Classification of PIDs Flashcards by Robert Mitchell

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

Autoimmunity, autoinflammation, malignancy and allergy.

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What is the mutation behind X-linked agammaglobulinemia?

Mutation in BTK

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What does AR ADA deficiency lead to?

accumulation of toxic purine degradation products that causes SCID.

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What is the cause for X linked SCID?

ILR2G mutation.

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what were the first innate inborn errors of immunity?

congenital neutropenia and CGD.

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

SCID causes susceptibility to broad range

Terminal complement deficiencies- Neisseria infections.

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

T cell-intrinsic IL-7R deficiency.

thymic stromal defects e.g. Di George syndrome.

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

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.

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

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

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What precision medicine could be used for STAT1 GOF?

JAK1/2 inhibitors.

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

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

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What kind of abberations of complement pahtways are seen?

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

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what kind of problems seen in intrinsic innate immunity?

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

cytokines

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What can different SCIDs be classified on?

absecnec of lympocyte T, B and NK cell populations.

Whether or not they have severe and syndromic features.

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What things might you need to consider with Antibody deficiencies?

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

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Examples of immune dysregulation?

EBV and EBV driven lympoproliferation

autoimmunity.

What kind of infections are seen with antibody deficiency?

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

Enteroviruses and protozoa like Giardia.

Not fungi

What pathogens are complement deficiency patients susceptible to?

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.

What infections are pahgocytic deficienceies associated with?

S aurues, P aureginosa, Salmonella typhi.

NOt viruses or protozoa.

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

What pathogens are CID susceptible to?

bacteria same for anitoides, plus Salmonella typhi.

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

range of viruses, especially RSV.

What tests would you do for neutrophil disorders?

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

Respiratory busrts NBT or DHR

Chemotaxis and killing

What tests would you do if suspecting lymphocyte defects?

Lymphocyte cell counts: T, B and NK cells.

proliferative function to non-specific and specific antigens.

Recent thymic output (TRECS)

Immunoglobulin defect test?

Immunoglobulin levels

pathogen specific antibodies

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

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

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

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

What makes RAG1/2 deficiency more complex?

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.

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

Yes you can have some T cells, these are often oligoconal and autoreactive. Can lead to inflammatory phenotype seen in Omenn's syndrome.

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

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

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

IL-1R, TLRs, TCR/BCR and TNFR and EDAR/RANK/VEGF3. So can affect T and B cells and have syndromic effects.

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

Present with a susceptibility to mycobacterial infection- isolated phenotype. MSMD.

Male: Multiple abcesses growing e.g on liver and spleen. Grew S. aureus What area of immune system affected? and What disease was it?

Suggestive of an innate defect. The disease was (probably X linked) CGD with absent gp91 expression.

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

Because IRAK4 deficiency will lack a robust enough inflammatory response.

What tests can you do when you suspect CGD?

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

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

two populations of neutrophils due to X linked inactivation.

What treatment options are available for CGD?

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

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?

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.

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

T-/B+/NK+ Lack of parathyroid development.

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

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

What can FISH highlgiht in most cases of DiGeorge syndrome?

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

What treatments for Di George?

supportive treatments and possible thymic transplant.