Classification of PIDs

Question 1

As well as impairment of development/funciton of the immune system and increased infection susceptibility, what other things can inborn errors of immunity encompass?

Answer 1

Autoimmunity, autoinflammation, malignancy and allergy.

Question 2

What is the mutation behind X-linked agammaglobulinemia?

Answer 2

Mutation in BTK

Question 3

What does AR ADA deficiency lead to?

Answer 3

accumulation of toxic purine degradation products that causes SCID.

Question 4

What is the cause for X linked SCID?

Answer 4

ILR2G mutation.

Question 5

what were the first innate inborn errors of immunity?

Answer 5

congenital neutropenia and CGD.

Question 6

Examples of PID that cause infections for:
a broad range of pathogens
specific pathogens

Answer 6

SCID causes susceptibility to broad range

Terminal complement deficiencies- Neisseria infections.

Question 7

Example of PID pathophysiology due to haematopoietic intrinsic and extrinsic defects.

Answer 7

T cell-intrinsic IL-7R deficiency.

thymic stromal defects e.g. Di George syndrome.

Question 8

What are the different phenoyptes you can get from mutations within STAT1?

Answer 8

LOF severe AR, then susceptibility to (non TB) mycobacterial infection and severe viral infections.

AD LOF then maybe only mycobacterial less severe.

GOF can present with CMC (fungal due to lack of Th17 response)
or autoimmunity.

Question 9

What does medelian susceptilibility to mycobacterial disease (MSMD) encompass?

Answer 9

Similar pheontype but due to mutations in different genes involved in the IFNy and IL12 axis.

Question 10

What precision medicine could be used for STAT1 GOF?

Answer 10

JAK1/2 inhibitors.

Question 11

What kind of problems in IEI can been seen in phagocytes?

Answer 11

Number or funciton.
e.g. intracellular killing (CGD)
chemotaxis (LAD-1)
granules
danger sensing (Dectin-1 AR)

Question 12

What kind of abberations of complement pahtways are seen?

Answer 12

loss of funciton (C1q or other deciciency)
Excessive activation (e.g. deficiency in factor H (AHUS) or CD55/59/DAF (PHD).

Question 13

what kind of problems seen in intrinsic innate immunity?

Answer 13

intracellular siganlling defects (e.g. IRAK4/MYD88)

cytokines

Question 14

What can different SCIDs be classified on?

Answer 14

absecnec of lympocyte T, B and NK cell populations.

Whether or not they have severe and syndromic features.

Question 15

What things might you need to consider with Antibody deficiencies?

Answer 15

Whether B cells are present? (XLA)
severity and patten of Immunoglobulin defiency (or hyper.)
functional deficiency- response to Ag/ vaccine challegne.

Question 16

Examples of immune dysregulation?

Answer 16

EBV and EBV driven lympoproliferation

autoimmunity.

Question 17

What kind of infections are seen with antibody deficiency?

Answer 17

respiratory tract infectiosn, mostly bacterial e.g pneumoniae Haemophilus influenza s aureus.

Enteroviruses and protozoa like Giardia.

Not fungi

Question 18

What pathogens are complement deficiency patients susceptible to?

Answer 18

Same for antibodies in terms of bacteria (s pneuoniae, Haemophilus influenxa s aureus etc.

Speicfically for Neisseria Meningitidis as well.

Not for enteroviruses or fungi or protozoa though.

Question 19

What infections are pahgocytic deficienceies associated with?

Answer 19

S aurues, P aureginosa, Salmonella typhi.

NOt viruses or protozoa.

But are susceptible to fungi (apergiullus and candida), and non-TB mycobacteria.

Question 20

What pathogens are CID susceptible to?

Answer 20

bacteria same for anitoides, plus Salmonella typhi.

Range of fungi
nonTB mycobacteria (+ TB)
also protozoa like pneumocystis jiroveci.

range of viruses, especially RSV.

Question 21

What tests would you do for neutrophil disorders?

Answer 21

neutrophil count (low- congenital neutropenia- high- LAD-1)

Respiratory busrts NBT or DHR

Chemotaxis and killing

Question 22

What tests would you do if suspecting lymphocyte defects?

Answer 22

Lymphocyte cell counts: T, B and NK cells.

proliferative function to non-specific and specific antigens.

Recent thymic output (TRECS)

Question 23

Immunoglobulin defect test?

Answer 23

Immunoglobulin levels

pathogen specific antibodies

anticytokine antibodies e.g.anti17 CMC or anti IFNy in mycobacterial infecitons.

Question 24

What is RAG1/2 deficiency affecting in immune cells? What it the T/B/NK phenotype for it?

Answer 24

RAG is important for the recombination of the T and BCR.

Null mutation can lead to T-/B-/NK+ SCID.

Question 25

What makes RAG1/2 deficiency more complex?

Answer 25

There are hypomorphic mutations in RAG that lead to residual RAG activity and varying severity and presentations.

Called Leaky RAG/ Omenn’s syndrome

May even in milder cases have late onset.

Question 26

Do you have T cells and B cells in leaky RAG and Omenn’s syndrome?

Answer 26

Yes you can have some T cells, these are often oligoconal and autoreactive.

Can lead to inflammatory phenotype seen in Omenn’s syndrome.

Question 27

Is NEMO a SCID or CID? What are syndromic features?

Answer 27

CID, syndromic features e.g. thin hair, pale skin, conical teeth.

Question 28

What pathways is NEMO and NF-kB pathway downstream of?

Answer 28

IL-1R, TLRs, TCR/BCR and TNFR and EDAR/RANK/VEGF3.

So can affect T and B cells and have syndromic effects.

Question 29

How else can a less severe mutation in e.g. 5’ unfolded region of NEMO preset like?

Answer 29

Present with a susceptibility to mycobacterial infection- isolated phenotype.

MSMD.

Question 30

Male:
Multiple abcesses growing e.g on liver and spleen.

Grew S. aureus

What area of immune system affected? and What disease was it?

Answer 30

Suggestive of an innate defect.

The disease was (probably X linked) CGD with absent gp91 expression.

Question 31

When an innate defect suspected, why would a high CRP result rule out IRAK4 deficiency?

Answer 31

Because IRAK4 deficiency will lack a robust enough inflammatory response.

Question 32

What tests can you do when you suspect CGD?

Answer 32

Neutrophil count.
DHR (becomes fluorescent upon neutrophil stimulation and ROS production)
NBT assay
levels of e.g. gp91 expression 
Then sequencing

Question 33

What would you expect to see in a DH3 test for the mother in an X linked CGD?

Answer 33

two populations of neutrophils due to X linked inactivation.

Question 34

What treatment options are available for CGD?

Answer 34

preventative antibiotics and antifungals (aspergillus)
prompt and aggressive treatment of infections
HSCT/ gene therapy.

Question 35

1m/o female
respiratory and diarrhoea
bacterial sepsis, RSV rota virus
cleft palate, hypocalcaemia and congenital cardiac defect.

What part of immune system affected and likely diagnosis?

Answer 35

RSV and a multitude of viral infections strongly associated with CID.

Defects are associated with abnormal developemtn of cells from 3rd and 4th pharangeal pouches.

Suggest Di George syndrome.

Question 36

What is the T/B/NK cell phenotype associated with Di George syndrome?
What is hypocalcaemia and low parathyroid hormone explained by?

Answer 36

T-/B+/NK+

Lack of parathyroid development.

Question 37

What do tests for T cells and Ig show for Di GEORGE syndrome?

Answer 37

T cell count low.
No TRECs (marke of recent thymic output)
IgG normal, but low IgA and IgM.

Question 38

What can FISH highlgiht in most cases of DiGeorge syndrome?

Answer 38

No probe hybridisation to chromosome 22 (q11) due to deletion.

Question 39

What treatments for Di George?

Answer 39

supportive treatments and possible thymic transplant.