CVID II Flashcards
What are some dysregulated features of T cells in CVID patients that might contribute to their autoimmunity?
Decrease in Tregs, increase in Tfh.
reduction in Th17? (Skew more towards Th1?)
STAT3 is downstream of Il-6 and IL-21.
what does APDS stand for? And what are two other syndromes associated with CVID?
Activated PI3K delta syndrome. CTLA4 haploinsufficiency and LBRA deficiency.
Is the cause of CVID monogenic or polygenic?
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.
deletions and null mutations known to be associated with CVID?
deletinos: ICOS
null mutations: CD19, CD20, CD81, IL21/R.
2 polymorphisms associated with CVID?
BAFFR and TACI
New genes associated with CVID?
NFKB1 (haploinsufficiency), PI3K, LRBA and CTLA4.
What does NFKB1 encode?
Encodes the precursor p105 for NF-kB (p50 and p65 subunits) which are normally sequestered by IkB
What does NFKB2 encode?
ecnodes p1000 precuros for p52.
What pathways is NF-KB involved in?
TLRs TCR, and CD40, OX40, CD27 activation pathways for class switching.
what is penetrance like of NFKB1 haploinsufficiency and NFKB2?
Low penetrance of symptoms with AD.
NFKB2 has high penetrance.
How does NFKB1 differ form NEMO?
NEMO assocaited with innate immunodeficiency, no obvious defects in innate immunity in NFKB1.
her you get lymphoma and autoimmunity (varying degrees of hypogammaglubnemia)
What is switched memory and CD21 levels like in NFB1 haploinsufficiency?
low switched memory B cell repsonses and increased CD21lo CD38lo population (only in symptomatic patients)- consistent with autoimmunity and splenamegaly- B cell dyregulation.
What is unusual for NFKB2 as a CVID?
more of an early onset.
What pathways is PI3K downstream of? What does this mean for activated PI3Kdelta sydrmoe?
More likley not to just affect humoural immunity.
what notbable infections does APDS show for a CVID?
as well as AI, bronchiesctasis, clymphonma, etheropathay, splenomagaly
Notbaly shows sever herpes virus infections (EBV, CMV)
What are features of APDS T cells?
reduced T cells, but raised CD8 T cells which have a more senescent (CD57+) phenotype.
What are B cells like in APDS?
low IgG and IgA. IgM may be normal or raised.
More unswitched B cells and transitional B cells
What precision treatments are available for APDS patients?
siroluimus/rapamycin mTOR inhibitors.
Other PI3K inhbitors (Idelalisib)
defining difference in presentation betwen NFKB1 LOF and APDS patients?
APDS patients are susceptible to herpesvirus infections. May preform a HSCT for these patients.
what is penetrace like for CTLA-4 haploinsufficiency?
incomplete pentrance classic immune dysregulation phenotype of AI lymphoproliferation and infections.
what targeted therapy might be avaiable for CTLA4 deficiency?
Abatacept (engineered fusion protein with CTLA-4 binding domain)
Will sequester B7 (CD80/86).
Defining feature of CTLA-4 haploinsufficieny (in common with APDS)?
suceptible to herpesvrius infections too.
What is the role of LRBA?
To rescue CTLA-4 from degradation pathways and get it back to cell surface.
Deficiencies therefore quasi CTLA-4 deficiencies
is LRBA AR or AD and what is unusual about it for a CVID?
LOF AR and unusally has very early presntaiton (6 months).
Do LRBA show evidence of immune dyregulation?
Yes, swithced memeory cells are reduced and lymphoma risk as well.
What can LRBA be treaed with?
abatacecpt.
