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MIIM30003 - Medical & Applied Immunology > Lecture 26 - Evolutionary Immunology - Adaptive > Flashcards

Lecture 26 - Evolutionary Immunology - Adaptive Flashcards

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USMLE® Step 1 flashcards
1
Q

In which organisms is adaptive immunity present?

A

Only higher organisms (vertebrates)

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2
Q

What are Ig superfamily domains?

Give examples of where they are found

A

Examples

  • BCR
  • TCR
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3
Q

What are VLRs?

Where were they first found?

What is their structure?

What is their function?

A

Variable lymphocyte receptors

  • Found in Hagfish and Lampreys
  • Large number of unique transcripts found that encoded LRR modules (leucine rich repeat)

Structure:

  • Made up of leucine rich repeat domains
    • similar to TLRs
    • stalk region
  • Arch shaped

Function

  • Recognise VLR antigen on the concave surface
  • VLRB+
    • VLRB+ lymphocytes recognise their Ag →
      • Lymphocyte proliferates
      • Soluble VLRB+ secreted
    • Analogous to B cells
  • VLRA+
    • VLRA+ lymphocytes recognise their Ag →
      • Lymphocyte proliferation
      • Release of cytokine homologues
    • Analogous to T cells
  • VLRC+
    • Analogous to γδ T cells
    • Found in epithelia (epidermal and intestinal)
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4
Q

What are FREP and Dscam?

In which organisms are they found?

What is structurally significant?

Describe their function in Drosophila

A

Highly diverse PRRs, but they are not part of the adaptive immune response:

  • No expansion
  • No memory

FREP: Fibrinogen related proteins

  • Molluscs

Dscam: Down syndrome cell adhesion molecules

  • Arthropods (eg. Drosophila)

Structure

  • Contain Ig SF domains
  • FREP
    • Fibrinogen domain at C terminus
    • 1-2 Ig domains at N terminus

Function in Drosophila:

  • Produced in haemocytes (ie fat body cells)
  • Secreted into haemolymph
  • Bind and opsonise pathogens
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5
Q

Describe gene encoding of VLRs

Describe gene assembly

How does it differ from assembly of BCRs and TCRs in higher order organisms?

A

Encoded by:

  • 3 types of VLR gene
    • A, B, and C
      • VLRA
      • VLRB
      • VLRC
  • The loci of the VLRs do not encode the repeats that end up in the middle of the protein
    • Multiple LRR gene cassettes present elsewhere in the genome

Gene assembly

  • Only occurs at one locus
    • VLRA, VLRB, or VLRC
  • Only one allele used (analogous to allelic exclusion)
  • Gene conversion
    • Addition of repeats from elsewhere in the genome within the VLR N and C terminal domains
    • Recombination between homologous sites in the chromosome:
      • CDA (cytidine deaminase) creates nicks in the DNA
      • Induction of DNA repair
  • Differences:
    • No random addition of nucleotides at the ends (N regions), since there is no TdT
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6
Q

What is CDA?

What is it evolutionarily related to?

A

Cytidine deaminase

  • Introduces nicks in DNA for gene conversion for assembly of VLRs
  • Followed by induction of DNA repair
  • Two types:
    • CDA1 ⇒ VLRA
    • CDA2 ⇒ VLRB

Related to AID

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7
Q

State the homologues of the following:

  • B cells
  • T cells
  • γδ T cells

What is the evidence?

  • Development
  • Effector function
  • Markers
A

B cells: VLRB+ lymphocytes

T cells: VLRA+ lymphocytes

γδ T cells: VLRC+ lymphocytes

Evidence:

  • Marker expression
    • VLRB+ lymphocytes express B cell markers
      • BLIMP
      • PAX5
    • VLRA+ lymphocytes express T cell markers
      • GATA3
      • CCR7
      • CTLA4
    • VLRC+ lymphocytes express γδ T cell markers
  • Function
    • The observed function of these VLR lymphocytes reflects the function of the various mammalian lymphocytes respectively
    • VLRA+ cells
      • Proliferation and expression of surface VLRA and effector cytokines after stimulation
      • Release of molecules onto VLRB+ cells: crosstalk analogous to T cell help
      • Recognition of processed antigen
    • VLRB+ cells
      • Secretion of soluble VLRB after activation
      • Recognition of native antigen
  • Development
    • VLRA+ cells develop in thymoid tissue in gills
    • VLRB+ cells develop in haematopoietic tissue in kidney
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8
Q

When do γδ T cells split from the conventional T cell lineage?

A

At the DN stage (ie whilst the TCR is being arranged)

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9
Q

In which organisms are VLRA/B/C+ cells found?

A

Agnathan fish (lampreys, hagfish)

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10
Q

Describe the function of RAG in higher order organisms

A

RAG: recombinase activating gene

  • Recognise RSSs (recognition signal sequences) adjacent to segments in BCR and TCR genes
  • Forms a 12-23 hairpin between segments
  • Cleaves DNA between the segments
  • → DNA repair machinery + TdT
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11
Q

What are transposons?

Describe the process

A

Mobile elements that integrate into the chromosome

Transposases:

  • Enzymes that excise and integrate elements into the DNA
  • Encoded by transposase genes

Integration/exision DNA sequences

  • There are the targets of the transposases
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12
Q

In which organisms did BCRs and TCRs emerge?

A

Gnathans (jawed fish)

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13
Q

Which sorts of domains are found in diverse receptors?

Give examples of receptors in which these domains are found

A
  1. Ig domains
  • BCRs
  • TCRs
  • Dscams (Drosophila)
  • FREP (Molluscs)
  1. Leucine rich repeats (LRRs)
  • TLRs
  • VLRs
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14
Q

Describe the diversity of FREPs

How does this come about?

A

More diversity than is encoded in the germ line

Mechanism

  • Not known
  • Hypothesised mechanisms of introduction of point mutations and somatic hypermutation
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15
Q

Describe how diversity of Dscam is generated

A

Gene:

  • Multiple exon clusters
  • Each cluster contains many segments

Diversification:

  • Alternate splicing selects one of the many segments in each exon
  • Generates many different combinations
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16
Q

Compare the features Dscam, VLRs and FREP

A

Dscam & FREP:

  • Very diverse, but not adaptive
    • No expanision or memory
  • Contain Ig domains

VLRs

  • Highly diverse
  • Adaptive (memory)
    • Experimentally shown second set rejection of skin grafts in Lamprey
  • Contain LRR domains
17
Q

Describe the structure of VLRs

A

Made up of LRRs

Repeats form a solenoid shape

(similar to TLRs)

Slight curve in the solenoid

18
Q

Compare CDA expression in the different VLR cells in agnathans

A

(Cytidine deaminase)

(Agnathans = jawless fish)

VLRA+ cells: CDA1

VLRB+ cells: CDA2

19
Q

Compare development of the following cells in agnathans:

  • VLRA+ cells
  • VLRB+ cells

What is the tissue distribution of VLRC+ cells?

A

VLRA+ cells: thymoid tissue in gill tips
VLRB+ cells: haematopoietic tissue in kidney and thyphylosole

VLRC+ cells:

  • Similar distributino to VLRA+ cells
  • Presumeable using CDA1 expression in the thymoid organs for VLRC generation
20
Q

Describe the proposed mechanism of evolution of diversity of BCRs

A

Two mechanisms: convergent evolution

  1. RAG1/2
    • Developed from transposons
    • Transposon inserted into Ig SF gene member, disrupting the gene
    • Seperation of RAG-1 and RAG-2 onto another locus in the genome over time, but the excision sites remained within the gene
    • Expansion of regions in Ig SF genes that could be acted upon by RAG-1 and RAG-2
    • RAG-1/2 could still act on all these regions
  2. Chicken BCR diversification
    • Little diversity in BCR V, D and J genes
    • However, many Pseudogenes for V region segments
    • Invariant BCR assembled from genes and expression of this on the surface of immature B cell
    • This triggers proliferation and gene conversion of Ig genes
    • AID dependent incorporation of pseudogene segments into the genes for BCR chains
      • Functional sIg ⇒ survival
      • Non-functional sIg ⇒ death
    • Mature B cells express diverse Ig
21
Q

What is CRISPR?

Where are they found?

Describe the mechanism of generation of CRISPR

A

CRISPR: Clustered regularly interspaced short palindromic repeats

  • Repeats in genome
  • Contained genomic DNA from viruses
  • Encoded near Cas locus

Found in Bacteria and Archaea

Generation:

  • Cas proteins mediated insertion of viral DNA into the genome
  • CRISPR expressed as only long transcript
  • Transcripted cleaved into hairpin structures
  • When the virus is encountered again, the viral DNA plasmids bind the hairpin structures
  • Cas then cleaves the viral DNA
22
Q

Describe adaptive immune responses in bacteria and archaea

A

CRISPR arrays

  • Adaptive: remembering past infections
  • Not, however, anticipatory
23
Q

Describe the CRISPR/Cas9 system

A

CRISPR:

  • Produces sgRNA
  • Guide RNA for targeted gene

Cas 9

  • Enzyme that causes ds nicks in target DNA
  1. Together, these molecules allow precise disruption of DNA at a certain location
  2. Once the disruption has taken place:
  3. Homology-directed recombination
    • Precise insertion of genetic material

This system has much potential

  • Generation of KO and knock-in animal models
  • Clinical applications: gene therapy?

MIIM30003 - Medical & Applied Immunology (30 decks)

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