EBV susceptible PIDs Flashcards
What stage of latency are the B cells in in the GC?
stage II latency, before becoming memory cells and latency 1/0.
What are the first two antibody responses seen and what antigens are they against?
anti- Viral cascade antigen (VCA) IgM
Then anti VCA IgG is seen second,
What is the first and second antibody responses against latent antigens?
IgG reponse against latent envelope antigens.
hen up to even 6 months later you see EBNA IgG responses.
Is B cell reponse important in controlling EBV infection?
Not thought to be functional, may just be reflecting T cell reponses.
What immune responses are seen in people with mono or who are asymptomatic?
mono; much greater CD8+ T cell response, and large lymphocytosis (not seen in asymptomatic).
However viral load doesn’t correlate with symptoms.
What are mono patients more at risk of developing?
EBV related disease like lymphoproliferative disease.
Biggest risk factor for EBV related disease? What are the diseases in these patients?
PIDs.
extreme fevers and inflammation- HLH
increased risk of lymphomas.
Why kind of PID might increase risk of B cell lymphomas?
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.
why might PID affecting T cell lead o EBV disease?
Don’t control lytic infectio or latent infection, leads to more growth transformed B cells.
(excessive lytic reproduction and mtagenesis make it more pathogenic?
Can EBV infect other cells?
May sometimes infect other cells - (extranodal T/NK cell lymphoma?)
What monogenic mutations have high risk of chronic active EBV and HLH?
coronia 1A, ITK and PRF1 (perforin)
What cancers are associated with EBV in immunocompetent people?
Hodgkins lymphoma, Diffuse large B cell lymphoma, Burkitts lymphoma.
Gastric carcinoma, Nasopharyngeal carcinoma and T/NK lymphoma.
Lymphomas associated wtih immunodeficient patients?
B cell lymphoproliferative disease (mature B cells?)
Smooth muscle carcinoma.
Immunopathologic diseases associated with EBV infection?
HLH, mono, chronic active EB and MS *autoimmunity)
What are clinical and immunological features of HLH?
Fever and hepatoplenomegaly, pancytopaenia and haemophagocytosis.
What do you have to have for chronic active EBV infection?
proven EBV infection, high viral load of EBV, fever hepatomegaly/ splenomegaly.
Tissue infiltration of EBV and lymphocytes.
What PID is strongly associated with HLH?
XLP (X linked lymphoproliferative disease)
What two categories of genetic basis for HLH are there that are triggered by EBV infection?
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)
What genetics defects associated with PIDs where EBV susceptibility is main issue?
XLP, XIAP, ITK, coronin 1A
PID with increased risk of EBV disease (but low penetrance)
WAS. WHIM (CXCR4 GOF)
Features of HLH?
hyper inflammation, macrophages phagocytosing RBC (and HSC of bone marrow), pancytopenia.
Pathogenesis of HLH?
CD8 T cell killing of EBV infected cell impaired- immune synapse and inflammation persists.
Recruitment of macrophages and further cytokine production.
Mutatoins responsible for docking/ granule transport sydormes susceptible to HLH, and XLP?
Chediak higashi syndrome: LYST Griscelli syndrome: Rabb27A XLP: SH2D1A FHL PRF1 and UNC13-4
Are presentaiton of XLP and XIAP variable?
Yes can be variable even with similar genetic and environmental backgrounds.
But can present with dysagammaglobunemia.
What does the deficent gene SH2D1A encode in XLP? And what is it downstream of?
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.
Is lymphoproliferative disease as much of a risk in XIAP deficiency?
No, but more susceptible to IBD and antiinflammatory disease alongside HLH.
What deficiency is resistant to EBV treatment and has pulmonary involvement and lymphoma risk?
ITK deficiency (downstream of TCR signalling and of CD27 and CD70 axis).
What deficiencies present iwth T NK B cell dysfunction and impaired generation of memory response against e.g. EBV.
CD27 and CD70 which are co-stimulatory molecules.
Which cells are CD27 an CD70 expressed on ?
CD27 expressed on T cells upstrema of ITK.
CD70 on B cells or EBV infected cells. (so also have lack of Igresponse against EBNA)
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?)
XMEN- magnesium channel deficiency important i T cell activation (goeson to help stimulate calcium release).
EBV specific rseonses can be supplemented with Mg supplements.
What similarity with CD27?CD70 deficiency does CTP synthase deficiency have?
lack of ability to make good long lasting EBV specific T memory cell responses.
Unlike SAP deficiency in XLP whihc results in low activation of T cells, what mutation has overactivation of T cells?
PI3Kdelta gain of funciotn mutaiton.
OVeractivatoin leads to increased apoptosis and lack of memory T cells and control.
What is the normal function of XIAP?
to inhibit apoptosis of T cells, to help NOD stimulation, and inhibit inflammasome?
What immunological mechanisms lie behind XIAP deficiency regarding its function?
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
