Primary Immunodeficiency in ADAPTIVE immunity

Question 1

List the adaptive immunodeficiencies

Answer 1

1) SCID
1b) Omenn Syndrome (most severe)
2) X linked agammaglobulinaemia
3) CD40Ligand: Hyper IgM (nothing else made) which is a combined immunodeficiency
4) Familial haemophagocytic ltmphohistiocytosis (FHL) which is a dis-regulated immunodisease where controls and signals are not transferred properly

Question 2

What is RAG SCID/Omenn syndrome?

Answer 2

An autosomal recessive disease where RAG1 or RAG2 enzymes are deficient. This means gene segments cannot be rearranged of T and B cell receptors (T-B-)so cells desroyed in thymus/bone marrow. There is NK+ cells so lymphoid progenitor for innate cells is not affected; immune defect happens after development of cell.

Question 3

Describe the symptoms of RAG SCID

Answer 3

-presents at 3-6 months
-No T and B cells but here is NK cells
-There is no gene product; no protein made
- recurrent infections due to T cells (pneumonia, mycobacteria and CMV)
-don’t present with extracellular diseases as young babies have IgG from mother.
=Fatal unless child has a stem cell transplant (HSCT)

Question 4

Describe the symptoms of Omenns, a varient of SCID.

Answer 4

It presents at birth, 3-6 months. It has a different presentation from standard RAG1/2 SCID. It has above normal amount of T cells and NK cells, but no B cells; cells look very activated.
However, The T cells are oligoclonal which means there is a limited number of clones and there is no regulatory T cells and so T cells are not controlled at all.

Question 5

What is Artemis?What is DNA-PK?

Answer 5

Together DNAPK-Artemis open hairpin (after Ku70/Ku80 enzymes have bound to broken ends of coding segments)

Question 6

What kind of SCIDs are there?

Answer 6

There are SCIDs for each of the enzymes in the rearrangement of gene segments

Enzymes: RAG1/2, Ku70, Ku80, DNAPK, Artemis, TdT, DNA ligase 4

Question 7

What is the difference between omens syndrome and SCID?

Answer 7

There is protein made in omens syndrome; they make protein but they do not function properly.

Question 8

Describe the characteristics of Omenns Syndrome

Answer 8

1) red rash skin-erythroderma
2) puffy skin- oedema
3) protracted diarrhoea as T cells are trying to destroy the gut leading to malnutrition.
4) enlarged spleen and liver, lymph nodes
5) very high numbers of eosinophils
6) very high IgE (but low IgG/A/M)
7) recurrent infection
8) overactive, self reactive T cells
9) out of control Th2 response making IL4, IL5 which isotope switch to IgG and release of immune cell (drives characterisics)
10) fatal: infection and out of control immune system.

Treatment: stem cell transplant once immune system has been dampened.

Question 9

What is antibody deficiency?

Answer 9

Antibodies not made (due to non functional, absent B cells) needed to deal with extracellular and encapsulated bacteria via opsonisation.

Question 10

Which infections signal a lack of which Ig?

Answer 10

Mucosal infections: IgA, and IgM.

Question 11

What is the order of Ig classes

Answer 11

IgG in placenta, newly synthesised at 6 months.
IgM quickly made to protect mucosal sites
IgA the last made class at 4 years.

Lack of Ig apparent after 6 months.

Question 12

What is the half life of IgG in vitro?

Answer 12

21 days, it is a stable molecule.

Question 13

What are the characteristics of X-linked agammaglobulinaemia

Answer 13

1 )No Ig, no B cells

2) males only affected
3) all pre-B cells die due to incorrect signalling via the preBCR: the are missing enzyme BTK, (bruton type kinase)

Question 14

In what way can females be affected by X-linked agammaglobulinaemia?

Answer 14

Random inactivation of one X chromosome due to suspected mutations but means they express the disease on the other chromosome.

Question 15

What are the clinic consequences of XLA

Answer 15

1) They present at 6 months once maternal Ab have diminished
2) recurrent infections
pyogenic/puss bacteria causing tissue/lung damge
3) meningoencephalitis from enterovirus which causes death
4) polio virus after received oral vaccination where live wildtype virus cannot be tackled by Ab and they get diseases
5) no problem with T cells.
Treatment: replacement of Immunoglobulin.

Question 16

Give some examples of pyogenic (puss-forming) bacteria

Answer 16

HIB, Strep.pneumococcus, pyrogenes and Staphlococcus

Question 17

What is X-linked CD40 ligand deficiency or Hyper IgM syndrome

Answer 17

Where there is failure to class switch, in males only. Deficiency of antibody (humoral) and cellular immunity.

If there is no CD40 on T cell it cannot bind tightly to B cell and so there is no signal in T cell in order to stimulate the B cell to class switch; only part of signal given.

More infection unresolved, means B cells are activated to make even more IgM that cannot change to other Ig.

Question 18

Why is hyper IgM syndrome a combined immunodeficiency?

Answer 18

CD40 and CD40R have multiple co-stimulatory functions in the immune system; affects lots of aspects.

Question 19

What is unusual about the lymph nodes in CD40L deficiency?

Answer 19

There are no germinal centers, B cells do not undergo class switching.

Question 20

Describe an experiment where CD40L deficiency is shown

Answer 20

• activate cells to make expression
• add labelled CD40 which binds to CD40L.
• flow cytometry shows normal cells with increased fluorscence, but in deficient patients there is no increase.
• Posiive control CD25 used that upregulates under the same activation(receptor for IL2) which show activation and shows binding.

Question 21

What are the consequences of CD40L deficiency

Answer 21

1) Recurrent infections
2) Pyogenic bacteria
3) susceptible to opportunistic infections due to other functions CD40L influences
4) severe neutropenia where differentiation pathways of the myeloid system are blocked controlled by CD40L.

Treatment: stem cell transplant before all the infection of liver.

Question 22

What is an opportunistic infection characteristic of CD40L deficiency?

Answer 22

cryptospridium parvum in the liver; they can’t activate their macrophages; this is fatal.

Question 23

What has to happen to a cytotoxic T cell in order for it to release cytokines?

Answer 23

1) collision and non spefic adhesion
2) specific recognition if alignment matches: this causes the redistribution of the cytoskeleton within the T cell.
3) granules release at contact site

his involves lots of proteins and signals.

Question 24

What is FHL?

Answer 24

A very rare autosomal recessive defect in lymphocyte cytotoxicity where the genes responsible for granule trafficking/release and pore formation are lacking.

This means there is a failure to kill virally infected cells with KN, or CD8+.

The virus doesnt kill, it is the overactivated inflammatory response due to lack of virus control that causes death. This is shown by the non-stop production of IFN-gamma

Question 25

What are the genes involved in granule function of CD8+?

Answer 25

• Gene perforin for perforin to make holes in cell membrane
• gene for Rab27a form vesicle docking
• gene for Munc13-4 for vesicle priming on surface
• gene syntaxin-11/Munc18-2 for fusion with cell membrane.

Involved in vesicle fusion and trafficking.

Question 26

How does FHL differ from normal responses?

Answer 26

virus, activated CD8+ cells, proliferation, production of IFN-y which activates macrophages to make IL6, TNFa proinflammatory cytokines.

In FHL, there is no resolution after this, as granules do not function so inflammation continues causing tissue damage, consistent bacterial damage and hemophagocytosis.

Question 27

What is hemophagocytosis?

Answer 27

Activated macrophages digest brain cells.

Question 28

What are the consequences of FHL?

Answer 28

1 )High persistent fever

2) Spleen and liver enlargment
3) Seizures, coma, confusion as nervous system cannot control virus
4) Severe anaemia, blood clotting and abnormal liver function
5) Constantly activated NK and CD8+ cells
6) IFN-y activates macrophages which means they reach accelerated phase.
7) Multiple organ failure and death

Question 29

What is accelerated phase/cytokine storm?

Answer 29

Lots of IFN-y activates macrophages which make cytokines that keep building up due to continued activation/constant IFNy.

Question 30

What detect method of primary immunodeficiency?

Answer 30

Neonatal screening for SCID: this can be done via a guthrie card and needle pick on baby as its born.

PCR used to measure how many T cells have T/B cell excision circles (not present in SCID)

Babys then assessed via flow cytometry to detect whether they have B/T cells.

Question 31

What are the ethics/standard involved in neonatal screening?

Answer 31

• disease is serious enough?
• proof of concept; is test good enough?
• well described disorders
• low false negative rate
• identify those likely to benefit; younger detection will benefit
• effective therapy available like stem cell transplant.