Immunology Flashcards
1
Q
Is neutrophil half life in the blood short or long?
A
Short, 7 hours
2
Q
Liver abscess is commonly associated with which primary immunodeficiency disorder?
A
Chronic granulomatous disease
3
Q
What is Kostmann syndrome?
A
Congenital neutropenia, promyelocytes can’t mature. HAX1 gene mutation. Aut rec
4
Q
Which disorder has poor neutrophil + macrophage function due to deficient NADPH oxidase?
A
Chronic granulomatous disease
5
Q
NADPH oxidase deficiency leads to inability to convert oxygen to superoxide. What is the next step in the ‘respiratory burst’?
A
Production of hydrogen peroxide from superoxide, using superoxide dismutase
6
Q
Which organisms contain the enzyme to break-down hydrogen peroxide, hence rendering them protected in CGD?
A
Catalase positive organisms (Staph aureus, Aspergillus) - body can’t kill them, so surrounds them and forms granulomas
7
Q
Gold standard test for CGD diagnosis?
A
Dihydrorhodamine 123 - turns fluorescent green
8
Q
In CGD, are T+B cells normal?
A
Yes
9
Q
In CGD, are Ig normal, high or low?
A
Often high due to chronic inflammation/infections
10
Q
Which prophylaxis is recommended for neutrophil disorders?
A
Bactrim (broad gram negative + Staph prophylaxis)
Itraconazole (good Aspergillus prophylaxis)
11
Q
3 cardinal features of Leucocyte Adhesion Deficiency?
A
Acronym LAD:
Late separation umbi
Absent pus/nil abscesses/poor wound healing
Dysfunctional neutrophils - can’t move to where they are required (absent CD18 on leucocytes which is required for adhesion/integrin; and high neutrophils in blood as can’t move to tissues)
12
Q
Explain the Complement classical pathway
A
- C1 -> antibody-antigen complex or CRP -> C4 -> C2
C4 -> C3 -> common pathway (MAC: C5-9)
13
Q
Explain the Complement lectin pathway
A
- C4 mannose-binding lectin (ie binding of this protein to pathogen carbohydrate) -> 2
- C4 -> 3 -> common pathway
14
Q
Explain the Complement alternative pathway
A
- constant low-grade activity (ie ready to escalate if needed)
- C3 from classical pathway or from touching microbial surface can cleave -> C3b -> C5-9
C3b -> C3 can re-stimulate to amplify response
Protein B/D and Properdin required for alternative pathway
15
Q
Deficient C1 esterase inhibitor can lead to what condition?
A
Hereditary angioedema
16
Q
What is the management of hereditary angioedema?
A
Danazol (androgen) which increases C1 esterase inhibitor levels
17
Q
Recurrent Neisseria is associated with which part of the Complement system?
A
- MAC: C5-9
- Properdin deficiency
18
Q
Which virus is most associated with agammaglobulinaemia?
A
Enterovirus
19
Q
What is the common cause of diarrhoea in antibody disorders?
A
Giardia
20
Q
What are the key organisms associated with antibody disorders?
A
Encapsulated: Strep pneumo, HiB Staph aureus, Pseudomonas Enterovirus Giardia Polio risk from live vaccine
21
Q
Is lymphoid tissue ie tonsils present in agammaglobulinaemia?
A
No
22
Q
At what stage are B cells arrested in x-linked agammaglobulinaemia?
A
Pre-B -> thus unable to form antibodies as aren’t mature plasma cells
23
Q
What is the enzyme implicated in x-linked agammaglobulinaemia?
A
Btk (tyrosine kinase) on Xq22
24
Q
CVID is due to partial impairment of T cell development and function leading to risk of infection + autoimmunity. Is lymphoid tissue ie tonsils present?
A
Yes: normal or enlarged Commonly associated with splenomegaly - B cells: N or low - T cells: variable number - Low Ig
25
CVID is associated with increased occurrance of which cancer?
EBV associated lymphoma
26
IgA is found in which parts of the body? Is IgA higher in tissues or blood?
Mucosa: resp, GIT
| Higher in tissues (MALT), low in blood
27
What 2 main signals stimulate B cells to produce IgA?
Il-5
| TGF-beta
28
In IgA deficiency, which Ig is commonly elevated as B cells try to compensate for reduced IgA?
IgE = allergy risk
29
How common is IgA deficiency?
1/500
| Most common PID
30
Which PID is associated with risk of severe reactions to blood products?
IgA deficiency
31
Poor response to polysaccharide vaccines is the best marker for which antibody condition?
IgG subclass deficiency
32
In the bone marrow, which Ig do B cells have on their surface?
IgD and IgM
33
How many receptors does each B cell have, which are capable of binding to the same antigen?
100,000
34
Which ligand do CD4 T cells express when they bind to B-cell+MCHclass2/antigen complex?
CD40 ligand - which attached to CD40 receptor on B cell
35
Class switching changes what part of the Ig?
Heavy chain determines Ig class
36
Ectodermal dysplasia (abnormal teeth, skin, nails, hair, reduced sweating) is associated with which primary immunodeficiency?
Hyper IgM syndrome
37
What is the inheritance of hyper IgE syndrome?
Autosomal dominant, STAT3 defect
38
Hyper IgE syndrome has elevated IgE with normal IgA, IgG and IgM. Which cell is commonly elevated in hyper IgE syndrome?
Eosinophils
39
Hyper IgE syndrome is associated with which 3 key features?
Staph: abscess/pneumatocoele
Rash, 'eczema'
Reduced vaccine/cell mediated response
40
Fractures and failure to shed primary teeth is associated with which immunodeficiency?
Hyper IgE syndrome
41
Which class of PID are associated with fatal reaction with live vaccines and high risk of maternal engraftment of T cells?
T cell defects / SCID
42
How is SCID detected on NST?
Reduced T cell receptor excision circles (maker of thymopoiesis)
43
25% of SCID is x-linked. Mutation for IL2RG gene that codes for common gamma chain receptor is found on which chromosome?
Xq13.1
44
Common gamma chain receptor in SCID affects which interleukin receptors?
IL2, 4, 7, 9, 15, 21
45
Which Igs trigger Classical pathway?
| Which Ig triggers Alternative pathway?
1. IgM & IgG
| 2. IgG
46
Which immune cells produce the most cytokines?
CD4 helper T cells
47
Th1 cells are important for which pathogens?
Intracellular
48
Th2 cells are important for which pathogens + which other conditions?
Extracellular
| Atopy
49
Which cytokines promote Th1 + Th2 cell production?
Il-12 -> Th1
| Il-4 -> Th2
50
Th1 cells produce which cytokine? & what does it do?
Interferon gamma
| Important for B cells to make IgG for opsonisation and activates macrophages
51
Th2 cells produce which cytokines? & what do they do?
Il-4, 5, 13 = important for IgE + eosinophils
| Il-10 = antiinflammatory
52
What is class switch recombination?
Antibody process of changing mu heavy change to change Ig class
53
What is the most common cause of hyper IgM syndrome?
X linked inherited defect of CD40 ligand gene (TNFSF5 gene) - this is expressed on activated CD4+ T cells and is required to interact with CD40 on B cells to enable class-switch recombination
= combined immunodeficiency
--> from infancy
--> sinopulmonary infections, esp encapsulated
--> opportunistic infections, PJP occurs in 40% and may be first feature
--> diarrhoea/cryptosporidium common
--> higher risk for malignancy/autoimmune/cytopenia
Normal number of B cells, but reduced CD27+ (memory) and no IgD+CD27+ (switched memory) cells
Normal/high IgM
Low IgG/IgA/IgE
Poor response to protein + polysaccharide vaccines
2/3rds neutropenic
Second most common cause: AID and UNG enzyme deficiencies, involved in class-switch recombination
= humeral immunodeficiency
--> recurrent sinopulmonary infections -> bronchiectasis risk
--> & lymphoid hyperplasia
Commonly presents age 2
54
Neutrophil disorders - number or function. Number issues?
1. Severe congenital neutropenia / Kostmann syndrome (HAX1 mutation)
2. Cyclical neutropenia (ELANE mutation) : normal between drops
3. X-linked neutropenia (Wiskott-Aldrich Gene mutation) : persistent
55
2 year old boy
Term
PHx staph aureus cervical lymphadenitis at 7 months of age
Presented with skin abscess: + for Serratia Marcessens (unusual pathogen)
Brother and father have recurrent abscesses
Chronic granulomatous disease
```
1:250,000
Defect in NADPH oxidase enzyme complex
Needed for neutrophils to make ROS - needed for pathogen killing
Most X-linked, gp91phox mutations
Infections: bacterial, fungal
- Catalase positive organisms; Staph aureus, Aspergillus (bilat pneumonia), Nocardia, Burkholderia
- adenitis
- abscess esp LIVER abscesses
Inflammatory (IBD) / Granulomas
```
Mx: bactrim, itraconazole; aggressively mx infections; HSCT
56
9 year old girl
Recurrent otitis media from age 2
Recurrent staph skin infections, multiple courses of antibiotics
Presents now with pneumonia
Autosomal recessive CGD
| - some residual NADPH oxidase function: better prognosis
57
11 month old male
Hx delayed umbilical cord separation (up to 3 weeks can be normal)
Large ulcerated skin lesion in nappy area, minimal pus at site of ulcer, WCC 48
```
Leucocyte adhesion deficiency
Aut recessive
Peripheral leucocytosis + neutrophilia
Recurrent bacterial infections
Absent pus, poor wound healing
Delayed cord separation, omphalitis
Gingivitis
```
LAD1
- most common
- beta2 integrin gene mutation (CD18)
LAD2
- CD15 mutation
LAD3
- mutation in KINDLIN3 required for beta1, 2 and 3 integrins
- bleeding tendancy
Mx: aggressively treatment infections; HSCT for LAD1 and 3; IL23 & IL12 blocker ustekinumab
58
Poor wound healing
| Periodontitis
Disorders of chemotaxis
59
Clues to neutrophil disorder
Neutropenia or neutrophilia
| Aspergillus or Burkolderia
60
What are toll like receptors?
Part of innate immune system
Expressed by antigen presenting cells
Type 1 transmembrane receptors
Recognise molecular structures of bacteria/viruses/fungi/parasites
&
Intracellularly cause signals ie MyD88 & IRAK4
to up-regulate immune response to that pathogen
Important in early life when adaptive immunity not so good yet
61
IRAK4 / MyD88 deficiency
Toll like receptors unable to initiate innate immune response as these are important signalling molecules downstream from toll like receptors
Aut recessive
Recurrent bacterial infections - strep pneumo, staph aureus
Poor inflammatory response: minimal fever, minimal CRP rise
Young children
Ix: CD62L shedding
Mx: immunisation, prophylactic antibiotics
62
Anhidrotic ectodermal dysplasia
Defect in:
NEMO (x linked) gene -- end pathway of toll like receptors
or
IKBA (aut dominant) gain of function
Viral & bacterial (pneumococcus) & fungal (candida) & atypical mycobacteria
Sparse hair, sparse conical teeth (pointy), can't sweat
63
Candida immune response
Dectin-1, CLR receptors
- > Th17 cell (STAT 3) -> Th1 helps (STAT 1)
- -> IL23, IL17
64
Recurrent/persistent candida (skin, mucous membranes, nails)
+
Endocrinopathy / Autoimmune / Immunodeficiency
Chronic mucocutaneous candidiasis
-- CARD9 deficiency = candida meningitis
65
STAT 1 role?
Important intracellular protein
Important for VIRAL immune response
Up-regulate interferon-gamma responses
STAT 1 loss of function = overwhelming viral infection
Partial loss of STAT 1 = mycobacterial infection risk
Ix: STAT 1 phosphorylation
STAT 2 loss of function = severe viral infection, MMR vaccine related measles infection
66
Susceptibility to human papilloma virus?
```
WHIM:
warts
hypogammaglobulinaemia
immunodeficiency
myelokathexis/neutropenia (can't move neutrophils from bone marrow due to lack of chemokine receptor: CXCL4)
```
EXER:
warts only
67
Susceptibility to mycobacterial disease?
IL12, IL18, IL23
Interferon gamma
STAT 1 partial loss of function
68
2 clues to innate immune defects:
Lack of fever/CRP response
Severe/recurrent disease with INDIVIDUAL pathogen eg HSV/HPV/candida
69
```
Major part of innate immunity
60 plasma and membrane/cell surface proteins
3 activating pathways
End in common lytic terminal cascade
Potant regulators
```
Complement system
70
3 roles of complement:
1. Opsonisation
& aid phagocytosis:
C3b or C4b binds to microbe
2. Recruit + activate leucocytes: by C3a, C5a
3. Osmotic lysis of microbe by membrane attack complex: C3b bound to microbe activates MAC
71
3 ways to activate pathway
1. Classical: Ag-Ab
C1q (REGULATOR: C1 esterase inhibitor), C4, C2
2. Lectin: lectin binding to mannose
C4, C2
3. Alternative: pathogen or apoptosis
C3b, factor B, factor D, p (factor H and I are REGULATORS)
--> C3 (C3 convertase) -> C3a (inflammation), C3b (opsonisation)
(REGULATORS: CR1, CD46, DAF)
--> C5 (C5 convertase) -> C5a (inflammation), C5b (initiates MAC)
(REGULATOR: CD59)
--> MAC: C5b, C6, C7, C8, C9
72
Low C4?
Consider Classical pathway problem
73
Low C3, normal C4?
Consider Alternative pathway problem
74
Deficient in C1, C2 or C4 (classical pathway) predisposes to?
Autoimmune disease
| Especially SLE - development of autoantibodies to nuclear proteins
75
Deficiency of C1 esterase inhibitor leads to?
Hereditary angioedema
-- autosomal dominant
Classical pathway uncontrollably activated --> Increased activation of Factor X11 and bradykinins = increased vascular permeability + angioedema
- - cutaneous
- - airway
- - GIT: abdo pain + vomiting
NO URTICARIA as it is not mast cell driven (the swelling is NOT itchy in hereditary angioedema)
- may have rash called erythema marginatum
Ix: C1 inhibitor defect = reduced C1 esterase inhibitor function assay & level (may have normal level but poor function!)
Attacks can be triggered by illness, trauma or spontaneous
Mx of attacks: Tranexamic acid, Danazol, C1 esterase inhibitor replacement
76
Deficiency of Alternative pathway / propordin / factor B: predisposes to?
Encapsulated organism infection esp Strep and Neisseria
77
Factor H and I deficiency leads to:
Uncontrolled activation of Alternative pathway --> Atypical haemolytic uraemic syndrome
78
Normal CH50, low AP50
Alternative pathway defect
79
Low CH50, normal AP50
Pre-C3 classical pathway defect
80
Low CH50 + AP50
MAC defect
= recurrent meningococcal, disseminated gonococcal infections
OR
C3 deficiency = abscess, OM, pneumoniae, bacteraemia
81
Normal CH50 + AP50
Properdin defect = recurrent meningococcal infection
82
Clues to complement defect:
Recurrent meningococcal / Hib / pneumococcal
Angioedema without urticaria/itch
83
Intrinsic T cell defect, CD40 ligand issue
Normal number of B cells
Low Igs
Presents:
- Early in life
- Opportunistic infections esp PCP pneumonia and cryptosporidium diarrhoea
Hyper IgM
84
Difficulty progressing from B cell to plasma cell
Low IgG, low IgA
Normal or low IgM
Nil B memory cells; poor antibody response
No T cell problem
Diagnose after age 4
High risk of autoimmunity / cytopenias
CVID
85
Medications which can cause hypogammaglobulinaemia
Steroid
Captopril
Carbamazepine, phenytoin
Anti-malarials
86
Vaccine requiring: T dependent antibody response (ie protein)
IgG, IgA, IgE
Tetanus
| Diptheria
87
Vaccine requiring: T independent antibody response (ie polysaccharide)
IgM, shorter lived
Pneumovax 23 (conjugate)
88
Minimal fever
Minimal CRP
Age 1, pneumococcal meningitis
Consanguineous parents
```
Toll-like receptor defect
Autosomal recessive:
IRAK4
Myd88
Impaired proinflam cytokine production: IL1, IL6 (responsible for CRP: from Hep3B cells)
IL1, IL6, TNF important for fever
```
89
Ectodermal dysplasia
NEMO
90
Absence of normal downregulation of macrophages, NK cells, CD8 cells -> cytokine storm: secrete ++ cytokines (IL2 = CD25, 6, 10, 12) & interferon gamma, TNF alpha, & phagocytose host cells (red cells / platelets / white cells). NK/CD8 cells unable to get rid of the excess activated macrophages.
Can be triggered by infection (most commonly EBV) or sporadic
MAS is a form of this condition, which is associated with juvenile idiopathic arthritis
Fever, organ involvement ie hepatitis/abnormal coags, neuro involvement, splenomegaly
Ix: CYTOPENIA, high trigs, high ferritin (macrophages are a primary source of ferritin), low fibrinogen, high CD25 (alpha chain of IL2 soluble) - related to disease activity, low NK activity (flow cytometry for surface expression of CD107alpha, also called LAMP-1 [lysosomal-associated membrane protein 1])
HLH
91
2 weeks post strep pharyngitis
Carditis, arthritis
Less commonly: migrating rash, subcut nodules, chorea
Presumed pathogenesis?
Molecular mimicry with bacterial antigen
| - mimics with myosin
