Immunodeficiency Flashcards
(80 cards)
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
2
Q
What is immunodeficiency?
A
Clinical situations where the immune system is not effective enough to protect the body against infection
3
Q
What are the 2 types of immunodeficiency?
A
Primary and secondary
4
Q
What does 1ary immunodeficiency involve?
A
Inherent defect within the immune system –> usually genetic
5
Q
What does 2ary immunodeficiency involve?
A
Immune system affected due to external causes
6
Q
What are 5 examples of 2ary causes of immunodeficiency?
A
- Breakdown in physical barriers
- Protein loss
- Malignancy
- Drugs
- Infection
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
8
Q
What can cause protein loss and then immunodeficiency?
A
Burns, protein losing enteropathy, malnutrition
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
10
Q
How can protein losing enteropathy lead to immunodeficiency?
A
Lose antibodies (type of protein)
11
Q
What malignancies can cause immunodeficiency?
A
Lymphoproliferative disease, myeloma
12
Q
Which drugs can lead to immunodeficiency?
A
Steroids, DMARDS, Rituximab, anti-convultants, myelosuppressive
13
Q
Why can steroids, DMARDS and Rituximab lead to immunodeficiency?
A
Suppress the immune system (for treatment in conditions such as rheumatoid arthritis)
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
15
Q
What infections can lead to immunodeficiency?
A
HIV, TB
16
Q
What can phagocytes be classified into?
A
Phagocytes are classified into neutrophils and monocytes.
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.
18
Q
What are pattern recognition receptors (PRRs)?
A
Phagocytes PRRs which recognise and bind to pathogen-associated molecular patterns (PAMPs).
19
Q
What are PAMPS?
A
PAMPs are components of pathogens and can include molecules like peptidoglycan and lipopolysaccharide (LPS).
20
Q
What are 2 examples of PAMPs?
A
peptidoglycan and lipopolysaccharide (LPS).
21
Q
How do phagoctes use PRRs?
A
To detect pathogens
22
Q
What is the main type of PRR?
A
Toll-like receptor (TLR)
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
24
Q
Where is LPS found?
A
Gram-negative bacteria
25
Where is flagellin found?
Bacteria
26
What can defects in TLR3 lead to?
Recurrent HSV encephalitis
27
What type of immunodeficiency is recurrent HSV encephalitis?
1ary
28
Where are PRRs found? What do they bind?
Pattern Recognition Receptors (PRRs) are receptors located on immune cells such as macrophages and dendritic cells. They bind to Pathogen Associated Molecular Patterns (PAMPs).
29
What are PAMPs?
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.
30
Once the PRR has bound a PAMP, what happens?
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)
31
What is Myd88 and IRAK-4?
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
32
What is IRAK4 deficiency?
IRAK-4 deficiency is an inherited disorder of the immune system (primary immunodeficiency).
33
Clinical presentation of IRAK4 deficiency?
* Recurrent bacterial infections by pyogenic bacteria
* Especially streptococcus and staphylococcus
* Pneumonia, meningitis, arthritis
* Poor inflammatory response
* Susceptibility to infection decreases with age
34
What is treatment for IRAK4 deficiency?
prophylactic antibiotics, iv immunoglobulin if severe
35
What is myd88 deficiency? How does it present?
MyD88 deficiency is an inherited disorder of the immune system (primary immunodeficiency). Presents similar to IRAK4
36
How is a phagolysosome formed?
After attachment, the phagocyte internalises the microbe into a phagosome. The phagosome then fuses with a lysosome to form a phagolysosome.
37
What is the NADPH complex? Where is it found?
* 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
gp91phox is one of the proteins forming the NADPH complex. What is this coded by?
X chromosome
39
Explain pathway of NADPH complex
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
What is chronic granulatomous disease?
Chronic granulomatous disease (CGD) is a rare inherited primary immune deficiency disorder that affects certain white blood cells.
41
How is CGD caused?
* 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
What is a granuloma?
A granuloma is a small area of inflammation - a collection of macrophages
43
Who does CGD typically affect? Why?
gp91phox is encoded by the X chromosome --\> typically affects males and females are normally carriers
Do a family history!
44
Typical presentation of CGD?
* Recurrent abscesses: lung, liver, bone, skin, gut
45
What are infections in patients with CGD are typically from?
Staphylococcus, Klebsiella, Serretia, Aspergillus, Fungi
46
Treatment for CGD?
haemopoeitic stem cell transplant, antibiotics
47
What test is needed to diagnose CGD?
* 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
What is the most useful test in determining if a patient has chronic granuomatous disease?
Neutrophil Function Test
49
What is complement? What is its role in the immune system?
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
Complement pathway revision
51
What do all 3 complement pathways result in?
Formation of Membrane Attack Complex (MAC) which kills pathogen
52
How does MAC kill pathogens?
The membrane attack complex (MAC) punches a hole through the plasma membrane of the target cell, killing the pathogen
53
What activates the **classical** complement cascade?
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
With a C2, C4 deficiency, what are patients predisposed to?
SLE, infections, myositis
55
Why are those with C2, C4 deficiency prone to SLE?
Thought to be due in part to the inability of complement to clear immune complexes and dying cells.
56
What can a C5-C9 deficiency lead to? How do patients present?
* A genetic condition affecting the complement membrane attack complex (MAC)
* Presents with repeated episodes of BACTERIAL meningitis
* Particularly **Neisseria meningitis**
57
Sequence of events after an antigen binds to a B cells via the **MHC II** complex.
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
How does the binding of antibodies to antigens inactivate antigens? 4 ways
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
What is X linked agammaglobulinaemia (XLA)?
X-linked agammaglobulinemia (XLA) is a condition that affects the immune system --\> very few B cells
60
Why is XLA seen almost exclusively in males?
Is X-linked
61
What defect leads to XLA?
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
What is BTK?
A tyrosine kinase that is encoded by the BTK gene in humans. BTK plays a crucial role in B cell development.
63
Where is the BTK gene found?
On the X chromosome
64
Other B cell defects diseases:
* CVID
* IgA deficiency
* X linked hyper IgM syndrome
* Transient hypogammaglobulinaemia of infancy
65
What does a defect in B cells lead to?
* Loss of antibody secretion.
* Usually leads to **recurrent bacterial infection** with pyogenic organisms.
* Most are very serious
66
How are B cell defects treated?
Treat with antibiotics then i.v IgG for life.
67
What is IgA deficiency?
* 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
**_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, ow IgG and IgA
Possible diagnosis?
Secondary antibody deficiency due to drugs used to suppress immune system in RA --\> common, you will see this!
69
What does Rituximab target?
Rituximab targets CD20, a transmembrane protein present on virtually all B cells
70
What is methotrexate?
An immunosuppressant used to treat inflammatory conditions, including rheumatoid arthritis.
71
Which antibody is the body's main defense against bacterial infection?
IgG antibodies are the body's main defense against bacterial infection. IgG treatment replaces these antibodies.
72
Why may the offspring of consanguineous parents be at increased risk to genetic disorders?
because of the expression of autosomal recessive gene mutations inherited from a common ancestor
73
In immunodeficiency disorders, why can children show normal levels of IgG?
As IgG can cross the placenta
74
What is severe combined immunodeficiency?
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
Why are defects in T cells usually more severe than B cells?
Since B cells also need T cell help - even if there are B cells, they don’t function
76
What are symptoms of T cell defects?
* Symptoms are recurrent infection with opportunistic infections, bacteria, viruses,
* Fungi (candida), protozoa (pneumocystis).
77
What family history increases risk of SCID?
Consanguinous parents
78
Treatment for SCID?
Paediatric emergency
* Antibiotics, antivirals, antifungals
* Asepsis needs to be maintained (sterile environment)
* Haemopoietic stem cell transplant is the only cure
79
Causes of SCID?
* 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
Summary
