CVID II

Question 1

What are some dysregulated features of T cells in CVID patients that might contribute to their autoimmunity?

Answer 1

Decrease in Tregs, increase in Tfh.
reduction in Th17? (Skew more towards Th1?)
STAT3 is downstream of Il-6 and IL-21.

Question 2

what does APDS stand for? And what are two other syndromes associated with CVID?

Answer 2

Activated PI3K delta syndrome. CTLA4 haploinsufficiency and LBRA deficiency.

Question 3

Is the cause of CVID monogenic or polygenic?

Answer 3

Polygenic with a lack of family history ad defects in other systems are abnormal.

Genes identified associated with CVID are unlikely to be causal alone.

Question 4

deletions and null mutations known to be associated with CVID?

Answer 4

deletinos: ICOS

null mutations: CD19, CD20, CD81, IL21/R.

Question 5

2 polymorphisms associated with CVID?

Answer 5

BAFFR and TACI

Question 6

New genes associated with CVID?

Answer 6

NFKB1 (haploinsufficiency), PI3K, LRBA and CTLA4.

Question 7

What does NFKB1 encode?

Answer 7

Encodes the precursor p105 for NF-kB (p50 and p65 subunits) which are normally sequestered by IkB

Question 8

What does NFKB2 encode?

Answer 8

ecnodes p1000 precuros for p52.

Question 9

What pathways is NF-KB involved in?

Answer 9

TLRs TCR, and CD40, OX40, CD27 activation pathways for class switching.

Question 10

what is penetrance like of NFKB1 haploinsufficiency and NFKB2?

Answer 10

Low penetrance of symptoms with AD.

NFKB2 has high penetrance.

Question 11

How does NFKB1 differ form NEMO?

Answer 11

NEMO assocaited with innate immunodeficiency, no obvious defects in innate immunity in NFKB1.

her you get lymphoma and autoimmunity (varying degrees of hypogammaglubnemia)

Question 12

What is switched memory and CD21 levels like in NFB1 haploinsufficiency?

Answer 12

low switched memory B cell repsonses and increased CD21lo CD38lo population (only in symptomatic patients)- consistent with autoimmunity and splenamegaly- B cell dyregulation.

Question 13

What is unusual for NFKB2 as a CVID?

Answer 13

more of an early onset.

Question 14

What pathways is PI3K downstream of? What does this mean for activated PI3Kdelta sydrmoe?

Answer 14

More likley not to just affect humoural immunity.

Question 15

what notbable infections does APDS show for a CVID?

Answer 15

as well as AI, bronchiesctasis, clymphonma, etheropathay, splenomagaly

Notbaly shows sever herpes virus infections (EBV, CMV)

Question 16

What are features of APDS T cells?

Answer 16

reduced T cells, but raised CD8 T cells which have a more senescent (CD57+) phenotype.

Question 17

What are B cells like in APDS?

Answer 17

low IgG and IgA. IgM may be normal or raised.

More unswitched B cells and transitional B cells

Question 18

What precision treatments are available for APDS patients?

Answer 18

siroluimus/rapamycin mTOR inhibitors.

Other PI3K inhbitors (Idelalisib)

Question 19

defining difference in presentation betwen NFKB1 LOF and APDS patients?

Answer 19

APDS patients are susceptible to herpesvirus infections. May preform a HSCT for these patients.

Question 20

what is penetrace like for CTLA-4 haploinsufficiency?

Answer 20

incomplete pentrance classic immune dysregulation phenotype of AI lymphoproliferation and infections.

Question 21

what targeted therapy might be avaiable for CTLA4 deficiency?

Answer 21

Abatacept (engineered fusion protein with CTLA-4 binding domain)

Will sequester B7 (CD80/86).

Question 22

Defining feature of CTLA-4 haploinsufficieny (in common with APDS)?

Answer 22

suceptible to herpesvrius infections too.

Question 23

What is the role of LRBA?

Answer 23

To rescue CTLA-4 from degradation pathways and get it back to cell surface.

Deficiencies therefore quasi CTLA-4 deficiencies

Question 24

is LRBA AR or AD and what is unusual about it for a CVID?

Answer 24

LOF AR and unusally has very early presntaiton (6 months).

Question 25

Do LRBA show evidence of immune dyregulation?

Answer 25

Yes, swithced memeory cells are reduced and lymphoma risk as well.

Question 26

What can LRBA be treaed with?

Answer 26

abatacecpt.