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PATH30001 - Mechanisms of Disease > Lecture 10 - Diseases of the Blood > Flashcards

Lecture 10 - Diseases of the Blood Flashcards

1
Q

Why do we feel ill during inflammation / infection?

A

Cytokines released by neutrophils

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2
Q

Describe the structure of the hematopoietic stem cell niche

A

• Stem cells, but also:

  • Endothelial cells
  • Osteoblasts
  • Innervation & vasculature
  • Stromal cells
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3
Q

What is the name for a decrease in the n° of white blood cells?
What about increase in n°?

A

Leukopenia: decrease

Leukocytosis: increase

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4
Q

What are some specific subtypes of leukopenia?

A

Neutropenia:
• Reduction in neutrophils
• Due to a wide variety of inflammatory reactions
• Not usually clinically significant

Agranulocytosis:
• Clinically significant reduction in neutrophils
• Susceptibility to bacterial and fungal infections

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5
Q

Outline the various causes of neutopaenia

A
  1. Decreased production
    • Stem cell suppression
    • Drugs (Chemotherapy, antibiotics)
    • Inherited defects: Kostmann syndrome
  2. Increased destruction
    • Immune mediated (SLE)
    • Splenomegaly, splenic sequestration
    • Increased peripheral demand
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6
Q

What are aplastic anaemias?

A

Low RBC numbers

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7
Q

What is splenic sequestration?

What can it lead to?

A 
Spleen blockage (secondary to another disease; e.g. sickled cell anaemia)
The spleen will have increased functionality, and thus lead to increased destruction of neutrophils (neutropaenia)
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8
Q

Describe immune mediated increased destruction of neutrophils

A

Cause:
• Idiopathic
• Due to a disorder (e.g. SLE)

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9
Q

List factors leading to leukocytosis

A
  • Size of the myeloid and lymphoid progenitor pools in BM
  • Rate of release from storage pools
  • Size of marginal pool
  • Rate of extravasation
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10
Q

What pathological features are seen in neutrophils in leukocytosis

A
  • Toxic granulations
  • Döhle bodies (cytoplasmic inclusions)
  • Cytoplasmic vacuoles
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11
Q

What is Lymphadenitis?

Describe some of the features & cause

A

Very sore lymph nodes

Cause:
• Microbial drainage from teeth and tonsils
• Systemic viral infection
• Bacteraemia

Features
• Usually self limiting
• Often experienced at the beginning of a cold
• Much lymphocyte hyperplasia of the lymph nodes

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12
Q

What are the categories of neoplasms of white blood cells?

A

Lymphoid
• Involving lymphocytes

Myeloid
• Involving innate immune cells

Leukaemia:
• Bone marrow involvement
• Large numbers of neoplastic cells entering blood

Lymphomas:
• Solid mass tumours

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13
Q

List some myeloid neoplasms

A
  • Acute myeloid leukaemia (AML)
  • Myelodysplastic syndromes
  • Chronic myeloid leukaemia (CML)
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14
Q

Describe the Philadelphia chromosome

Which neoplasms can it bring about?

A
  • T(9;22) chromosomal translocation
  • Bcr-Abl fusion protein; constitutively active tyrosine kinase
  • ‘Always on’ → proliferation

Can lead to acute leukaemias

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15
Q

Why are white blood cells in particular susceptible to translocations?

A

Due to the high levels of proliferation

→ Sheer number, statistically, there will be errors

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16
Q

What is leukaemia?

A

Malignancy of progenitor cells in the bone marrow

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17
Q

What is the molecular pathogenesis of leukaemias?

What is the result of these mutations?

Give some examples

A
  • Chromosome translocations
  • Transcription factor mutations

Result:
• Increased proliferation
• Increased self-renewal
• Decreased differentiation

e. g.
1. t(9;22) → Philadelphia chromosome
2. MLL protein fusion / rearrangement

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18
Q

What is the aetiology of acute leukaemia?

A
  1. Genetic factors
  2. Chronic immune stimulation
  3. Iatrogenic factors
  4. Smoking
  5. Infectious causes
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19
Q

Describe genetic factors leading to acute leukaemia

A

Non random chromosomal abnormalities:
• Chromosomal translocations (bcd-abl)

• Transcription factor mutations:

  • Duplication of MLL protein
  • Fusion of MLL with a ‘fusion partner gene’
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20
Q

What are some iatrogenic factors of leukaemia aetiology?

A
  • Irradiation

* Chemotherapy

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21
Q

Describe how infectious agents can bring about leukocyte neoplasms.

List the infectious agents

A
  1. HPV
  2. EBV
  3. Human T-cell leukaemia virus (HTLV)
  4. Kaposi sarcoma herpesvirus (KSHV)
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22
Q

Describe chronic immune stimulation causing acute leukaemia

A
  • H. pylori infection → gastric B-cell lymphoma

* Gluten sensitive enteropathy → intestinal T-cell lymphoma

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23
Q

Which cells are affected in the vast majority of lymphoid neoplasms?

A

B cells (90%)

The rest are of course T cell based

24
Q

Describe the onset of acute leukaemias

A

Very abrupt

Onset is seen within days or weeks of the first symptoms

25
Q

What are the symptoms of ALL?

A

Related to depression of bone marrow function

  • Anaemia → fatigue
  • Neutropaenia → infection → fever
  • Thrombocytopaenia → haemorrhagic tendency

Neoplastic cell expansion →
• Bone pain
• Headache
• Nausea

26
Q

Compare prognosis of ALL in adults and children

A

Children: 95% remission, 80% cure
Adults: 40% remission

27
Q

Describe the mutations needed to cause ALL

A

Chromosomal mutations
• Dysregulation of transcription factor production
→ Aberrant signalling in B and T cell development

NB single mutations aren’t sufficient to cause cancer
→ Build up of mutations required

28
Q

Compare common mutations in B and T cell ALL

A

T cell:
• NOTCH1 TF

B cell:
• PAX5 TF
• E2A TF

29
Q

What are the pathological differences between AML and ALL?

A

Different surface markers of the neoplastic cells

AML:
• More cytoplasm seen in blasts than ALL

30
Q

What are the risk factors for MM?

A
  • Men

* Elderly

31
Q

What is seen in the skull on an X ray in MM?

A

Black dots, indicating decreased calcification

32
Q

What histological features are seen in plasma cells in MM?

A
  • Many vacuole type structures containing much Ig

* Spots visible within the nuclei

33
Q

Describe biochemical diagnosis of MM

A

‘Blood Ab electrophoresis tests’

  1. Normal:
    • Smear of IgG: indicates diverse range of Ig, as in normal immune response
  2. MM patient serum:
    • Single band: indicates a single specificity of IgG
34
Q

Which pathway is affected in MM?

What is the role of this pathway?

A

The hedgehog pathway
• Important for stem cell self-renewal
• In MM; the pathway is overactive (active w/o stimulus)
• Cells constantly self renew and proliferate

35
Q

Describe the action of myeloma cells bringing about the main pathologic feature of MM

A
  1. Myeloma cells produce MIP1a
  2. MIP1-α increases RANKL expression from BM stromal cells
  3. RANKL activates osteoclasts
  4. Bone resorption
36
Q

What is smouldering MM?

A

Asymptomatic, pre-clinical stage very common in older people (3%)

37
Q

What are the treatments of MM?

A

Chemotherapy (quite effective)

Different treatments based on ‘type’

38
Q

What controls the development of the various WBCs from stem cells in the bone marrow?

A

Cytokines

39
Q

What’s the name for a clinically significant reduction in neutrophils and increased susceptibility to bacterial and fungal infections?

A

Agranulocytosis

40
Q

Which drugs can cause Leukopenia?

A

Chemotherapy

Many antibiotics

41
Q

What is the name for sore lymph nodes?

A

Lymphadenitis

42
Q

What is seen in histological sections of the lymph node in lymphadenitis?

A
  • Increased n° of GC’s in lymph nodes

* Increased cell density in GC’s and nodes in general

43
Q

Compare AML and CML

A

AML:
• Accumulation of immature progenitors in BM
• Acute onset

CML:
• Increased production of one (or more) terminally differentiated WBC’s

44
Q

Which mutation is commonly seen in ALL?

A

Philadelphia chromosome due to chromosome translocation

45
Q

Describe what happens to cells in ALL

A

Greatly increased numbers of blasts (immature B or T cells)

46
Q

How is ALL diagnosed?

A
  1. Blood smear
    • Presence of great numbers of blasts
  2. Expression of B cell markers, indicating increased n°’s of blasts
47
Q

Why is MM a significant disease?

A

1% of all cancer deaths in western countries

48
Q

What is the main risk factor for MM?

A

Old age

49
Q

Which organ is most affected by MM?

A

Bone

50
Q

Which isotope of monoclonal Ab is most commonly seen in MM?

Which classes are uncommon?

A

IgG is common (also IgA)

IgM, IgE & IgD are uncommon

51
Q

Which factors promote the proliferation and survival of MM cells?

A

Autocrine and paracrine signals from stromal cells:

• IL-6

52
Q

Describe the variability in severity of MM

A

Good outcome: associated with translocations involving cyclin D
Poor outcome: certain deletions

53
Q

Is chemotherapy effective in MM?

What about for Anaplastic Large-Cell lymphoma?

A

MM: Yes
→ 50-70% remission

ALCL:
→ up to 80% cure rate

54
Q

What is Anaplastic large cell lymphoma?

A

• ALK positive: anaplastic lymphoma kinase gene rearrangement
→ Constitutively active tyrosine kinases
→ Proliferation and cell survival

55
Q

Why ALK positive?

A

Anaplastic lymphoma kinase is present

56
Q

Why is ALK positive a great opportunity for a vaccine?

A

Inhibitors of ALK (the overactive tyrosine-kinase) are in development
This is a chance for a great selective, targeted therapy

Also, ALK-antigen is a target for vaccine development

PATH30001 - Mechanisms of Disease (34 decks)

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