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Immunology 2 > Lecture 4: Tolerance > Flashcards

Lecture 4: Tolerance Flashcards

1
Q

Types of bonds between antigen and antibody

A
  1. Hydrogen Bonds
  2. Electrostatic Forces
  3. Van Der Walls Force
  4. Hydrophobic Bond
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2
Q

Describe the entire process of antigen recognition (both cell membrane assosciated and soluable)

A
  1. Microbial surfaces induce complement, MBL, acute phase proteins (Lectine pathway)
  2. Microbial PAMPS = PRR = phagocytosis = APC = TH cell recog MCH 2 = B cell activation = plasma cells
    MCH 1 on cells show antigen fragments to Tc cells
    Refer to lecture slide
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3
Q

Facts about PAMPS

A

evolutionarily conserved structures on pathogens

all PAMPs are produced by microbes, but not by the host organism

different types of microbes express different PAMPs

PAMPs are invariant (never changing) among pathogens of a given class
- allows a limited number of germline-encoded PRRs to detect any microbial infection (eg a type of gram neg bacterial PAMP is the conserved lipid A portion of liposaachrides (located on ALL gram neg bacteria) and because of this, only one type of PRR directed against this PAMP is needed to detect the presence of almost ANY gram neg bacteria)

PAMPs often perform physiologic functions that are essential for microbial survival
- limited in their ability to either mutate or lose expression of PAMPs in order to avoid recognition by the innate immune system

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4
Q

PAMPS on bacteria

A 
Lipoteichoic acid
Lipoproteins
Peptidoglycan
DNA
Flagellin
Lipopolysaccharides (only on Gram Neg)
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5
Q

PAMPS on Virus

A

Protein coat

Nucleic Acid

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6
Q

PAMPS on Parasite

A

GPI anchor

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7
Q

PAMPS on Yeast

A

Zymosan (Beta glycan)

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8
Q

List the 4 types of PRR’s

A

Toll-like receptors (TLR)
Nucleotide-binding oligomerization domain-like receptors (NLR)
C-type lectin receptors (CLR)
RIG-1 like receptors (RLR)

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9
Q

Where are PRR expressed?

A

Cell surface, cytsol, phagocytic vessels.

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10
Q

Describe TLR PRR

  • Located
  • Recognise..
  • Example
A
  • transmembrane protein on cell membrane and endosome
  • recongises protein, nucleic acids, glycans
    Example: TLR4 recognises lipopolysacchardies on all gram neg bacteria
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11
Q

Describe CLR PRR

  • Located
  • Recognise..
  • Example
A

transmembrane protein on cell membrane
recognises glycans from fungi/bacteria cell walls
Example: Dectin-1/CLEC7A recognises Beta -1,3 glycans in cell wall of fungi

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12
Q

Describe NLR PRR

  • Located
  • Recognise..
  • Example
A

Cytoplasmic receptors
Recongnise all PAMP types
AIM2 recongises viral and bacterial DNA
NOD1 and NOD2 recognise bacterial peptidoglycan

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13
Q

Describe RLR PRR

  • Located
  • Signal..
  • Example
A

Cytoplasmic receptors of viral RNA
Signal via mitochondrial adapter protein MAVS causing antiviral response
Example: RIG1

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14
Q

What is central tolerance
where does it happen?
Purpose?

A

occurs inside the organ of maturation, the thymus for T-Cells and bone marrow for B-Cells.

main way theimmunesystem learns to discriminate self from non-self.

T cells and B cells that can recognize and bind to self-antigens are eliminated.

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15
Q

What is Peripheral tolerance
where does it happen?
Purpose?

A

occurs outside the organ of maturation, at the site of antigen recognition. (the circulation, lymph node, lymph organ, or other tissues)

Key to preventing over-reactivity of theimmunesystem to various environmental entities (allergens, gut microbes, etc.)

Self-reactive T and B cells are either suppressed, deleted or become anergic (functionally unresponsive to antigen).

Respond to any and every antigen present

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16
Q

What process does central tolerance use (T cells)?

How are Treg cells formed?

A

POS and Neg selection

Intermediate binding to self antigen forms treg cells

17
Q

Describe T -cell peripheral tolerance and 3 methods of it

A

Occurs when T-cells fail to form their effector function.

Anergy
- T cells become inactivated

Clonal deletion
- activation-induced cell death

Suppression
- achieved by the action of Treg’s ( Treg cell prevents APC and T cell joining together). Via CD25 on Treg cells binding to receptors or release IL-10/Il-35 inhibtory cytokines

18
Q

How are self antigens formed?

A

Healthy tissues and organs shed low levels of component proteins

Cells undergo apoptosis (normal turnover process)

This occurs without inflammation

Dendritic cells help to clear up apoptotic cells and will display the self antigens

The APCs will display these self-antigens to the T cells in lymph nodes

No inflammation so no co-stimulatory molecules displayed by the APC which is required to activate T cells

Normal functioning T cell wont activate
Autoreactive T cell will try to activate

19
Q

T-cell peripheral tolerance: anergy detailed process

A

Anergic T-cell clones cannot respond to normal antigenic stimuli:
- they do not produce IL-2or IL-2R

Co-stimulation is important for the activation of T cells:

A: Normal Signal 2: CD28 on T cell binds to CD80/CD86 on APC (signal 2 and signal 1 is MCH2 binding with CD4+ and TCR)

B: Disruption of the CD28/CD80/86 signal

C: Failure to express CD 80/86 can lead to anergy

D: CTLA-4 is a molecule that also interacts with greater affinity to CD80/86, leading to disruption of the costimulatory signal and anergy.

20
Q

T-cell peripheral tolerance: clonal deletion detailed process

A

T-cells activated by APC express IL-2and IL-2R for autocrine facilitation of proliferation
Self-reactive activated T-cells also increase their expression of death receptors (e.g. Fas) and their ligands
Ligation of Fas leads to T-cell apoptosis
thereby ending the immune response

Upon uptake and processing of antigen by APCs (1) and subsequent presentation of the processed peptide to a CD4+ T cell (2), IL-2 production and expression of the IL-2R occurs followed by their autocrine binding (3), leading to T cell activation. Activated T cells express Fas (4) and FasL (5) on their surfaces or as soluble s-FasL after cleavage of the membrane-associated FasL (6). The interaction of Fas either with s-FasL (7) or with membrane-associated FasL (8) leads to apoptosis (9) by activation-induced cell death (AICD), thus ending the immune response

21
Q

T cell peripheral tolerance: T cell suppression

A

Mediated by Tregs
Tregs can suppressTh cellsvia direct cell-cell contact, or by secretion of inhibitory cytokines (IL-10, TGF-B)

During active inflammation, Tregs do not prevent protective immune function

Naive T cells in the periphery can become Tregs by acquiring Foxp3 expression.

22
Q

B cell central tolerance Mechanisms

A

Anergy, Light chain rearrangment, deletion

Self-antigens expressed by BM stromal cells, haemopoietic cells, blood molecules

The strength with which BCR of immature B cell binds to antigens in the BM is tested

No / weak interaction, they leave BM to migrate to peripheral lymphoid tissue
Auto-reactive B cells either eliminated or inactivated

23
Q

T cell peripheral tolerance Mechanisms

A

Anergy, suppression, clonal deletion

24
Q

B cell Central tolerance: B cell Receptor 
editing to Light chain

A

BCR binds strongly to multivalent self-antigen / self-antigen present in high concentrations

Development arrested
BCR of autoreactive immature B cell is modified
- self reactive light chain deleted and replaced with new one
If new BCR no longer self-reactive it continues to develop

If new BCR still self-reactive further light chain rearrangement may occur
If does not resolve – apoptosis
= CLONAL DELETION

25
Q

B cell Central tolerance Anergy

A

Self-reactive B cells that bind to monovalent self-antigens are made unresponsive by central B cell tolerance

  1. Further development arrested = anergy
  2. down regulation of BCR
    expression
    3.block in BCR signalling

They don’t die immediately – they enter peripheral circulation

26
Q

B cell peripheral tolerance process; T cell independent and dependent

A

T cell independent activation:
- Weak/no interaction = normal
- Strong interaction
apoptotic signals = Clonal deletion

T cell dependant activation
- Auto reactive T cells are eliminated by Central tolerance in the thymus
- B cell remains unresponsive
= ANERGY

(CD4 and TCR on TH cell bind to the MCH2 creating signal 1 and CD40L on T cell binds to CD40 receptor on B cell)

27
Q

Why Does The Body Not Attack The Normal Gut Flora?

A

Innate immune barrier: PAMP and PRR

Polysaccharide A activation of specific receptors on Treg cells causing NO immune response.

28
Q

Mechanisms of immune privelaged sites

A
  • lack of lymphatic drainage
    • blood barrier
    • immunosuppressive cytokines (Il-10, TGF-B)
    • expression of FasL
29
Q

Mechanisms of autoimmunity

A

Immunologic Abnormalities
Defective tolerance or regulation
Abnormal display of self-antigens
Inflammation or an initial innate immune response

Genetic Basis
- strongest associations withMHC genes.

Role of Infections
Bystander activation
Molecular mimicry

Other factors
Damage to tissues caused by inflammation, ischemic injury, or trauma, may lead to the exposure of self-antigens that are normally concealed from the immune system.
Hormonal influences, drugs

Immunology 2 (10 decks)

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