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IMM005 > An approach to immune deficiency diseases > Flashcards

An approach to immune deficiency diseases Flashcards

1
Q

What information have immune deficiencies provided us with?

A

A lot of information regarding the parts of the immune system

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2
Q

What are the two categories of immunodeficiencies?

A

Primary

Secondary

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3
Q

Hallmarks of all immunodeficiencies

A

Recurrent infections

Inflammatory disorders

Increased risk of malignancy

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4
Q

What does the immune system provide us with?

A

Defense mechanisms to pathogens and malignant cells

Is tolerant to self and does not react to harmless substances

Elicits a controlled response that switches on and off when the pathogen has been destroyed

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5
Q

What are the three disorders of the immune response?

A

Allergy - eczema, asthma, food

Autoimmunity - lupus, type I diabetes

Immunodeficiency - primary and secondary (HIV, immune-suppressing medications)

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6
Q

Important factor about the disorders of the immune response

A

They have overlapping features

A patient commonly presents with features of all conditions

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7
Q

What causes primary immunodeficiency disorders?

A

Caused by mutations in key genes important for immune function

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8
Q

Causes of primary immunodeficiency disorders

A

Familial

Sporadic

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9
Q

How are primary immunodeficiency disorders clustered together?

A

> 320 distinct molecular causes

Clustered into main categories depending on what arm of the immune system is affected

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10
Q

Prevalence of PID

A

1 in 1200

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11
Q

Causes of secondary immunodeficiencies

A

HIV

Immunosuppressive therapy

Chemotherapy

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12
Q

Characteristics which make us suspicious of PID

A

Predisposition to infection

Family history

Poor growth in children

Variable presentation

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13
Q

Which infections are PID sufferers predisposed to?

A

Different infections depending on which part of the immune system is deficient

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14
Q

Common types infections caused by low neutrophil and B cell count

A

Bacterial infections

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15
Q

Common types infections caused by low T cell counts

A

Viral infections

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16
Q

Common types infections caused by low T cell and neutrophil count

A

Fungi

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17
Q

Important cells required for mycobacterial clearance

A

T cells

Macrophages

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18
Q

Classes of PID clustered depending on what part of the immune system is deficient

A

Humoral immune defects

T cell defects

Combined immune defects

Neutrophil defects

Other immune defects

Defined syndromes

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19
Q

Examples of humoral immune defects

A
  • XLA
  • selective IgA deficiency
  • specific antibody deficiency
  • transient hypogammaglobulinemia of infancy
  • hyper IgM syndromes
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20
Q

Which primary immune defect is most common in adults?

A

Humoral immune deficiencies

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21
Q

Hallmarks of humoral immune defects

A

Low level of immunoglobulins in the presence of normal or low B cell count

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22
Q

What mutation leads to X linked agammaglubilinemia?

A

BTK protein

Required for B cell formation and maturation

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23
Q

Level of antibody in the blood of XLA sufferers

A

No antibody production

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24
Q

What is selective IgA deficiency an example of?

A

Some immunodeficiencies which are selective to specific classes of B cell antibody

IgA deficiecy is most common

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25
Q

Presentation of selective IgA deficiency

A

Normally asymptomatic

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26
Q

Pathogenesis of specific antibody deficiency

A

Normal amount of antibodies

But the antibodies don’t work well

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27
Q

What is transient hypogammaglobulinemia of infancy?

A

Developmental delay in the production of antibodies

But the immunoglobulin count returns to normal after 2 years

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28
Q

What is hyper IgM syndrome?

A

Disease characterised by defects in class switch recombination

Resulting in low IgG and IgD with normal or high IgM

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29
Q

Examples of deficiencies caused by T cell defects

A

DiGeorge syndrome

Idiopathic T cell lymphopenia

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30
Q

What mutation underlies DiGeorge syndrome?

A

22q deletion

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31
Q

Presentation of DiGeorge syndrome

A

Cardiac problems

Intellectual disability

Thymic defects

Low or absent T cell production

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32
Q

What causes idiopathic T cell lymphopenia?

A

Can’t explain

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33
Q

What are the two main subclasses of combined immune defects?

A

Severe combined immunodeficiency

Combined T cell and antibody production

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34
Q

What is important regarding SCID?

A

Important to identify early on

Without diagonsis, the patient dies within the first weeks of life

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35
Q

Types of combined T cell and antibody production defects

A

Wiskott Aldrich Syndrome

CD40/CD40L deficiency

DOCK8 deficiency

Late onset combined immunodeficiency disorder

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36
Q

Mutation underling Wiskott Aldrich Syndrome

A

Caused by loss of function WASp protein mutation

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37
Q

Why do mutations to WASp lead to deficient antibody production?

A

Important in managing cytoskeletal composition of cells

Important in managing B and T cell interactions

= Don’t produce good antibodies

38
Q

Why does CD40/CD40L deficiencies lead to low B and T cell count?

A

CD40/CD40L interaction is important for proper class switching

Gives rise to hyper IgM syndrome

39
Q

What is different between CD40/CD40L and hyper IgM syndrome?

A

Hyper IgM syndrome affects only the antibody production

CD40/CD40L causes a combined immunodeficiency because both T and B cells are in low numbers

40
Q

Presentation of DOCK8 deficiency

A

Recurrent infections

Eczema

41
Q

Important factor regarding DOCK8 deficiencies

A

Many are genetically undefined following whole genome and exome sequencing

42
Q

What is late onset combined immunodeficiency disorder?

A

SCID-like presentation in older child or adult

No genetic cause found

43
Q

What causes neutrophil defects?

A

Increased breakdown of neutrophils in the periphery

Lack of formation of neutrophils

44
Q

Types of neutrophil defects

A

Autoimmune neutropenia

Severe congenital neutropenia

Chronic granulomatous disease

Leukocyte adhesion defect

45
Q

Example of a defined syndrome

A

Chediak-higashi syndrome

46
Q

What causes Chediak-higashi syndrome?

A

Defects in monocytes and dendritic cells

47
Q

Unique presentation of Chediak-higashi syndrome sufferers

A

Occulocutaneous albinism

Caused by abnormalities in neutrophil and melanin granules

48
Q

What other immune defects exist?

A

Complement defects - gives rise to a range of presentations from autoimmune disease to predisposition to infection

IRAK-4 deficiencies

Rare defects to monocytes and dendritic cells

49
Q

What tests can be due to measure immune function?

A

Cell number

Cell function

More complex tests

50
Q

How can we assess T cell number?

A

Flow cytometry allows us to see if cells are present and how high their count is

51
Q

How can we assess B cell number?

A

Measuring the IgG/IgA/IgM/IgE count

52
Q

How can we assess T cell function?

A

CFSe dye becomes incorporated into the T cells

Stimulation with agonist should lead to increased proliferation

Gradually the dye becomes less concentrated

Used to assess T cell proliferation

53
Q

What more complex tests can be done to assess lymphocyte number?

A

T cells - check if you have both naive and memory T cells, check if T cells are polyclonal

B cells - look at post-vaccine responses to check for dynamic function of B cells

54
Q

What extended tests can be carried out if the basic tests show abnormal results?

A

Can measure protein expression

Carry out functional studies

Look at genetics to identify SNPs that explain the phenotype

55
Q

Example of protein expression used to diagnose a immunodeficiency

A

Wiskott Aldrich syndrome is caused by a lack of WASp production

Western blotting results show absent WASp protein

56
Q

Example of a functional study used to diagnose a immunodeficiency

A

STAT1 phosphorylation tests

Some conditions are caused by the overstimulation of the immune system

Check for overstimulation using STAT1

57
Q

Which cell marker is low in XLA?

A

CD19

Due to low B cell production

58
Q

Which condition is caused by the same pathway as SCID?

A

CVID

Characterised by low but detectable B cell count

Marked decrease in IgG and at least one of the isotypes IgM or IgA

Poor vaccine response

59
Q

What is significant about lymphocyte studies of SCID sufferers?

A

Low T cell production

No thymic shadow on X-ray

If just B cell count low = XLA

60
Q

Why can a lot of mutations lead to a SCID-like phenotype?

A

Because a lot of genes are required for normal T cell function

61
Q

Which mutations lead to defective T cells?

A

Cytokine signalling

Antigen presentation

VDJ recombination

T cell receptor signalling

Basic cellular functions

Lymphocyte survival

62
Q

Describe how the concept of newborn screening can be applied to SCID sufferers

A

SCID is very severe, so it is a priority to identify the condition early in life

Identification before 3 months of age improves survival

Allows the patients to undergo a bone marrow transplant

63
Q

What test is specific for the identifiication of immunodeficiencies?

A

TREC

CREBS

64
Q

Describe the technology behind TREC

A

Relies on the fact that a circular protein structure is excluded during VDJ recombination

If this is low = linked to SCID due to low T cell count

65
Q

Describe the pathogenesis behind CGD

A

Neutrophils use a transmembrane enzyme called NAPDH oxidase to oxidise NADH and make superoxide ions

Superoxide is used downstream to make bleach using myeloperoxidase

CGD arises due to mutations in the transmembrane enzyme

This leads to abnormal respiratory burst formation

66
Q

Subunits of the NADPH enzyme

A

p22

p40

p47

p67

gp91

67
Q

Which subunit in the NADPH oxidase is the most commonly mutated in CGD?

A

gp91

68
Q

Inheritance of CGD mutations

A

Normally recessive

69
Q

Why are gp91 mutations the most common causes of CGD?

A

It is X-linked

The others are recessive

70
Q

Three ways to assess neutrophil function

A

DHR

NBT

Gene expression

71
Q

Explain how a DHR assays are carried out to look for neutrophil function

A

Stain neutrophils with DHR

This becomes fluorescent following the respiratory burst

Change in fluorescence is detected through peak distribution changes

In patients with CGD, there is no change in the peak distributions since the neutrophils cannot undertake normal respiratory burst

72
Q

Explain how NBT assays are carried out to look at neutrophil function

A

Deposition of blue dye to neutrophils following respiratory burst

Does not happen in CGD

73
Q

Explain how gene expression tests are carried out to test for CGD

A

Expression of CPG9fox

No expression in CGD

74
Q

What causes secondary immunodeficiencies?

A

Either not enough immune cells are produced or an external factor is blocking their function

75
Q

Causes of secondary immune deficiencies

A

Malnutrition

Loss of immune components

Other systemic diseases

Tumour and malignancies

Immunosuppressive therapies

Infectious disease

76
Q

How can immune components be lost leading to secondary immune deficiencies?

A

Lost passively in the intestine

Proteins lost in the urine

77
Q

What systemic disease is linked to immune deficiency?

A

Diabetes

78
Q

How can cancers lead to immune deficiency?

A

Cytotoxic therapies cause immune suppression

79
Q

Describe the complicated nature of immunosuppressive therapy

A

They are commonly used for inflammatory conditions

But their use can also lead to secondary immune deficiencies

  • steroids
  • steroid-sparring agents
  • biologic agents (monoclonal antibodies)
80
Q

Which infectious diseases lead to immunodeficiency?

A

HIV

Malaria

81
Q

Therapies for PID patients

A

Prevention and treatment of infections

Replacement of immunoglobulins

Screening for complications

Immunosuppression for inflammatory complications

Targeted therapies

Transplantation

Gene therapy

82
Q

Examples of targeted therapies used for PID sufferers

A

Monoclonal antibodies to switch on and off pathways

83
Q

How can human stem cell therapy be used for PID treatment?

A

Potentially curative treatment option for severe forms of PID

Involves the restoration of immune cell number and function from HLA-matched healthy stem cell donors

84
Q

Describe the process of stem cell transplant for PID sufferers

A
  1. Collect and process stem cells
  2. Patient undergoes chemotherapy and radiotherapy to get rid of faulty immune cells
  3. Donor cells enter the bone marrow and regenerate the immune system
85
Q

What are the risks of stem cell therapy?

A

Immunosuppression causes risks like infection

86
Q

Which forms of PID can gene therapy be a potential therapy for?

A

ADA

Wisckott Aldrich syndrome

CGD

All caused by faulty proteins

87
Q

What are the advantages of gene therapy?

A

Option is the patient is not suited for a bone marrow transplant

Avoids graft vs host disease

88
Q

Describe the process behind gene therapy to restore function in the immune system

A

Insert a virus containing DNA coding for the functional protein into the host cell

Implant the host cell into the recipient

The recipient will now start producing the faulty protein

89
Q

What is the goal of stem cell therapy?

A

Replace the whole immune system

90
Q

What is the goal of gene therapy?

A

Replace the malfunctional protein

IMM005 (17 decks)

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