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*8. Haematology > Physiology: immunodeficiency > Flashcards

Physiology: immunodeficiency Flashcards

1
Q

Primary vs secondary immunodeficiencies?

A
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2
Q
A
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3
Q

2 immunodeficiencies of innate immunity?

A

Chronic granulomatous disease
Leukocyte adhesion deficiency (type 1)

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4
Q

Chronic granulomatous disease
- What are the phagocytes?
- Within the phagolysosome, what are the 2 main enzyme systems that kill the microbe? (see pic)

A
  • Neutrophils and macrophages
  • Inducible nitric oxide synthase (iNOS) and phagocyte oxidase
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5
Q

Chronic granulomatous disease
- What enzyme is mutated?
- Does this enzyme have multiple subunits?
- Gp91 is the most commonly mutated gene in chronic granulomatous disease - what chromosome is it on?

A
  • Phagocyte oxidase
  • Yes
  • Gp91 is on the X chromosome
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6
Q

Chronic granulomatous disease
- Why are granulomas formed?

A

Deficiency in phagocyte oxidase
Phagocytes are unable to clear infectious organisms as efficiently
Leads to cellular infiltrate (of macrophages and Th1 cells0 coming to wall off the site of infection –> granuloma

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7
Q

Chronic granulomatous disease
- Aside from granuloma formation, what is the other main clinical outcome of CGD?

A

Susceptibility to persistent bacterial and fungal infections in the first 2 years of life; often by commensal organisms

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8
Q

Chronic granulomatous disease
- Treatments?

A

Antibiotics, anti inflammatories, HSC transplant

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9
Q

Leukocyte adhesion deficiency (type 1)

A
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10
Q

Leukocyte adhesion deficiency
- What is mutated?
- Mode of inheritance?
- Effect on leukocytes?

A

B2 integrins
Autosomal recessive
Leukocytes can roll across the endothelium, but can’t adhere and therefore migrate to site of infection

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11
Q

Leukocyte adhesion deficiency
- WBC count?
- Antibody responses?
- Bacterial infections? If so, genuine or opportunistic?

A
  • Abnormally high WBC count
    Normal antibody responses
    Recurrent severe bacterial infections; genuine
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12
Q

Leukocyte adhesion deficiency
- Other clinical outcomes?

A
  • Delayed wound healing
  • Severe gingivitis
  • Delayed separation of the umbilical cord
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13
Q

Leukocyte adhesion deficiency
- Treatment?

A

Prophylactic antibiotics
Bone marrow transplant

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14
Q

Severe combined immunodeficiency
- Which immune cells does it impact?
- Impact on T cell dependent antibody responses and why?

A

Always T cells; sometimes B cells and/or NK cells
Prevents these from happening (eg. isotype switching)

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15
Q

Severe combined immunodeficiency
- 3 main genetic defects?

A

Y chain receptor
RAG-1/2 enzymes
Purine salvage pathway enzymes

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16
Q

Severe combined immunodeficiency: y chain receptor
- What chromosome is this gene found on?
- Normal role of the y chain?
- Y chain mutation: impact on T cells, B cells, and NK cells?

A
  • X chromosome
  • Antigen binds to alpha chain; which activates y chain –> ultimately leads to release of cytokines involved in T cell and NK cell development
  • Lack of T and NK cells; B cells unaffected
17
Q

Severe combined immunodeficiency: RAG-1/2 enzymes
- Are these enzymes autosomal or X linked?
- Normal function of these enzymes?
- Effect of mutation? On T, B, NK cells?

A

Autosomal
Molecular scissors - recombine antigen receptor gene segments (from VDJ), to create diversity in antigen receptors
Without RAG, developing lymphocyes can’t express antigen receptors - no B or T cells; NK cells unaffectd

18
Q

Severe combined immunodeficiency: purine salvage pathway enzymes
- Normal function of these enzymes?
- Impact of mutation? On T, B, NK cells?

A

Nucleic acid catabolism (breakdown)
Leads to accumulation of metabolites that are toxic to lymphocytes - no B, T, NK cells.

19
Q

Severe combined immunodeficiency
- Outcomes?

A
  • First symptom is often thrust in the mouth and/or nappy area
  • Coughs and pneumonia due to viral infection are common
  • Intractable diarrhoea caused by viruses or E. coli
  • Develop opportunistic infections, patients will die without treatment
20
Q

Severe combined immunodeficiency
- Common treatments?

A

Prophylactic antibiotics
IV immunoglobulins
Hygiene measures
Avoidance of live attenuated vaccines

21
Q

Severe combined immunodeficiency
- Novel treatments?

A
  • Bone marrow transplants
  • Enzyme replacement therapy (for those deficient in adenosine deaminase, a purine salvage pathway enzyme)
  • Gene therapy (can be curative!)
22
Q

Severe combined immunodeficiency: bone marrow transplants
- Does the level of MHC matching impact long tern survival?
- Is it possible for bone marrow recipients to reject a graft? Why/why not? What is the other issue?

A

Yes
No - as SCID patients lack T cells. Host vs graft disease is the issue - T lymphocytes in the graft recognise the host as foreign

23
Q

2 X linked lymphocyte diseases?

A

X linked agammagloulinemia with hyper IgM
X linked lymphoproliferative syndrome

24
Q

X linked agammagloulinemia with hyper IgM
- Normal function of CD40L?

A

CD40L of T cells bind to CD40 on B cells.
This interaction causes T cells to release cytokines, promoting B cell proliferation + isotype switching in the germinal centres

25
Q

X linked agammagloulinemia with hyper IgM
- What is mutated?
- What chromosome is it located in?

A

CD40L
X chromosome

26
Q

X linked agammagloulinemia with hyper IgM
Impacts on:
- Plasma cells?
- Isotypes?
- Lymphocyte levels?
- Neutrophil levels?

A

Present
IgM high; others low/absent
Normal
Low

27
Q

X linked agammaglobulinemia
- Impact of having only IgM?

A

They are low affinity - not as effective as other isotypes at neutralisation
Can lead to recurrent bacterial infections
Can also lead to susceptibility to opportunistic intracellualar pathogens

28
Q

X linked agammaglobulinemia with hyper IgM
- Treatment?

A

IV y globulin
Prophylactic antibodies
Haematopoietic stem cell transplant

29
Q

X linked lymphoproliferative syndrome
SLAM and SAP molecules

SLAM
- What cells is it expressed in?
- Do they generally interact homotypically?
- Binding does what to the tyrosine residues in the cytoplasmic domain?

SAP
- What cells is it expressed in?
- What chromosome makes it?
- What does it bind to?
- What signal does it do?

A

SLAM
- B, T, NK cell
- Phosphorylates them

SAP
- Cytotoxic T cell, NK cell
- X chromosome
- Phosphorylated tyrosine residues
- Kills the target cell

30
Q

X linked lymphoproliferative syndrome
- Effect of mutation to SAP?

A

Lack of killing of target cell

31
Q

X linked lymphoproliferative syndrome
- 3 clinical outcomes?

A

Fulminating infectious mononucleosis - inability to control EBV infection

B cell lymphomas and/or lymphoproliferation

Dysgammaglobulinaemia, which can progress to hypoglammaglobulinemia

*8. Haematology (8 decks)

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