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M2M: Mod 1, 3 > 1. Immune deficiencies 1 > Flashcards

1. Immune deficiencies 1 Flashcards

0
Q

What are the possible reasons for failure to respond to an infection?

A 
No B lymphocytes
No CD4 T lymphocytes
No B or T lyphocytes
No signal from CD4 to B cell
Failure of the B cell to respond to the T cell signal
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1
Q

What are the adaptive immune system cells?

A

T cells, NK cells and B cells arising from the early lymphoid progenitor.

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2
Q

What is a primary immune deficiency?

A

There are 8 classes of PIDs defined by the IUIS spanning the adaptive and innate immune systems.

PIDs are a large group of disorders (>200) that result in recurrent infections.
*NOT caused by other diseases, treatments, or environmental exposure to toxins.

Mostly genetic disorders
Most diagnosed in children under 1 yo

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3
Q

What are examples of combined T and B cell deficiencies?

A
  • Severe combined immunodeficiency disorder (SCID)
  • Complete DiGeorge syndrome
  • CD40 and CD40L deficiencies (HIGM)
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4
Q

What are examples of antibody deficiencies?

A
  • CD40 and CD40L deficiencies (HIGM)
  • Ig deficiencies (X-linked agammaglobulinaemia, XLA; X-linked lymphoproliferative disease, XLP; selective IgA deficiency)
  • Common Variable Immunodeficiency (CVID)
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5
Q

What are combined immune deficiencies?

A

Subset = Severe Combined Immune Deficiencies

  • refers to the combined loss of humoral and cellular immunity
  • humoral means liquid immunity = antibody = B cell
  • cellular means cell mediated = T cell
  • Because CD4 T cells regulate B cells, defects in T cells can only be SCID
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6
Q

What are antibody deficiencies?

A
  • refers to the loss of some or all humoral immunity with cellular immunity intact
  • absent B cells (but normal T cells)
  • common variable immune deficiency (CVID) *missing 1 or 2 Ab types
  • Hyper IgM syndromes (HIGM)
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8
Q

What are the components of an antibody?

A

Ab is a disulphide linked dimer of heavy & light chain heterodimers.
Membrane bound Ig is the BCR for Ag.

  • 9 different heavy chain classes: μ, δ, γ1-4, α1-2, ε
  • 2 diff. L chain classes: κ and λ

Both the H & L chains contain constant, which are identical within a class of Ig; and variable regions, which differ between all Ig molecules.

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9
Q

Human olfactory receptor genes

A

Humans have approximately 400 functional genes coding for olfactory receptors and the remaining 600 candidates are pseudogenes.

Human genome contains ~30,000 genes, so 1/30 encodes odorant receptors!

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10
Q

Why would evolution favour a mechanism that relies on a complex, error prone gene rearrangement process over the tried and true “one gene one polypeptide” approach?

A

Because it allows for combinatory rearrangement that can generate huge amounts of variation with relatively small numbers of minigene segments.

1,100,000 possible VH/VL combinations can be generated from 115 minigene segments.

Human 2nd Ig L chain locus (Igλ) is as diverse Igκ, adding another 1,100,000 possible VH/VL combinations.

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11
Q

What is Ab diversity generated by?

A
  1. random selection of minigene segments for joining at each locus
  2. independent rearrangement at H & L chain loci
  3. imprecision of junctions
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12
Q

What is the process of V(D)J recombination?

A
  1. Site recognition and DNA cleavage using RAG1/2 & HMG1 responsible for rearrangement of Ig genes
  2. NHE joining using normal cell repair mechanisms that recognise chromosome breaks
  3. Ligation also using normal cell mechanisms (XRCC4, DNA ligase IV; TdT)
    * TdT adds random nucleotides onto broken ends. This is exclusive to lymphocytes in H chain rearrangement and increases variation
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13
Q

What is the order of the Ab-producing process in terms of the rearrangement of the chains?

A

Heavy chains are rearranged first (DJ, then VDJ).
Then if successful, light chains are rearranged, kappa first then lamda.
Success at one allele of H and one of L results in a complete Ig.

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14
Q

What is the success of rearrangement at each stage?

A

1/3 chance because the reading frame must be retained and the reading frame is read in triplets/codons of 3 nucleotides.

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15
Q

What are the mutations that block B cell development?

A

ELP to Pre-Pro-B = E2A
Pro-B to Pre-B large = RAG, PAX5, Syk, Igα/β
Pre-B large to Pre-B small: BTK*, BLNK, SLC

*BTK is not part of receptor of Ig, is mutation that blocks development through signaling and is not a rearrangement protein

Progress through B cell development is mediated by successful Ig gene rearrangement.

Immature B cells are only able to leave the bone marrow if they express a functional Ig on their surface.

Surface expressed Ig is called the B cell receptor (BCR).

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16
Q

What happens when the cell signals success in Ig VH gene rearrangement?

A

The Ig heavy chain pairs with the two surrogate light chains (SLC).

The SLC are the same in every B cell and are not generated by rearrangement and serve the purpose of a generic light chain. (No good for Ag binding)

The IgH-SLC complex pairs with two signaling chains called Igα and Igβ to form the pre-BCR.

The pre-BCR sends ‘success’ signal into the cell.

17
Q

What happens in the success signalling following Ig VL gene rearrangement?

A

The Ig light chain pairs with the existing Ig heavy chain to form a complete Ig.

The IgHL complex pairs with Igα and Igβ now form the BCR that sends the success signal into the cell for the completion of the first stage of B cell development.

18
Q

What are the agammaglobulinaemia without B cells mutations that affect human B lymphocyte development?

A

XLA, μ heavy chain, surrogate light chain, Igα/β, BLNK

Symptoms:

  • no or very little serum Ig of any isotype
  • no circulating B cells but normal T cells
  • recurrent infections primarily Strep. pneumonia; Haemophilus influenza
  • recurrent otitis in children and sinusitis in adults
  • XLA mean age of diagnosis is 3 y.o.
19
Q

What causes XLA?

A

Mutations in BTK (Bruton’s tyrosine kinase) cause XLA with over 600 unique, inactivating mutations identified.

Btk tyrosine phosphorylates PLCγ2, which is recruited to the plasma membrane via BLNK following activation by Btk.

Mutations occur along the entire gene with no single mutation occuring more than 3%.

Mutations maintained in population by de novo events.

20
Q

What are examples of developmental combined immune deficiencies and what are their symptoms?

A 
T-B-NK-
Adenosine Deaminase (ADA)

T-B+NK-
γc chain
JAK3
IL7Ra

T-B-NK+
RAG1/2
Artemis
DNA ligase

Symptoms:

  • no or very little serum Ig of any isotype
  • may be circulating B cells but no T cells or NK cells
  • recurrent viral, fungal and bacterial infections
  • usually lethal in early childhood
21
Q

What does intravenous immunoglobulin therapy involve?

A

Current therapy for agammaglobulinaemia without B cells, aka IVIg or Intragam

  • Purified IgG from pooled human sera using alcohol fractionation
  • contains all IgG subclasses and traces of IgM and IgA
  • Dose is 400-600mg/kg once per month in clinic
  • 2 to 4 hours infusion

Idea is to maintain IgG levels at 5g/L at trough, normal is 12g/L with half life of 21 days

  • costs US$50,000 per yr
  • following 300 patients over 5 years, only 20% remained infection free
  • 80% had 1 or more major infectious complications (pneumonia, sinusitis, chronic lung disease)
22
Q

What does subcutaneous immunoglobulin therapy involve?

A

Aka SCIg

  • self administered weekly
  • dose is 100 - 150mg/kg (40-60mL of a 16% IgG solution for a 70kg patient)
  • delivered via small pump to abdomen, thigh, forearms
  • in use for approx 10 yrs, no major side effects
23
Q

What is RSS?

A

The recombination signal sequence is a unique nucleotide sequence that is the RAG recognition sequence, adjacent to each minigene segment.

24
Q

What is RAG1/2?

A

Recombination - essential for rearrangement

Enzymes expressed uniquely in B cells and T cells that recognise sequence and cut DNA next to it. They are essential to Ig gene recombination, providing recognition and cleavage activity

*if you put RAG1/2 in fibroblast of muscle cells, they will rearrange their Ig genes!

25
Q

What is HMG1?

A

High mobility group 1 protein

  • chromatin binding
  • structural protein also required for rearrangement but not unique to Ig gene rearrangement
26
Q

What is Artemis/DNA-Protein Kinase catalytic subunit (DNA-PKcs)/Ku70,80 responsible for?

A

Recognition and synapsis of the DNA ends

27
Q

What does DNA ligase IV/x-ray repair complementing Chinese hamster cells 4 (XRCC4) do?

A

Joins DNA ends

28
Q

What is TdT?

A

Terminal deoxynucleoAdyl transferase is unique to B cells and adds extra, random nucleotides to the broken ends at V-D-J junctions.

M2M: Mod 1, 3 (13 decks)

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