Clincal applications of immunology Flashcards
1
Q
What is a challenge in performing viral diagnostics in immunocompromised individuals?
A
Virology usually uses serology to detect IgM/IgG antibodies to indicate presence of viral infection -> not present in immunocompromised indviduals
2
Q
What are alternatives for serology for the detection of viral infections in immunocompromised individuals? (4)
A
- Viral culture
- DNA/RNA PCR
- Viral antigen detection
- T-cell responses (difficult to measure in diagnostic setting)
3
Q
Which cells are infected by parvovirus B19?
A
Reticulocytes
4
Q
What is the effect of reticulocyte infection by parvovirus B19?
A
Anaemia
5
Q
Describe the pattern of viral load of a parvirus B19 infection in healthy individuals
A
Rapid rise of viral load with a high peak, rapid decline upon start of antibody response
6
Q
What are the symptoms of the first stage of parvovirus B19 infection? (4)
A
- Fever
- Chills
- Myalgia
- Headache
(note: can also be asymptomatic)
7
Q
What are the symptoms of the second stage of parvovirus B19 infection? (2)
A
- Rash
- Arthralgia
(note: can also be asymptomatic)
8
Q
What causes the rash after parvovirus B19 infection?
A
Deposition of immune complexes in the skin
9
Q
What causes arthralgia after parvovirus B19 infection?
A
Deposition of immune complexes in the joint
10
Q
In which group are rash and arthralgia after parvovirus B19 infection most common?
A
Women of adult age
11
Q
Which patients are susceptible to severe illness upon parvovirus B19 infection? Why? What kind of disease can occur?
A
IIndividuals with haematological conditions -> they have a high turnover of erythrocytes, and so also many reticulocytes in the blood -> high amount of cells that parvovirus B19 can infect -> higher viral load
This can result in a transient aplastic crisis
12
Q
What is the problem of parvovirus B19 infections in immunocompromised individuals?
A
Often cannot produce an effective antibody response, allowing for chronic infection
13
Q
Which therapy is often given in chronic parvovirus B19 infections in immunocompromised individuals?
A
IVIG
14
Q
Which supportive treatment is frequently needed for chronic parvovirus B19 infections in immunocompromised individuals?
A
Blood transfusions due to severe anaemia
15
Q
What is the downside of using IVIG for treatment of viral infections in immunocompromised individuals?
A
Serum antibody titres can no longer be used to guage whether an autologous immune response is starting
16
Q
Which diagnostic tool is used to diagnose parvovirus B19 infections in immunocompromised individuals?
A
PCR
17
Q
How many polyomaviruses are there? Which are they?
A
3:
1. BK virus
2. JC virus
3. Thrichodysplasia spinulosa polyomavirus (TSPyV)
18
Q
In which organ does BK virus occur? When is this a problem?
A
Kidney, can cause problems after kidney-Tx
19
Q
What are common features of all polyomaviruses? (2)
A
- All are latent
- All are highly pevalent in the population
20
Q
What disease do polyomaviruses cause in healthy populations?
A
No disease
21
Q
Trichodysplasia spinulosa polyomavirus can give a unique syndrome under certain circumstances. What are these circumstances?
A
Primary TSPyV infection in severely immunocompromised individuals, usually post-Tx
Latent patients do not experience this syndrome
22
Q
What is the danger of JC virus in immunocompromised individuals?
A
Can cause progressive multifocal leukoencephalopathy (PML), a severe form of encephalitis
23
Q
Which populations are at risk of JC-mediated progressive multifocal leukoencephalopathy (PML)? (3)
A
- Haematological malignancies
- Post-HTx/Lu-Tx
- AIDS (pre-cART)
24
Q
Which drug caused a strong rise of JC-mediated progressive multifocal leukoencephalopathy (PML)? Why?
A
Natalizumab -> MS drugs preventing lymphocytes from passing the blood-brain barrier, preventing adequate surveillance of latent JC in the brain
25
To which viral family does cytomegalovirus (CMV) belong?
Herpesviruses
26
What is the no. 1 virus causing problems in Tx-patients?
CMV
27
What is the seroprevalence of CMV during adolescence & adulthood?
Adolescence: 40%
Adulthood: 70%, with a 1% yearly risk of primo infection
28
How can CMV be transmitted?
Direct & indirect contact with bodily fluids
29
Which bodily fluids are capable of transmitting CMV? (6)
1. Saliva
2. Urine
3. Blood
4. Breast milk
5. Sperm
6. Tissue fluid in solid organ tranplantation
30
What is a primo CMV infection? (definition)
CMV infection in a CMV-negative person
31
What is CMV reactivation? (definition)
Replication of latent CMV
32
What is CMV reinfection? (definition)
CMV-positive person infected with new CMV strain
33
What is recurrent CMV infection? (definition)
All CMV reactivation + reinfection
34
What is the clinical picture in the vast majority of healthy CMV-carriers?
Asymptomatic
35
What can be symptoms of CMV when it does turn symptomatic? (4)
1. Mild viral syndrome
2. Guillain-Barré syndrome (rare)
3. Hepatitis (rare)
4. Lymphoproliferative disease (rare)
36
What is CMV end-organ disease? (definition) In which population does it occur?
Organ dysfunction due to CMV replication in that organ
Occurs in transplant patients
37
Which organs can be affected by CMV end-organ disease? How? Which are most common? (8)
1. Brain: encephalitis
2. Eye: retinitis = common
3. Lung: pneumonitis
4. Stomach & intestines: gastro-enteritis (=common, mainly colitis)
5. Liver: hepatitis
6. Kidney: nephritis
7. Bladder: cystitis
8. Oesophagus: oesophagitis
38
What are the diagnostics of CMV end-organ disease? (3)
1. Characteristic cytopathic effect in pathology
2. Immunohistochemistry
3. Quantitive CMV PCR in plasma (supportive)
39
What is the characteristic cytopathic effect of CMV?
Owl eyes
40
What is CMV syndrome? (definition)
Fever + bone marrow suppression due to CMV infection
41
What is the effect of bone marrow suppression in CMV syndrome?
Neutropenia & thrombopenia
42
What is CMV disease? (definition)
All CMV end organ disease + CMV syndrome
43
Which situations give high, intermediate and low risk of CMV infection after solid organ transplantation?
High risk: donor+/recipient-
Intermediate risk:
-Donor+/recipient+
-Donor-/recipient+
Low: donor-/recipient-
44
Which situations give high, intermediate and low risk of CMV infection after HSCT?
Recipient+ = high risk
Recipient- = low risk
45
How is CMV prevented after transplantation?
Prophylactic use of antivirals
46
What is the incidence of CMV reactivation & CMV disease in allo-HSCT?
CMV reactivation: 2/3 of patients (measured in blood)
CMV disease: 1/3
47
What is the incidence of CMV reactivation & CMV disease in auto-HSCT?
CMV reactivation: 40%
CMV disease: <5%
48
Which class of drugs are used for the prophylactic & treatment of herpesviruses, including CMV?
Nucleoside analogues
49
Which drugs are used in the treatment of CMV? (3)
1. (Val)ganciclovir
2. Cidofovir
3. Foscarnet
50
What is the downside of the use of antivirals for herpesviruses?
All have quite high toxicity
51
Which three strategies are there for the deployment of CMV-antivirals post-Tx?
1. Prophylaxis = treat regardless of CMV DNA in blood
2. Pre-emptive therapy = only treat when CMV DNA in blood rises
3. Therapy = only treat upon CMV disease
52
What is a new development surrounding CMV diagnostics?
The use of cell-mediated immunity assays to predict CMV disease risk after stopping prophylaxis
53
What is IVIG?
Intravenous immunoglobulin = human IgG pooled from a large number of donors
54
Which isotypes of antibodies can be found in IVIG?
Mainly IgG with trace amounts of IgM & IgA
55
Many % of the IgG in IVIG is monomeric, and how much is dimeric?
95% monomeric, 5% dimeric
56
How many % of the IgG in IVIG is composed by each of the subclasses of IgG?
IgG1 = 55-70%
IgG2 = 30-45%
IgG3 = 1-4%
IgG4 = 0,5%
57
What is the estimated variety of antibodies in a dose of IVIG?
10^9
58
What is an alternative method of administered antibodies when IVIG is not an option?
SCIg = subcutaneous immunoglobulins
59
What are advantages of SCIg over IVIG? (2)
1. Can be given in an at-home setting
2. Has a depot function -> slow release of antibodies
60
Which two IVIG regimens are there?
1. Low dose IVIG: 0,3-0,5 g/kg
2. High dose IVIG: >0,6 g/kg
61
What is the application of low-dose IVIG?
Replacement for patients with primary IgG deficiencies
62
What is the application of high-dose IVIG?
Immunomodulation
63
For which immunomodulatory goals is high-dose IVIG used? (3)
1. Anti-inflammatory therapy for auto-immune diseases
2. Prophylaxis/treatment of antibody-mediated rejection after kidney transplantation
3. Hyperimmunoglobulins to target specific diseases
64
In which instances are hyperimmunoglobulins (form of IVIG) used? (3)
1. Antiviral therapy against HBV (HBIG)
2. Antiviral therapy against CMV (CMV-Ig)
3. Rho(D) immunoglobulins for Rh- mothers carrying Rh+ childeren
65
What are FDA-approved indications of IVIG? (7)
1. Primary immunoglobulin deficiency
2. Chronic lymphocytic leukaemia (CLL)
3. Kawasaki's disease
4. Idiopathic thrombocytopenic purpura (ITP)
5. Multifocal motor neuropathy (MMN)
6. Chronic inflammatory demyelinating neuropathy (CIDP)
7. Dermatomyositis
66
How many off-label uses are there for IVIG?
~150
67
Why is there a shortage in IVIG?
Recent high demand in the fields of haematology & neurology
68
What is Kawasaki's disease?
Vasculitis of unkown aetiology, causing necrosis of medium-sized vessel walls
69
In which age group does Kawasaki's disease primarily occur?
Children <5
70
What are the symptoms of Kawasaki's disease? (4)
1. High fever
2. Red eyes
3. Strawberry tongue
4. Swollen lymph nodes
71
What is a severe complication of Kawasaki's disease?
Coronary artery aneurysms
72
What is the treatment of Kawasaki's disease? (2)
1. First: high dose acetyl salicylic acid to suppress inflammation
2. Followed by high-dose IVIG
73
What is immune thrombocytopenic purpura (ITP)?
Thrombocytopenia due to antibodies against thrombocytes
74
What is the aetiology of immune thrombocytopenic purpura (ITP)?
Unknown
75
What are the symptoms of immune thrombocytopenic purpura (ITP)? (3)
1. Bruising/purpura
2. Nose bleeding
3. Spontaneous haemorrhages
76
What are severe complications of immune thrombocytopenic purpura (ITP)? (3)
1. Intracerebral haemorrhage
2. Gastrointestinal bleedings
3. Other internal bleedings
77
What is the therapy of immune thrombocytopenic purpura (ITP)?
Start with high dose corticosteroids, if insufficient: high dose IVIG
78
What is Guillain-Barré syndrome (GBS)?
Acute inflammatory demyelinating polyneuropathy affecting peripheral nerves
79
What are the symptoms of Guillain-Barré syndrome (GBS)?
Paralysis of feet, hands and or/trunk
80
What is a life-threatening complication of Guillain-Barré syndrome (GBS)?
Paralysis of breathing muscles
81
How many % of Guillain-Barré syndrome (GBS) patients require artificial ventilation?
25%
82
What is the aetiology of Guillain-Barré syndrome (GBS)?
Antibodies against bacterial pathogens cross-react to myelin sheath of periheral nerves
83
What is the treatment of Guillain-Barré syndrome (GBS)?
High dose IVIG
84
Why are there large differences in efficacy of IVIG in Guillain-Barré syndrome (GBS) patients?
Large inter-patient variation in IVIG titres due to catabolism
85
What are lower levels of IVIG in serum in Guillain-Barré syndrome (GBS) correlated with?
Worse recovery
86
Why is a second round of IVIG not recommended for Guillain-Barré syndrome (GBS) patients?
Does not lead to faster recovery, but does cause more side effects
87
How can endogenous IgG be distinguished from IVIG?
Using allotypes of antibodies
88
What is an antibody allotype?
Differences due to SNPs in the constant domain of antibodies
89
What are the two parts of an antibody that can have anti-inflammatory actions?
1. F(ab)2
2. Fc
90
What are the F(ab)2-dependent anti-inflammatory modes of action of IVIG? (2)
1. Neutralization of antibodies, cytokines, soluble receptors, membrane-bound receptors & toxins
2. Cell depletion
91
What are the Fc-dependent anti-inflammatory modes of action of IVIG? (5)
1. Saturation of FcRn
2. Inhibition of complement
3. Blocking of activating FcγR
4. Modulation of immune cell activation
5. Expansion of regulatory T-cells
92
How does the FcγRI differ from the other FcγRs?
FcγRI is the only high-affinity receptor -> monomeric immunoglobulins are able to bind to and activate this receptor
93
How does the FcγRIIB differ from the other FcγRs?
FcγRIIIB is the only inhibitory FcγR
94
How can IVIG block activating FcγRs?
By saturating the FcγRs, pathogenic antibodies can no longer bind these receptors
95
Which cell types are susceptible to blocking of their FcγRs by the Fc-domain of IVIG? (3)
1. Macrophages
2. NK-cells
3. Neutrophils
96
In which disease has the blocking of FcγRs by IVIG been shown?
ITP
97
How was FcγR blocking by IVIG Fc-domain shown in ITP mouse models?
Mice treated with anti-thrombocyte antibodyes, and co-treated with:
-Nothing -> thrombocyte depletion
-IVIG -> partial prevention of thrombocyte depletion
-IVIG F(ab)2 -> thrombocyte depletion
So: only IVIG with an Fc-domain can prevent thrombocyte depletion
98
What is an important factor for the capacity of IVIG to block FcγRs?
Glycosylation
99
Which glycosylation of serum IgG causes a weak binding to FcγRs? What is the effect of this?
Which glycosylation of serum IgG causes a strong binding to FcγRs? What is the effect of this?
Gal-, Fuc+ = weak binding -> auto-immunity & inflammation
Gal+, Fuc- = strong binding -> immunomodulation
100
What is the advantage of Gal+, Fuc- antibodies?
Can strongly bind to FcγRs, displacing auto-antibodies
101
How can saturation of the FcRn have an immunomodulatory effect?
FcRn recycles auto-antibodies -> by saturating this receptor, catabolism of auto-antibodies is sped up
102
What is the mechanism of IgG catabolism by the FcRn? (3)
1. Uptake in the endosome of endothelial cells, followed by lysosomal degradation of unbound IgG
2. FcRn can bind IgG in endosomes at low pH
3. FcRn is transported to the cell surface and releases IgG in pH-neutral environment
103
How can IVIG cause immunomodulation by macrophages?
By causing upregulation of the inhibitory FcγRIIB
104
What is the effect of upregulation of FcγRIIB on macrophages?
Decreased phagocytosis of opsonized cells
105
The majority of FcγRs on the cell surface are normally [activating/inhibitory]
Majority is activating
106
Which mechanism of action of FcγRIIB upregulation by IVIG was discovered in mice?
1. IVIG binds to macrophages in the spleen, inducing IL-33 production
2. IL-33 induces IL-4 & IL-13 production in macrophages
3. IL-4 upregulates FcγRIIB on macrophages
107
To which lectin on macrophages in the spleen of mice does IVIG bind? What is the analogous lectin in humans?
Mice: SIGN-R1
Humans: DC-sign
108
True or false: IVIG can cause upregulation of the FcγRIIB in humans
False; this mechanism has been shown in mice, but not in humans -> it causes upregulation of FcγRIIIB (which is activating)
109
Which discovery makes it unlikely that the mechanism of action of IVIG in humans is caused by upregulation of the FcγRIIB on macrophages in the spleen?
IVIG also has effect in splenectomized individuals
110
How was the expansion of Tregs by IVIG discovered in mice?
Administration of IVIG in an EAE mouse-model for MS causes:
1. Less severe EAE
2. Higher % of Tregs in CD4+ subset
3. Effect of IVIG disappears when Tregs are depleted
111
What is the effect of IVIG on Tregs in humans?
1. No increase in Treg numbers
2. Increased Treg activity
3. Increased Treg suppressive capacity
112
Which two factors point to increased Treg activity after IVIG administration in humans?
1. HLA-DR expression increases
2. FoxP3 expression increases
113
What are the hypotheses for the upregulation of Treg activity by IVIG? (4)
1. IVIG induces production of IL-33 by macrophages -> Treg expansion
2. IVIG binds to DC-inhibitory receptor -> co-stimulatory signals that induce Tregs
3. IVIG induces PGE2 which induces Treg expansion
4. IVIG is internalized by APCs and presented to T-cells in a non-activating/inflammatory environment (no costimulation) -> Tregs
114
What are the general advantages of IVIG as a treatment? (3)
1. No acute adverse effects
2. No long-term adverse effects
3. Long half-life -> only 1 treatment per 3-6 weeks
115
What are the general disadvantages of IVIG as a treatment? (4)
1. IV administration with long infusion times
2. Variation between brands & lots of IVIG
3. High costs
4. Limited amount of safe, virus-free human plasma can lead to shortages
116
Which developments are underway to increase IVIG effectivity and/or reduce the needed amounts of IVIG? (3)
1. Synthetic IVIG: trimerig IgG Fc blocks binding of pathogenic immune complexes to FcγR
2. IVIG with modified glycosylation to control its effects
3. Human IgG1 Fc/antibody that binds FcRn -> simulates FcRn blocking effect of IVIG
