Autoimmune haematology Flashcards
How do platelets form part of hte innate immune system
roll around epithelium and are one of the first barrriers to infection
What is the type of apoptosis seen with a high antigen laod?
extrinsic pathway and active apoptosis
What is the type of apoptosis seen when there is a low antigen load?
intrinsic pathway and passive apoptosis
How does impaired fas function contribute to autoimmunity?
unchekced expansion of autoreactive lymphocytes—antibody and T cell mediated autoimmunity
How does overactive fas function contribute to autoimmunity?
excessive Fas mediated killing in target tissues—cytotoxic cell mediated autoimmunity
How many patients with autoimmune disease have a Fas mutation approximately?
<1%
What are the different actions of antibody that can lead to AI haematology disease?
neutralisation of clotting factor; inhibition of enzyme actiivty; coating of cells and activation of macrophages FcR medaited premature destruction of cell
What is the most common AI haematology disease?
immune thrombocytopenia
What are the 2 methods of developing antibody to factor VIII?
if have haemophilia A- given synthetic FVIII from young age can develop antibodies or if given when have activated immune system; acquired due to infection or malignancy
What is the pathogenesis of thrombotic thrombocytopenic purpura?
antibody prevents ADAMTS13 from cleaving von willebrand factor which is very sticky for platelets resulting in microthrombi
What is the overall pathogenesis of immune thrombocytopenia?
antiplatelet antibodies coat plaelets which reacts with Fc on macropahges who remove the platelts and megakaryocytes
What is the result of untreated TTP?
80% mortality rate
What type of antibody mediates ITP?
IgG
What would happen if ITP was mediated by IgM?
rather than activating Fc receptor would activate complelent leading to lysis of the receptor
In how many patients are autoantibodies detected in ITP?
60%
Why might only 60% have detectable antibodies in ITP?
difficult to detect them; T cell mediated disease as well; maybe IgM so compleemnt lyses immediately
Why do you get petechiae with ITP?
platelets arent/ coating the vessels maing them leakier
What is the most common antibody found in ITP?
anti-glycoprotein IIb/IIIa
What suggests that FOXP3 cells are dysregulated in ITP?
IPEX patients get ITP
What indicates that megakaryoctes are suppressed in ITP?
compared with controls, produce variably less megakaryocytes, when remove antibodies from serum, improves
What are hte T cell abnormalities seen in ITP?
increased Th1 in chronic ITP; decreased Th2 and decreased numbers of FOXP3 cells
What studies show the role of increased proliferation of T cells in ITP?
increased thymidine incorporation (marker of T cell prolfieration)
How are megakaryoctes affected in ITP?
antibodies bind to bone marrow megakaryocytes impairing their maturation and platelt production
What are the mechanisms of rituximab mediated cytotoxicity?
apoptosis; inhibition of proliferation; complement-mediated lysis or phagocytosis; cell-mediated cytotoxicity; enhancement of the susceptibility to chemotherapy-induced cytotoxicity
Which cells don’t express CD20?
plasma cells and pre-pre B cells
How many patients with ITP respond to rituximab
50%
What is given along with rituximab?
dexamethasone- helps destroy plasma cells not targeted by rituximab and helps prevents anti-mouse antibodies
What is one of hte advantages of giving rituximab treatment?
it patients have a good response to rituximab, its effects tend to last for years
What is the effect of rituximab on T cells?
corrects the Th1/Th2 ratio in responders ; imrpvoes Treg numbers
What infection is a problem with rituximab?
reactivation of hep B - avoid in acitve disease or give antivirals
Why should vaccines been given before rituximab therapy?
reduces vaccine responses
How can rituximab affect b cells in the long-term with repeated courses?
a late rare complication is hypogammaglobulinaemia
Waht are hte 3 general treatment options for antibodies against FVIII?
overwhelm the inhibitor; bypass the inhibitor and remove the inhibitor
How can you overwhelm the inhibitor in FVIII disease?
high dose human plasma dervied FVIII or porcine FVIII
How can the inhibitor in FVIII be bypassed?
recombinant acgitvated coag factor VII; prothrombin complex concentrates
How can the inhibitor be removed in FVIII disease?
exchange plasmapheresis; desmopressin; IVIgG
How has rituximab be used in FVIII inhibitors?
was used in 4 patients who all responded
How does dexamethasone affect the Th1/Th2 balance?
decreases the Th1/Th2 ratio; increases Tregs
What pre-medication should anti-D be given with?
steroids; paracetamol and antihistamine
How does anti-D therapy work in ITP?
if coat the RBCs with antibody, then macrophage is overwhlemed and destroys the RBCs instead of hte platelets
What type of patietns with ITP don’t respond to rituximab?
immunodeficient patietns
How does IVIgG work in ITP?
FcR blockade; immune modulation–decreased phagocytosis of platelts
What is the MOA of MMF?
reversibly inhibits inosine monophosphate dehydrogenase= which controls purine synthesis used in the proliferation of B and T cells
Who can MMF not be used in?
pregnancy
What are some of the issues with MMF?
fatal infeciton; PML; shingles
What treatment offers the best chance for clinical remission with ITP?
splenectomy
What % of patients remain refractory after splenectomy with ITP?
10%
What are the most common complications of splenectomy?
infection and thrombosis
Why does giving thrombopoeitin work in ITP?
make lost of platelets to overwhelm the immune system
How do TPO-RAs work?
promote megakaryocyte and platelet development through the same way as endogenous TPO
What pathway does TPO work thtough?
Jak-Stat: same as cytokines
What receptor does TPO act upon?
c-Mpl
What is the MOA of eltrombopag?
is a TPO receptor agonist which targets the transmembrane part of the receptro
What is the efficacy of romiplostin?
70-90% response rates
How may TPO-RAs induce tolerance?
increased platelets allows reconstitution of Treg population
What further research is needed in ITP?
trials comparing second line treatments are needed
Why is destruction of T cells effective in antibody mediated diseases?
prevention of B cell stimulation
What is ITP characterised by?
isolated thrombocytopenia
What are the immunological causes of ITP?
pathogenic anti-platelet autoantibodies; T cell mediated platelet destruction and impaired megakaryocytes
What is the contributions of primary and secondary ITP ?
primary-80%
What are the symptoms of ITP?
petechiae; purpura; mucosal bleeding in GU/GI or oral tracts
What suggests taht a functional deficit of TPO is present in patietns with ITP?
2/3rds of patients with ITP have a normal or decreased TPO plasma level
What morphological abnormalities have been seen in megakaryocytes in ITP?
apoptotic ultrastructure and activation of aspase 3
What cytokines are raised in ITP?
IL-17; IL-2 and IFNy
Where does phagocytic breakdown of platelts occur in ITP?
spleen or liver
What suggestst that platelets undergo protein degradation by APCs followed by antigen presentation to T cells?
there have been other antibody specificities other than classic surface glycoproteins such as cytosolic proteins
What is the effect of oxidative stress in the context of autoimmunty?
favours the production of autoantibodies
Why does the presence of antiplatelet autoantibodies increase the risk of thrombotic events?
perhaps due to procoagulant microparticles released by activated platelets
How is BAFF related to ITP?
higher levels in patietns with ITP, promoter region polymorphisms are associated stronly
What may be responsible for the reduced FOXp3 numbers in patients with ITP?
CD3+ T cells have a lower rate of apoptosis and higher clonal expansion rate leading to increased type 1 cytokines ; dysregulated cellular immunity; increased CD16+ monocytes seen in ITP which release IL-12 promoting Th1 and inhibits Th17 downregulating Tregs ; reduced IDO from Dcs
What may cause the Th1/Th2 imbalance seen in ITP?
mediated by reduced secretion of platelet-derived chemokines and cytokiens
What supports the role of pDCs in ITP pathology?
platelet counts in ITP are highly correlated with the number of circulating pDCs (lower)
What shows teh impaired development of MKs in ITP?
decreased ploidy and granularity
What is the effect of autoantibodies on MK cells in itp?
approx 2/3rds of pts have antibodies that are able to significantly inhibit MK maturation from TPO-treated CD34 HSCs and induce apoptosis in vitro
How are MKs involvedi n the regulation of the immune system?
regulate other cells in the BM niche invluding plasma cells and inhibition of T cell activation and production of IL-10
Who tends to get the chronic version of ITP?
adults
What are the first line treatments for ITP?
steroids wtih or without IVIg and anti-D
What are the second line therapies for ITP
?
splenectomy or rituximab
What is the effect of steroids in ITP?
increase Tregs; restore Th1/Th2 ratio; decrease BAFF to reduce B ells
