EBV susceptible PIDs

Question 1

What stage of latency are the B cells in in the GC?

Answer 1

stage II latency, before becoming memory cells and latency 1/0.

Question 2

What are the first two antibody responses seen and what antigens are they against?

Answer 2

anti- Viral cascade antigen (VCA) IgM

Then anti VCA IgG is seen second,

Question 3

What is the first and second antibody responses against latent antigens?

Answer 3

IgG reponse against latent envelope antigens.

hen up to even 6 months later you see EBNA IgG responses.

Question 4

Is B cell reponse important in controlling EBV infection?

Answer 4

Not thought to be functional, may just be reflecting T cell reponses.

Question 5

What immune responses are seen in people with mono or who are asymptomatic?

Answer 5

mono; much greater CD8+ T cell response, and large lymphocytosis (not seen in asymptomatic).

However viral load doesn’t correlate with symptoms.

Question 6

What are mono patients more at risk of developing?

Answer 6

EBV related disease like lymphoproliferative disease.

Question 7

Biggest risk factor for EBV related disease? What are the diseases in these patients?

Answer 7

PIDs.
extreme fevers and inflammation- HLH
increased risk of lymphomas.

Question 8

Why kind of PID might increase risk of B cell lymphomas?

Answer 8

Maybe a defect in B cell differentiatoin.

Instead of EBV infected latent cell progressing to L0 memory B cell- stays as growth transformed B cell.

Question 9

why might PID affecting T cell lead o EBV disease?

Answer 9

Don’t control lytic infectio or latent infection, leads to more growth transformed B cells.

(excessive lytic reproduction and mtagenesis make it more pathogenic?

Question 10

Can EBV infect other cells?

Answer 10

May sometimes infect other cells - (extranodal T/NK cell lymphoma?)

Question 11

What monogenic mutations have high risk of chronic active EBV and HLH?

Answer 11

coronia 1A, ITK and PRF1 (perforin)

Question 12

What cancers are associated with EBV in immunocompetent people?

Answer 12

Hodgkins lymphoma, Diffuse large B cell lymphoma, Burkitts lymphoma.

Gastric carcinoma, Nasopharyngeal carcinoma and T/NK lymphoma.

Question 13

Lymphomas associated wtih immunodeficient patients?

Answer 13

B cell lymphoproliferative disease (mature B cells?)

Smooth muscle carcinoma.

Question 14

Immunopathologic diseases associated with EBV infection?

Answer 14

HLH, mono, chronic active EB and MS *autoimmunity)

Question 15

What are clinical and immunological features of HLH?

Answer 15

Fever and hepatoplenomegaly, pancytopaenia and haemophagocytosis.

Question 16

What do you have to have for chronic active EBV infection?

Answer 16

proven EBV infection, high viral load of EBV, fever hepatomegaly/ splenomegaly.

Tissue infiltration of EBV and lymphocytes.

Question 17

What PID is strongly associated with HLH?

Answer 17

XLP (X linked lymphoproliferative disease)

Question 18

What two categories of genetic basis for HLH are there that are triggered by EBV infection?

Answer 18

familial HLH (caused by granule release deficiency e.g. PFR1 and MUNC13-4)
PID with HLH susceptibility (e.g. Chediak higashi syndrome and Griscelli, XLP, and XIAP deficiency)

Question 19

What genetics defects associated with PIDs where EBV susceptibility is main issue?

Answer 19

XLP, XIAP, ITK, coronin 1A

Question 20

PID with increased risk of EBV disease (but low penetrance)

Answer 20

WAS. WHIM (CXCR4 GOF)

Question 21

Features of HLH?

Answer 21

hyper inflammation, macrophages phagocytosing RBC (and HSC of bone marrow), pancytopenia.

Question 22

Pathogenesis of HLH?

Answer 22

CD8 T cell killing of EBV infected cell impaired- immune synapse and inflammation persists.
Recruitment of macrophages and further cytokine production.

Question 23

Mutatoins responsible for docking/ granule transport sydormes susceptible to HLH, and XLP?

Answer 23

Chediak higashi syndrome: LYST
Griscelli syndrome: Rabb27A
XLP: SH2D1A
FHL
PRF1 and UNC13-4

Question 24

Are presentaiton of XLP and XIAP variable?

Answer 24

Yes can be variable even with similar genetic and environmental backgrounds.

But can present with dysagammaglobunemia.

Question 25

What does the deficent gene SH2D1A encode in XLP? And what is it downstream of?

Answer 25

Encodes SAP, an adaptor protein downstream of SLAM B-T cell interactions in both T and NK cells. Deficiency leads to impaired T cell apoptosis Tfh development and impaired cytotoxicity.

Question 26

Is lymphoproliferative disease as much of a risk in XIAP deficiency?

Answer 26

No, but more susceptible to IBD and antiinflammatory disease alongside HLH.

Question 27

What deficiency is resistant to EBV treatment and has pulmonary involvement and lymphoma risk?

Answer 27

ITK deficiency (downstream of TCR signalling and of CD27 and CD70 axis).

Question 28

What deficiencies present iwth T NK B cell dysfunction and impaired generation of memory response against e.g. EBV.

Answer 28

CD27 and CD70 which are co-stimulatory molecules.

Question 29

Which cells are CD27 an CD70 expressed on ?

Answer 29

CD27 expressed on T cells upstrema of ITK. CD70 on B cells or EBV infected cells. (so also have lack of Igresponse against EBNA)

Question 30

What defect is seen in patients iwth impaired T cell proliferation (impaired NK/T cells), skin infections, thrombocytopenia, Chickepox and most commonly EBV infection (and lymphoproliferatoin?)

Answer 30

XMEN- magnesium channel deficiency important i T cell activation (goeson to help stimulate calcium release). EBV specific rseonses can be supplemented with Mg supplements.

Question 31

What similarity with CD27?CD70 deficiency does CTP synthase deficiency have?

Answer 31

lack of ability to make good long lasting EBV specific T memory cell responses.

Question 32

Unlike SAP deficiency in XLP whihc results in low activation of T cells, what mutation has overactivation of T cells?

Answer 32

PI3Kdelta gain of funciotn mutaiton. | OVeractivatoin leads to increased apoptosis and lack of memory T cells and control.

Question 33

What is the normal function of XIAP?

Answer 33

to inhibit apoptosis of T cells, to help NOD stimulation, and inhibit inflammasome?

Question 34

What immunological mechanisms lie behind XIAP deficiency regarding its function?

Answer 34

No stimulation of NOD and no apoptosis of T cells via XIAP. More persistence leads to greater TLR stimulation. No inhibition of inflammasome, greater inflammasome nd inflammation