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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
Presentation of selective IgA deficiency
Normally asymptomatic
26
Pathogenesis of specific antibody deficiency
Normal amount of antibodies But the antibodies don't work well
27
What is transient hypogammaglobulinemia of infancy?
Developmental delay in the production of antibodies But the immunoglobulin count returns to normal after 2 years
28
What is hyper IgM syndrome?
Disease characterised by defects in class switch recombination Resulting in low IgG and IgD with normal or high IgM
29
Examples of deficiencies caused by T cell defects
DiGeorge syndrome Idiopathic T cell lymphopenia
30
What mutation underlies DiGeorge syndrome?
22q deletion
31
Presentation of DiGeorge syndrome
Cardiac problems Intellectual disability Thymic defects Low or absent T cell production
32
What causes idiopathic T cell lymphopenia?
Can't explain
33
What are the two main subclasses of combined immune defects?
Severe combined immunodeficiency Combined T cell and antibody production
34
What is important regarding SCID?
Important to identify early on Without diagonsis, the patient dies within the first weeks of life
35
Types of combined T cell and antibody production defects
Wiskott Aldrich Syndrome CD40/CD40L deficiency DOCK8 deficiency Late onset combined immunodeficiency disorder
36
Mutation underling Wiskott Aldrich Syndrome
Caused by loss of function WASp protein mutation
37
Why do mutations to WASp lead to deficient antibody production?
Important in managing cytoskeletal composition of cells Important in managing B and T cell interactions = Don't produce good antibodies
38
Why does CD40/CD40L deficiencies lead to low B and T cell count?
CD40/CD40L interaction is important for proper class switching Gives rise to hyper IgM syndrome
39
What is different between CD40/CD40L and hyper IgM syndrome?
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
Presentation of DOCK8 deficiency
Recurrent infections Eczema
41
Important factor regarding DOCK8 deficiencies
Many are genetically undefined following whole genome and exome sequencing
42
What is late onset combined immunodeficiency disorder?
SCID-like presentation in older child or adult No genetic cause found
43
What causes neutrophil defects?
Increased breakdown of neutrophils in the periphery Lack of formation of neutrophils
44
Types of neutrophil defects
Autoimmune neutropenia Severe congenital neutropenia Chronic granulomatous disease Leukocyte adhesion defect
45
Example of a defined syndrome
Chediak-higashi syndrome
46
What causes Chediak-higashi syndrome?
Defects in monocytes and dendritic cells
47
Unique presentation of Chediak-higashi syndrome sufferers
Occulocutaneous albinism Caused by abnormalities in neutrophil and melanin granules
48
What other immune defects exist?
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
What tests can be due to measure immune function?
Cell number Cell function More complex tests
50
How can we assess T cell number?
Flow cytometry allows us to see if cells are present and how high their count is
51
How can we assess B cell number?
Measuring the IgG/IgA/IgM/IgE count
52
How can we assess T cell function?
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
What more complex tests can be done to assess lymphocyte number?
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
What extended tests can be carried out if the basic tests show abnormal results?
Can measure protein expression Carry out functional studies Look at genetics to identify SNPs that explain the phenotype
55
Example of protein expression used to diagnose a immunodeficiency
Wiskott Aldrich syndrome is caused by a lack of WASp production Western blotting results show absent WASp protein
56
Example of a functional study used to diagnose a immunodeficiency
STAT1 phosphorylation tests Some conditions are caused by the overstimulation of the immune system Check for overstimulation using STAT1
57
Which cell marker is low in XLA?
CD19 Due to low B cell production
58
Which condition is caused by the same pathway as SCID?
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
What is significant about lymphocyte studies of SCID sufferers?
Low T cell production No thymic shadow on X-ray If just B cell count low = XLA
60
Why can a lot of mutations lead to a SCID-like phenotype?
Because a lot of genes are required for normal T cell function
61
Which mutations lead to defective T cells?
Cytokine signalling Antigen presentation VDJ recombination T cell receptor signalling Basic cellular functions Lymphocyte survival
62
Describe how the concept of newborn screening can be applied to SCID sufferers
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
What test is specific for the identifiication of immunodeficiencies?
TREC CREBS
64
Describe the technology behind TREC
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
Describe the pathogenesis behind CGD
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
Subunits of the NADPH enzyme
p22 p40 p47 p67 gp91
67
Which subunit in the NADPH oxidase is the most commonly mutated in CGD?
gp91
68
Inheritance of CGD mutations
Normally recessive
69
Why are gp91 mutations the most common causes of CGD?
It is X-linked The others are recessive
70
Three ways to assess neutrophil function
DHR NBT Gene expression
71
Explain how a DHR assays are carried out to look for neutrophil function
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
Explain how NBT assays are carried out to look at neutrophil function
Deposition of blue dye to neutrophils following respiratory burst Does not happen in CGD
73
Explain how gene expression tests are carried out to test for CGD
Expression of CPG9fox No expression in CGD
74
What causes secondary immunodeficiencies?
Either not enough immune cells are produced or an external factor is blocking their function
75
Causes of secondary immune deficiencies
Malnutrition Loss of immune components Other systemic diseases Tumour and malignancies Immunosuppressive therapies Infectious disease
76
How can immune components be lost leading to secondary immune deficiencies?
Lost passively in the intestine Proteins lost in the urine
77
What systemic disease is linked to immune deficiency?
Diabetes
78
How can cancers lead to immune deficiency?
Cytotoxic therapies cause immune suppression
79
Describe the complicated nature of immunosuppressive therapy
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
Which infectious diseases lead to immunodeficiency?
HIV Malaria
81
Therapies for PID patients
Prevention and treatment of infections Replacement of immunoglobulins Screening for complications Immunosuppression for inflammatory complications Targeted therapies Transplantation Gene therapy
82
Examples of targeted therapies used for PID sufferers
Monoclonal antibodies to switch on and off pathways
83
How can human stem cell therapy be used for PID treatment?
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
Describe the process of stem cell transplant for PID sufferers
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
What are the risks of stem cell therapy?
Immunosuppression causes risks like infection
86
Which forms of PID can gene therapy be a potential therapy for?
ADA Wisckott Aldrich syndrome CGD All caused by faulty proteins
87
What are the advantages of gene therapy?
Option is the patient is not suited for a bone marrow transplant Avoids graft vs host disease
88
Describe the process behind gene therapy to restore function in the immune system
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
What is the goal of stem cell therapy?
Replace the whole immune system
90
What is the goal of gene therapy?
Replace the malfunctional protein

IMM005 (17 decks)

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