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Yr 2 - Clinical Pathology > Immunodeficiency > Flashcards

Immunodeficiency Flashcards

1
Q

Branches of innate and adaptive immune system

A

Innate immunity:

  • General, not antigen specific but can recognise broad classes e.g. bacteria
  • Rapid speed of onset
  • Does not alter on repeated exposure
  • No memory

Adaptive immunity:

  • antigen specific
  • Slower response, but more potent
  • Subsequent exposure- more effective response
  • memory
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2
Q

What is immunodeficiency?

A

Clinical situations where the immune system is not effective enough to protect the body against infection

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3
Q

What are the 2 types of immunodeficiency?

A

Primary and secondary

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4
Q

What does 1ary immunodeficiency involve?

A

Inherent defect within the immune system –> usually genetic

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5
Q

What does 2ary immunodeficiency involve?

A

Immune system affected due to external causes

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6
Q

What are 5 examples of 2ary causes of immunodeficiency?

A
  1. Breakdown in physical barriers
  2. Protein loss
  3. Malignancy
  4. Drugs
  5. Infection
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7
Q

What is an example of a disease that causes a breakdown in physical barrier?

A

Cystic Fibrosis –> compromised mucosal barrier in lung which leads to recurrent infection

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8
Q

What can cause protein loss and then immunodeficiency?

A

Burns, protein losing enteropathy, malnutrition

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9
Q

What is protein losing enteropathy?

A

a pathological condition in which there is an increased loss of proteins through the gastrointestinal tract, which leads to low serum proteins

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10
Q

How can protein losing enteropathy lead to immunodeficiency?

A

Lose antibodies (type of protein)

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11
Q

What malignancies can cause immunodeficiency?

A

Lymphoproliferative disease, myeloma

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12
Q

Which drugs can lead to immunodeficiency?

A

Steroids, DMARDS, Rituximab, anti-convultants, myelosuppressive

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13
Q

Why can steroids, DMARDS and Rituximab lead to immunodeficiency?

A

Suppress the immune system (for treatment in conditions such as rheumatoid arthritis)

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14
Q

What is myelosuppression?

A

A condition in which bone marrow activity is decreased, resulting in fewer red blood cells, white blood cells, and platelets

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15
Q

What infections can lead to immunodeficiency?

A

HIV, TB

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16
Q

What can phagocytes be classified into?

A

Phagocytes are classified into neutrophils and monocytes.

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17
Q

Difference in location of function of neutrophils vs macrophages?

A

Monocytes circulate in blood and then become macrophages once in tissues. Neutrophils function in circulation.

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18
Q

What are pattern recognition receptors (PRRs)?

A

Phagocytes PRRs which recognise and bind to pathogen-associated molecular patterns (PAMPs).

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19
Q

What are PAMPS?

A

PAMPs are components of pathogens and can include molecules like peptidoglycan and lipopolysaccharide (LPS).

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20
Q

What are 2 examples of PAMPs?

A

peptidoglycan and lipopolysaccharide (LPS).

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21
Q

How do phagoctes use PRRs?

A

To detect pathogens

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22
Q

What is the main type of PRR?

A

Toll-like receptor (TLR)

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23
Q

There are many different types of TLRs. What PAMP does:

a) TLR3
b) TLR4
c) TLR5

recognise?

A

a) dsRNA (viral RNA in viruses)
b) TLR4 - lipopolysachharide
c) TLR5 - flagellin

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24
Q

Where is LPS found?

A

Gram-negative bacteria

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25
Q

Where is flagellin found?

A

Bacteria

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26
Q

What can defects in TLR3 lead to?

A

Recurrent HSV encephalitis

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27
Q

What type of immunodeficiency is recurrent HSV encephalitis?

A

1ary

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28
Q

Where are PRRs found? What do they bind?

A

Pattern Recognition Receptors (PRRs) are receptors located on immune cells such as macrophages and dendritic cells. They bind to Pathogen Associated Molecular Patterns (PAMPs).

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29
Q

What are PAMPs?

A

A PAMP is a specific arrangement of carbohydrates, lipids and nucleic acids on the surface of a pathogen that signals to a phagocyte that a cell is foreign.

Many different molecules can act as PAMPs, including peptidoglycan, endotoxin and flagellin.

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30
Q

Once the PRR has bound a PAMP, what happens?

A

An intracellular cascade of events that leads to the production of inflammatory cytokines

These inflammatory cytokines then stimulate other events (e.g. production of CRP by liver)

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31
Q

What is Myd88 and IRAK-4?

A

Myeloid differentiation factor 88 (MyD88) is a critical component of the toll-like receptor pathway

IRAK-4 (interleukin-1 receptor-associated kinase 4), in the IRAK family, is a protein kinase involved in signaling innate immune responses from Toll-like receptors

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32
Q

What is IRAK4 deficiency?

A

IRAK-4 deficiency is an inherited disorder of the immune system (primary immunodeficiency).

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33
Q

Clinical presentation of IRAK4 deficiency?

A
  • Recurrent bacterial infections by pyogenic bacteria
    • Especially streptococcus and staphylococcus
      • Pneumonia, meningitis, arthritis
  • Poor inflammatory response
  • Susceptibility to infection decreases with age
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34
Q

What is treatment for IRAK4 deficiency?

A

prophylactic antibiotics, iv immunoglobulin if severe

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35
Q

What is myd88 deficiency? How does it present?

A

MyD88 deficiency is an inherited disorder of the immune system (primary immunodeficiency). Presents similar to IRAK4

36
Q

How is a phagolysosome formed?

A

After attachment, the phagocyte internalises the microbe into a phagosome. The phagosome then fuses with a lysosome to form a phagolysosome.

37
Q

What is the NADPH complex? Where is it found?

A
  • NADPH oxidase is a membrane-bound enzyme complex that can be found in the membranes of phagosomes
    • ​Composed of several proteins
  • Used to engulf microorganisms
38
Q

gp91phox is one of the proteins forming the NADPH complex. What is this coded by?

A

X chromosome

39
Q

Explain pathway of NADPH complex

A
  1. NAPDH releases an electron which binds to an oxygen
  2. This leads to a superoxide being formed
  3. This then leads to production of hypochlorous acid
  4. This acid kills bacteria/fungi that has been engulfed
40
Q

What is chronic granulatomous disease?

A

Chronic granulomatous disease (CGD) is a rare inherited primary immune deficiency disorder that affects certain white blood cells.

41
Q

How is CGD caused?

A
  • Caused by genetic defects in the gene components that encode the NADPH oxidase enzyme complex.
    • Defect in gp91phox
  • Phagocytes unable to produce hydrogen peroxide to fight specific kinds of bacteria and fungi.
42
Q

What is a granuloma?

A

A granuloma is a small area of inflammation - a collection of macrophages

43
Q

Who does CGD typically affect? Why?

A

gp91phox is encoded by the X chromosome –> typically affects males and females are normally carriers

Do a family history!

44
Q

Typical presentation of CGD?

A
  • Recurrent abscesses: lung, liver, bone, skin, gut
45
Q

What are infections in patients with CGD are typically from?

A

Staphylococcus, Klebsiella, Serretia, Aspergillus, Fungi

46
Q

Treatment for CGD?

A

haemopoeitic stem cell transplant, antibiotics

47
Q

What test is needed to diagnose CGD?

A
  • Neutrophil function test
  • Measure Dihydrorhodamine reduction using flow
  • Nitro blue tetrazolium dye reduction
    • healthy neutrophils should go purple in presence of this dye
    • in CGD neutrophils are unable to change colour of dye
48
Q

What is the most useful test in determining if a patient has chronic granuomatous disease?

A

Neutrophil Function Test

49
Q

What is complement? What is its role in the immune system?

A

Non immunoglobulin proteins, that are important in the immune system for:

  • Cell lysis (kill invading bacterium)
  • Control of inflammation
  • Stimulate phagocytosis

Sequence of events activates complement proteins

50
Q

Complement pathway revision

A
51
Q

What do all 3 complement pathways result in?

A

Formation of Membrane Attack Complex (MAC) which kills pathogen

52
Q

How does MAC kill pathogens?

A

The membrane attack complex (MAC) punches a hole through the plasma membrane of the target cell, killing the pathogen

53
Q

What activates the classical complement cascade?

A

The classical complement pathway is initiated by antigen-antibody complexes with the antibody isotypes IgG and IgM

(N.B. The classical complement pathway can also be activated by apoptotic cells, necrotic cells, and acute phase proteins.)

54
Q

With a C2, C4 deficiency, what are patients predisposed to?

A

SLE, infections, myositis

55
Q

Why are those with C2, C4 deficiency prone to SLE?

A

Thought to be due in part to the inability of complement to clear immune complexes and dying cells.

56
Q

What can a C5-C9 deficiency lead to? How do patients present?

A
  • A genetic condition affecting the complement membrane attack complex (MAC)
  • Presents with repeated episodes of BACTERIAL meningitis
    • Particularly Neisseria meningitis
57
Q

Sequence of events after an antigen binds to a B cells via the MHC II complex.

A
  1. This B cell (a professional APC) presents this antigen + MHC II complex to a naive T helper cell (CD4)
  2. Naive T helper cell then differentiates and proliferates
  3. T helper cell (CD4) produces cytokines
  4. Cytokines stimulate B cells to form memory B cells and plasma cells (make antibodies)
58
Q

How does the binding of antibodies to antigens inactivate antigens? 4 ways

A
  1. Neutralisation
    1. Enhances phagocytosis
  2. Agglutination
    1. Enhances phagocytosis
  3. Precipitation of dissolved antigens
    1. Enhances phagocytosis
  4. Activation of complement system
    1. Leads to cell lysis
59
Q

What is X linked agammaglobulinaemia (XLA)?

A

X-linked agammaglobulinemia (XLA) is a condition that affects the immune system –> very few B cells

60
Q

Why is XLA seen almost exclusively in males?

A

Is X-linked

61
Q

What defect leads to XLA?

A

Mutations in the Bruton’s Tryrosine kinase (BTK) gene:

  • Needed for B cell signalling and B cell maturation
  • B cell maturation not completed in the bone marrow
62
Q

What is BTK?

A

A tyrosine kinase that is encoded by the BTK gene in humans. BTK plays a crucial role in B cell development.

63
Q

Where is the BTK gene found?

A

On the X chromosome

64
Q

Other B cell defects diseases:

A
  • CVID
  • IgA deficiency
  • X linked hyper IgM syndrome
  • Transient hypogammaglobulinaemia of infancy
65
Q

What does a defect in B cells lead to?

A
  • Loss of antibody secretion.
  • Usually leads to recurrent bacterial infection with pyogenic organisms.
  • Most are very serious
66
Q

How are B cell defects treated?

A

Treat with antibiotics then i.v IgG for life.

67
Q

What is IgA deficiency?

A
  • People with this deficiency lack immunoglobulin A (IgA), a type of antibody that protects against infections of the mucous membranes lining the mouth, airways, and digestive tract.
  • Less serious (some completely well)
  • Higher risk of autoimmune diseases e.g. coeliac
68
Q

Case 1:

–History of rheumatoid arthritis- severe

–No infections most of adult life, but two year history of recurrent bacterial chest infections- 5 courses of antibiotics over the winter period

–PMH: asthma

–Drug Hx: currently on methotrexate and infliximab, previously rounds on Rituximab. Has also had gold, sulfasalazine in the past

–Ix: slightly low B and T cells, low IgG and IgA

Possible diagnosis?

A

Secondary antibody deficiency due to drugs used to suppress immune system in RA –> common, you will see this!

69
Q

What does Rituximab target?

A

Rituximab targets CD20, a transmembrane protein present on virtually all B cells

70
Q

What is methotrexate?

A

An immunosuppressant used to treat inflammatory conditions, including rheumatoid arthritis.

71
Q

Which antibody is the body’s main defense against bacterial infection?

A

IgG antibodies are the body’s main defense against bacterial infection. IgG treatment replaces these antibodies.

72
Q

Why may the offspring of consanguineous parents be at increased risk to genetic disorders?

A

because of the expression of autosomal recessive gene mutations inherited from a common ancestor

73
Q

In immunodeficiency disorders, why can children show normal levels of IgG?

A

As IgG can cross the placenta

74
Q

What is severe combined immunodeficiency?

A

Patients with SCID have a genetic defect that affects T cells and at least one other type of immune cell (hence “combined immunodeficiency”). Types of SCID are classified by which immune cells, T, B, and/or NK cells, are defective.

75
Q

Why are defects in T cells usually more severe than B cells?

A

Since B cells also need T cell help - even if there are B cells, they don’t function

76
Q

What are symptoms of T cell defects?

A
  • Symptoms are recurrent infection with opportunistic infections, bacteria, viruses,
  • Fungi (candida), protozoa (pneumocystis).
77
Q

What family history increases risk of SCID?

A

Consanguinous parents

78
Q

Treatment for SCID?

A

Paediatric emergency

  • Antibiotics, antivirals, antifungals
  • Asepsis needs to be maintained (sterile environment)
  • Haemopoietic stem cell transplant is the only cure
79
Q

Causes of SCID?

A
  • Defect/absence of critical T cell molecule e.g. TCR, common gamma chain
  • Loss of communication e.g. MHCII deficiency (T cells and B cells are there but can’t talk to each other)
  • Metabolic e.g. Adenosine deaminase deficiency
80
Q

Summary

A
81
Q

Which TLR recognises LPS?

A

TLR4

82
Q

Which TLR recognises flagellin?

A

TLR5

83
Q

which TLR recognises dsRNA?

A

TLR3

84
Q

Function of C3b?

A

Opsonisation of pathogens

85
Q

Recurrent HSV encephalitis is due to a defect in what?

A

TLR3

86
Q

Which components of the complement pathway are anaphylatoxins?

A

C3a, C4a and C5a

87
Q

Effects of anaphylatoxins?

A

Smooth muscle contraction, vasodilation, histamine release from mast cells, and enhanced vascular permeability.

Yr 2 - Clinical Pathology (80 decks)

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