costimulation become unresponsive (anergic/tolerant)
  • Microbes + cytokines produced during innate IRs to microbes, induce the expression of costimulators
  • Activated APCs also produce cytokines that stimulate the differentiation of naïve TCs into effector cells.
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10
Q
  1. The four step in TC activation involves Positive Co-stimulation. Explain the details.
A

Even after adhesion molecules, TCs require ADDITIONAL signals to achieve full activation: “Two signal hypothesis”:

- Signal 1 = Ag recognition (TCR + MHC + peptide)
- Signal 2 = co-stimulatory signal from DC
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11
Q
  1. Why is Interleukin-2 (IL-2) important in TC maturation?
A

IL-2 is essential for promoting TC proliferation & differentiation into effector TCs. Several transcription factors must bind to the regulatory elements in the promotor to initiate IL-2 transcription (NFAT, AP-1, KF-kB)

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12
Q
  1. What are RESIDENT memory TCs?
A

Those that do not circulate in blood, often positioned at sites of possible antigen encounter. There are involved in the first line of adaptive response.

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13
Q
  1. Discuss the types of Antibody Classes.
A

2 types of light chain:

  • Kappa & lambda (each BC expresses one or the other, but not both)
  • differ in Constant domain, but no functional differences

5 types of heavy chain

  • delta, mu, gamma, epsilon, alpha
  • differ in Constant domain AND in function

Ab classes/isotypes are named according to HEAVY chain (respective of Greek alphabet name, e.g. mu = IgM). They have different functions.

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14
Q
  1. Describe the steps in TC activation in lymph nodes.
A
  • Induction of response: DCs migrate to lymph nodes. Antigen captured by DCs is recognised in lymphoid organs by corresponding naïve TCs. These TC populations expand and differentiate into mature effector TCs. Differentiated effector TCs enter circulation.
  • Effector TCs and other leukocytes migrate to the site of the antigen. Effector TCs encounter antigens in peripheral tissues (eg cells with intracellular microbes; MHC-I molecules expressed with antigens for effector TC recognition). Effector TCs are activated (via cytokines?).
  • TC effector functions. CD4: Leukocyte activation (inflammation); phagocytosis and killing of microbes. CD8: CTL killing of infected cell.
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15
Q
  1. Describe Ab-Ag interactions.
A

Ag-binding CDR loops can come together:
- to form clefts accommodating small molecules / flat surfaces capable of accommodating larger molecules

The hinge gives flexibility. (see #19)

Parts of Ag’s recognised by Ab’s are ‘epitopes’/’determinants’

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16
Q
  1. Where does antigen bind on antibodies?
A

The variable regions of both heavy & light chains each contain 3 hyper-variable regions called COMPLEMENTARITY-DETERMINING REGIONS (or CDRs).

This is where antigen binds.

17
Q
  1. What are the differences between Central memory & Effector memory TCs?
A

Largely defined on the basis of circulation:

- CM circulate through lymphoid tissues
- EM circulate through non-lymphoid tissues

Functional differences:
- CM highly proliferative
EM enhanced effector functions

18
Q
  1. In selection of TC clones, differ positive selection from negative selection.
A

POSITIVE: Ensures that the TCRs are usable.

- Expression of CD4/8, as directed by TCR interactions with either MHCII/I
- Selects for low-affinity anti-self (survival)

NEGATIVE: Removes dangerous TCRs
Purges high-affinity self-reacting TCs (death)

19
Q
  1. What are the typical features of the Innate Immune System?
A
  • Exists in all animals (as opposed to adaptive only in vertebrates).
  • BARRIERS: Physical & Chemical
  • Phagocytic cells (neutrophils, macrophages), DCs, NKCs, ILCs
  • Cells look for ‘foreign’ elements, i.e. PAMPs (e.g. nucleic acids like viral ssRNA, proteins like bacterial flagellin), or DAMPs (stress-induced proteins, crystals, or nuclear proteins)
20
Q
  1. B Lymphocytes….

a) eliminate phagocytosed microbes
b) kill infected cells and eliminate reservoirs of infection
c) target intracellular microbes
d) secrete antibody as their effector mechanism

A

d) secrete antibody as their effector mechanism

BCs are part of the Humoral Immunity (Adaptive IS). Their antibodies function to block infections & eliminate EXTRAcellular microbes.

a, b & c are all of TCs in Cell-Mediated Immunity. (a) in particular is the targeted aim of Helper T Lymphocytes, which activate macrophages to achieve this. (b) in particular is the function of Cytotoxic T Lymphocytes.

21
Q
  1. Differ AFFINITY from AVIDITY
A

AFFINITY: strength of binding bw 1 AgBS on an Ab mol & its corresponding epitope.

AVIDITY: overall strength of the interaction bw the Ab and its Ag.
- depends on both affinity & valency of interactions

22
Q
  1. Differ the following features of the adaptive and innate immune systems:

a) diversity
b) specificity
c) memory
d) non-reactivity to self
e) blood proteins
f) cellular/chemical barriers

A

Innate referenced first, compared to Adaptive:

a) Limited diversity, germline-encoded (including receptors) || large; receptors produced by some recombination of gene segments
b) Molecules shared by groups of related microbes (PAMPs) & molecules produced by damaged host cells (DAMPs) || microbial AND nonmicrobial antigens
c) no memory vs memory capability
d) both a non-reactive to self
e) complement, others || antibodies
f) skin, mucosal epithelia; antimicrobial molecules || lymphocytes in epithelia; Ab’s secreted at sEp

23
Q
  1. How do the kinetics of the Innate Immune System differ from the Adaptive Immune System?
A

I - quick response, in the span of hours

A - more sophisticated, and thus require some time to develop; a lag for effective response

24
Q
  1. Discuss IMMUNOLOGICAL TOLERANCE.
A
  • Random recombination events mean sometimes you’ll generate a receptor that recognises “self” proteins
  • A system for determining which lymphocyte clones will be allowed to survive: retain useful clones & eliminate potentially harmful ones

Two types of tolerance mechanisms:

  1. Central mechanism - occurs in the primary lymphoid tissues
  2. Peripheral tolerance mechanism - primarily mediated by regulatory TCs

A BREAKDOWN IN TOLERANCE CAN LEAD TO AUTOIMMUNE DISEASES.

25
Q
  1. The first step in TC activation is Ag recognition. Explain the details.
A
  • TCR recognises peptide-MHC (Ag specificity)
  • TCR recognition is MHC-restricted
  • TCR binding to peptide-MHC is low affinity (stabilised in step 2; co-receptors)
  • The TCR itself doesn’t transduce activation signals (TCs don’t have the ability to signal themselves; need the TCR complex)
  • 2 or more TCR must be engaged, for several minutes to commence activation (fewer than 10 are all that’s required)
26
Q
  1. Explain the transition from Naïve to Effector to Memory TCs.
A

Several changes:
- Phenotypic changes: useful to define populations
- Transcriptional profile changes: equipped for survival & response
- Metabolic changes: adaptation to needs
Epigenetic

27
Q
  1. The second step in TC activation involves Co-Receptors. Explain the details.
A
  • CD4 co-receptor on ThCs: binds conserved beta2 chain on MHC class II.
  • CD8 co-receptor on CTLs: binds conserved alpha3 chain on MHC class I.
  • stabilises low affinity binding of TCR to peptide-MHC
  • ensures appropriate TC type is activated
  • Activation occurs via signalling through the TCR COMPLEX (CD3 molecules always associated with TCR in cell membrane)
    • Provide activation signal transduction via immunoreceptor tyrosine-based activation motif (ITAM) sequences
28
Q
  1. Describe the control (regulation) of TC activation.
A
  • Activation is tightly controlled by several receptors on TCs binding to ligands on DC
  • TC activation involves ‘cross-talk- bw TC & DC
  • An exchange of signals occurs at the “IMMUNOLOGICAL SYNPASE”, = The point of contact bw TC & DC.
  • TC activation is coordinated by a series of steps:
    1. Ag recognition
    2. Co-receptors
    3. Adhesion molecules
      1. Co-stimulation
29
Q
  1. What is the IMMUNOLOGIC SYNAPSE?
A

Several surface proteins & signalling molecules are rapidly mobilised to the site.

  • Aka supramolecular activation cluster (SMAC)
  • cSMAC vs pSMAC
  • Stable contact
  • Specific delivery of effector molecules

When TCs are engaging APCs, there’s a group of receptors coming into play (aka SMAC).
Many receptors are important for TCs to recognise a tumour/infected cell. This is critical for their function.

30
Q
  1. DCs capture antigen and travel to local lymph nodes. Explain this process and differ DCs in the periphery vs in the lymph nodes.
A

DC in the periphery:

- PRRs (phagocytic recognition receptor) recognise PAMPs
- High phagocytic capacity 
- Process protein antigens onto MHC I & II
- Migrate to TC zones (in response to PAMPs, DAMPs & cytokines)

DC in the lymph nodes:
- Home to TC zones
Express the required surface molecules to activate naïve TCs (MHC, co-stimulatory molecules, cytokines)

31
Q
  1. Briefly Describe BCRs. (function/aim)
A

BC Receptors are in fact membrane bound antibodies.

  • Antibodies & BCRs are also known as Immunoglobulins (Ig)
  • Naive BCs express IgM & IgD
  • Both membrane-bound & secreted forms bind EXTRACELLULAR ANTIGENS
  • When secreted, Ab’s perform EFFECTOR FUNCTIONS
  • BCs are the ONLY cells that synthesise Ab’s (BCs always see extracellular antigens, in their native form)
    • distributed in biological fluids throughout the body - they are present in plasma, mucosal secretions, interstitial fluid of the tissues.
32
Q
  1. Discuss the involvement of VDJ Recombinase in TC Diversity.
A

VDJ Recombination enzymes mediate VDJ recombination. They are lymphoid specific and are only expressed by immature T & BCs.

VDJ-R is composed of the recombinase activating gene 1 & 2 proteins (RAG-1 & -2).

If one is deficient in RAG, no mature T or B cells will develop. This is ‘Primary Immunodeficiency’ - when one is born with defective genes that result in non-functional VDJ-R enzymes.

33
Q
  1. What constitutes “Cell-mediated Immunity”?
A

T CELL Lymphocytes

  • Cytotoxic (CD8): cytolytic granules (cytokines, chemokines)
  • Helper (CD4): cytokines (chemokines)
34
Q
  1. Describe the STRUCTURE of ANTIBODIES.
A
  • 4 polypeptide chains assembled into a Y shape
  • 2 identical LIGHT (L) chains (25 kD) || 1 variable domain 1 constant
  • 2 identical heavy (H) chains (50 kD) || 1 variable domain 3-4 constant
  • the 2 variable regions make up the ANTIGEN BINDING SITE
35
Q
  1. What are TCR Co-receptors and what do they do?
A

Need other receptors than TCRs alone to help activate the TC:

  • Bind to non-polymorphic regions of MHC
  • Cytoplasmic tails bind to Src family kinase Lck
  • CD4 = Class II, CD8 = Class I (NB same designation as MHC classes)
  • Responsible for MHC restriction
  • Facilitate TC activation process by bringing Lck close to CD3 ITAMs

However these are still enough to activate the TC… (see #11)

36
Q
  1. What terms are described by the following?
    a) Random recombination of VDJ/VJ segments
    b) Random addition & subtraction of nucleotides at V-D-J or D-J junction
A

a) COMBINATORIAL diversity - i.e. where we pick random segments of the genes, that gives us a repertoire
b) JUNCTIONAL diversity - where gaps are filled randomly with nucleotides

37
Q
  1. What binds antigen in the antigen-binding site of antibody molecules?
A

Weak non-covalent forces:

  • Hydrogen bonds: shared hydrogen ion
  • Electrostatic forces: opposite charges
  • Van der Waals forces: electron clouds
  • Hydrophobic forces: exclude water molecules

NB binding is reversible

38
Q
  1. The third step in TC activation involves Adhesion Molecules. Explain the details.
A
  • LFA-1 (expressed on DC): leukocyte function-associated antigen-1 (CD11a)
    • An integrin molecule expressed in TC membrane
  • binds ICAM-1: intercellular adhesion molecule-1 (CD54)
    • Adhesion molecules on APC
  • adhesion molecules INCREASE binding affinity of TCR to peptide-MHC complex

But still not enough!

BMED2404 (6 decks)

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