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Module 3 > Autoimmune haematology > Flashcards

Autoimmune haematology Flashcards

1
Q

How do platelets form part of hte innate immune system

A

roll around epithelium and are one of the first barrriers to infection

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2
Q

What is the type of apoptosis seen with a high antigen laod?

A

extrinsic pathway and active apoptosis

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3
Q

What is the type of apoptosis seen when there is a low antigen load?

A

intrinsic pathway and passive apoptosis

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4
Q

How does impaired fas function contribute to autoimmunity?

A

unchekced expansion of autoreactive lymphocytes—antibody and T cell mediated autoimmunity

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5
Q

How does overactive fas function contribute to autoimmunity?

A

excessive Fas mediated killing in target tissues—cytotoxic cell mediated autoimmunity

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6
Q

How many patients with autoimmune disease have a Fas mutation approximately?

A

<1%

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7
Q

What are the different actions of antibody that can lead to AI haematology disease?

A

neutralisation of clotting factor; inhibition of enzyme actiivty; coating of cells and activation of macrophages FcR medaited premature destruction of cell

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8
Q

What is the most common AI haematology disease?

A

immune thrombocytopenia

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9
Q

What are the 2 methods of developing antibody to factor VIII?

A

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

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10
Q

What is the pathogenesis of thrombotic thrombocytopenic purpura?

A

antibody prevents ADAMTS13 from cleaving von willebrand factor which is very sticky for platelets resulting in microthrombi

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11
Q

What is the overall pathogenesis of immune thrombocytopenia?

A

antiplatelet antibodies coat plaelets which reacts with Fc on macropahges who remove the platelts and megakaryocytes

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12
Q

What is the result of untreated TTP?

A

80% mortality rate

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13
Q

What type of antibody mediates ITP?

A

IgG

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14
Q

What would happen if ITP was mediated by IgM?

A

rather than activating Fc receptor would activate complelent leading to lysis of the receptor

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15
Q

In how many patients are autoantibodies detected in ITP?

A

60%

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16
Q

Why might only 60% have detectable antibodies in ITP?

A

difficult to detect them; T cell mediated disease as well; maybe IgM so compleemnt lyses immediately

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17
Q

Why do you get petechiae with ITP?

A

platelets arent/ coating the vessels maing them leakier

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18
Q

What is the most common antibody found in ITP?

A

anti-glycoprotein IIb/IIIa

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19
Q

What suggests that FOXP3 cells are dysregulated in ITP?

A

IPEX patients get ITP

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20
Q

What indicates that megakaryoctes are suppressed in ITP?

A

compared with controls, produce variably less megakaryocytes, when remove antibodies from serum, improves

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21
Q

What are hte T cell abnormalities seen in ITP?

A

increased Th1 in chronic ITP; decreased Th2 and decreased numbers of FOXP3 cells

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22
Q

What studies show the role of increased proliferation of T cells in ITP?

A

increased thymidine incorporation (marker of T cell prolfieration)

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23
Q

How are megakaryoctes affected in ITP?

A

antibodies bind to bone marrow megakaryocytes impairing their maturation and platelt production

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24
Q

What are the mechanisms of rituximab mediated cytotoxicity?

A

apoptosis; inhibition of proliferation; complement-mediated lysis or phagocytosis; cell-mediated cytotoxicity; enhancement of the susceptibility to chemotherapy-induced cytotoxicity

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25
Q

Which cells don’t express CD20?

A

plasma cells and pre-pre B cells

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26
Q

How many patients with ITP respond to rituximab

A

50%

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27
Q

What is given along with rituximab?

A

dexamethasone- helps destroy plasma cells not targeted by rituximab and helps prevents anti-mouse antibodies

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28
Q

What is one of hte advantages of giving rituximab treatment?

A

it patients have a good response to rituximab, its effects tend to last for years

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29
Q

What is the effect of rituximab on T cells?

A

corrects the Th1/Th2 ratio in responders ; imrpvoes Treg numbers

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30
Q

What infection is a problem with rituximab?

A

reactivation of hep B - avoid in acitve disease or give antivirals

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31
Q

Why should vaccines been given before rituximab therapy?

A

reduces vaccine responses

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32
Q

How can rituximab affect b cells in the long-term with repeated courses?

A

a late rare complication is hypogammaglobulinaemia

33
Q

Waht are hte 3 general treatment options for antibodies against FVIII?

A

overwhelm the inhibitor; bypass the inhibitor and remove the inhibitor

34
Q

How can you overwhelm the inhibitor in FVIII disease?

A

high dose human plasma dervied FVIII or porcine FVIII

35
Q

How can the inhibitor in FVIII be bypassed?

A

recombinant acgitvated coag factor VII; prothrombin complex concentrates

36
Q

How can the inhibitor be removed in FVIII disease?

A

exchange plasmapheresis; desmopressin; IVIgG

37
Q

How has rituximab be used in FVIII inhibitors?

A

was used in 4 patients who all responded

38
Q

How does dexamethasone affect the Th1/Th2 balance?

A

decreases the Th1/Th2 ratio; increases Tregs

39
Q

What pre-medication should anti-D be given with?

A

steroids; paracetamol and antihistamine

40
Q

How does anti-D therapy work in ITP?

A

if coat the RBCs with antibody, then macrophage is overwhlemed and destroys the RBCs instead of hte platelets

41
Q

What type of patietns with ITP don’t respond to rituximab?

A

immunodeficient patietns

42
Q

How does IVIgG work in ITP?

A

FcR blockade; immune modulation–decreased phagocytosis of platelts

43
Q

What is the MOA of MMF?

A

reversibly inhibits inosine monophosphate dehydrogenase= which controls purine synthesis used in the proliferation of B and T cells

44
Q

Who can MMF not be used in?

A

pregnancy

45
Q

What are some of the issues with MMF?

A

fatal infeciton; PML; shingles

46
Q

What treatment offers the best chance for clinical remission with ITP?

A

splenectomy

47
Q

What % of patients remain refractory after splenectomy with ITP?

A

10%

48
Q

What are the most common complications of splenectomy?

A

infection and thrombosis

49
Q

Why does giving thrombopoeitin work in ITP?

A

make lost of platelets to overwhelm the immune system

50
Q

How do TPO-RAs work?

A

promote megakaryocyte and platelet development through the same way as endogenous TPO

51
Q

What pathway does TPO work thtough?

A

Jak-Stat: same as cytokines

52
Q

What receptor does TPO act upon?

A

c-Mpl

53
Q

What is the MOA of eltrombopag?

A

is a TPO receptor agonist which targets the transmembrane part of the receptro

54
Q

What is the efficacy of romiplostin?

A

70-90% response rates

55
Q

How may TPO-RAs induce tolerance?

A

increased platelets allows reconstitution of Treg population

56
Q

What further research is needed in ITP?

A

trials comparing second line treatments are needed

57
Q

Why is destruction of T cells effective in antibody mediated diseases?

A

prevention of B cell stimulation

58
Q

What is ITP characterised by?

A

isolated thrombocytopenia

59
Q

What are the immunological causes of ITP?

A

pathogenic anti-platelet autoantibodies; T cell mediated platelet destruction and impaired megakaryocytes

60
Q

What is the contributions of primary and secondary ITP ?

A

primary-80%

61
Q

What are the symptoms of ITP?

A

petechiae; purpura; mucosal bleeding in GU/GI or oral tracts

62
Q

What suggests taht a functional deficit of TPO is present in patietns with ITP?

A

2/3rds of patients with ITP have a normal or decreased TPO plasma level

63
Q

What morphological abnormalities have been seen in megakaryocytes in ITP?

A

apoptotic ultrastructure and activation of aspase 3

64
Q

What cytokines are raised in ITP?

A

IL-17; IL-2 and IFNy

65
Q

Where does phagocytic breakdown of platelts occur in ITP?

A

spleen or liver

66
Q

What suggestst that platelets undergo protein degradation by APCs followed by antigen presentation to T cells?

A

there have been other antibody specificities other than classic surface glycoproteins such as cytosolic proteins

67
Q

What is the effect of oxidative stress in the context of autoimmunty?

A

favours the production of autoantibodies

68
Q

Why does the presence of antiplatelet autoantibodies increase the risk of thrombotic events?

A

perhaps due to procoagulant microparticles released by activated platelets

69
Q

How is BAFF related to ITP?

A

higher levels in patietns with ITP, promoter region polymorphisms are associated stronly

70
Q

What may be responsible for the reduced FOXp3 numbers in patients with ITP?

A

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

71
Q

What may cause the Th1/Th2 imbalance seen in ITP?

A

mediated by reduced secretion of platelet-derived chemokines and cytokiens

72
Q

What supports the role of pDCs in ITP pathology?

A

platelet counts in ITP are highly correlated with the number of circulating pDCs (lower)

73
Q

What shows teh impaired development of MKs in ITP?

A

decreased ploidy and granularity

74
Q

What is the effect of autoantibodies on MK cells in itp?

A

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

75
Q

How are MKs involvedi n the regulation of the immune system?

A

regulate other cells in the BM niche invluding plasma cells and inhibition of T cell activation and production of IL-10

76
Q

Who tends to get the chronic version of ITP?

A

adults

77
Q

What are the first line treatments for ITP?

A

steroids wtih or without IVIg and anti-D

78
Q

What are the second line therapies for ITP

?

A

splenectomy or rituximab

79
Q

What is the effect of steroids in ITP?

A

increase Tregs; restore Th1/Th2 ratio; decrease BAFF to reduce B ells

Module 3 (33 decks)

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