Auto-immune disease Flashcards
1
Q
What are the pathological processes in early RA? (4)
A
- Capillary formation
- Hyperplastic synovial membrane
- Hyperthropic synoviocytes
- Influx of immune cells into the joint
2
Q
Which immune cells can be found in the joint in early RA? (3)
A
- Neutrophils
- T-cells
- B-cells
3
Q
What are the pathological processes in established RA? (5)
A
- Plasma cells in the joint
- Synovial villi formation
- Extensive angiogenesis
- Bone erosion
- Pannus formation
4
Q
Which two cell types are the main contributors to the production of RA-related cytokines?
A
- Macrophages
- T-cells (Th17)
5
Q
Which cytokines are the main cytokines in RA? (6) Are they pro- or anti-inflammatory? By which cell types are they produced?
A
Pro-inflammatory:
1. TNF-α = macrophage
2. IL-6 = macrophage
3. IFN-γ = Th17
4. IL-17A = Th17
Anti-inflammatory:
1. TGF-β = macrophage
2. IL-10 = macrophage
6
Q
Various RA-related diseases have involvement of the same pathways, with a different predominant cytokine. What is the central cytokine in all these diseases?
A
TNF-α
7
Q
If TNF-α is combined with IL-17/IL-23, which group of (3) diseases can occur? On which cell-type is the pathogenesis of this cluster dependent?
A
- Spondylarthritis ankylopoietica (SpA)
- Psoriasis
- Psoriatic arthritis (PsA)
T-cell dependent
8
Q
Which cytokine(s), in addition to TNF-α, is/are involved in the pathogenesis of spondylarthritis ankylopoietica (SpA)?
A
IL-17/IL-23
9
Q
Which cytokine(s), in addition to TNF-α, is/are involved in the pathogenesis of psoriasis?
A
IL-17/IL-23
10
Q
Which cytokine(s), in addition to TNF-α, is/are involved in the pathogenesis of psoriatic arthritis (PsA)?
A
IL-17/IL-23
11
Q
If TNF-α is combined with IL-6, which group of (2) diseases can occur? On which pathological process is this cluster dependent?
A
- Rheumatoid arthritis (RA)
- Giant cell arteritis (CGA)
Early phase T-cell-dependent, late phase inflammasome-dependent
12
Q
Which cytokine(s), in addition to TNF-α, is/are involved in the pathogenesis of rheumatoid arthritis (RA)?
A
IL-6
13
Q
Which cytokine(s), in addition to TNF-α, is/are involved in the pathogenesis of giant cell arteritis (CGA)?
A
IL-6
14
Q
If TNF-α is combined with IL-1, which group of (3) diseases can occur? On which pathological process is this cluster dependent?
A
- Gout
- Juvenile idiopathic arthritis (JIA)
- Other auto-inflammatory diseases
Inflammasome-mediated
15
Q
Which cytokine(s), in addition to TNF-α, is/are involved in the pathogenesis of gout?
A
IL-1
16
Q
Which cytokine(s), in addition to TNF-α, is/are involved in the pathogenesis of juvenile idiopathis arthritis (JIA)?
A
IL-1
17
Q
How can knowledge of involved cytokines aid the treatment of auto-immune/auto-inflammatory disease?
A
The cytokines or their downstream signalling can be targeted as a therapeutic intervention
18
Q
Which four main ways are there to target cytokine signalling?
A
- Monoclonals against cytokines
- Soluble receptors to catch cytokines
- Monoclonals against cytokine receptors
- Blocking of downstream receptor signalling
19
Q
In which pathological processes in RA is IL-6 involved? (4)
A
- B-cell differentiation -> antibody production
- Mediation of chronic inflammation through activation of immune cells
- Osteoclast activation -> bone resorption -> bone/joint destruction
- Synoviocyte activation -> pannus formation -> joint destruction
20
Q
Which two types of IL-6 signalling can be distinguished?
A
- Classical IL-6 signalling
- Trans IL-6 signalling (trans-signalling)
21
Q
What is the configuration of the IL-6 receptor?
A
IL-6R supported by 2 gp130 chains
22
Q
What is classical IL-6 signalling?
A
Surface-bound IL-6R supported by 2 gp130 chains gets activated by IL-6
23
Q
What is IL-6 trans-signalling?
A
Soluble IL-6R activates IL-6 signalling pathways in cells lacking IL-6R, but expressing gp130
24
Q
Joint destruction in RA is a two-step process. What are the two steps?
A
- Cartilage destruction
- Bone erosion
25
What are the processes involved in cartilage destruction in RA? (3)
1. Matrix metalloproteases (MMPs) released under inflammatory conditions break down cartilage
2. Invasion of synovial fibroblasts into the cartilage -> pannus formation
3. Chondrocyte death
26
Which cells are the main producers of matrix metalloproteases (MMPs) in cartilage destruction in RA?
Chondrocytes
27
What is the first step in cartilage destruction by matrix metalloproteases (MMPs) in RA? Is this step reversible?
Proteoglycan loss; still reversible
28
What is the first step of irreversible damage in joint destruction in RA?
Chondrocyte death during cartilage destruction
29
Which cytokines are involved in cartilage destruction in RA? (3) What is their role?
1. IL-1 -> activation of synovial fibroblasts
2. IL-17 -> activation of synovial fibroblasts
3. TNF-α -> production of MMPs by chondrocytes
30
Which cytokines activate synoviocytes in cartilage destruction in RA? (2) What is the effect of synoviocyte activation? (2)
IL-1 & IL-17
Synoviocyte activation leads to:
1. Pannus formation
2. Production of TNF-α
31
Which cytokines are involved in driving the release of MMPs by chondrocytes in cartilage destruction in RA? (2)
IL-1 & TNF-α
32
What is the main process of bone destruction in RA?
Osteoclast activation -> bone resorption
33
What kind of cell type are osteoclasts?
Myeloid-derived cells
34
Which receptor is the main activating receptor of osteoclasts? What is its ligand?
RANK, stimulated by RANK-ligand (RANK-L)
35
What is the role of OPG in the regulation of osteoclast activation?
OPG = RANK-L decoy receptor -> blocks RANK-RANKL signalling
36
Which cytokine cascasde leads to increased expression of RANK on osteoclasts in bone resorption in RA?
IL1 -> TNF-α -> IL-17 -> increased RANK expression
37
Which cytokines can downregulate osteoclast activity, downregulating bone resorption? (2)
IL-4 & IL-10
38
What is the prototypic JAK/STAT signalling pathway? (5)
1. Activation of receptor by ligand
2. JAK phosphorylation
3. STAT phosphorylation & dimerization
4. Nuclear translocation
5. Modification of gene transcription
39
How many different JAKs and STATs are there?
JAKs: 4
STATs: 6
40
How can a limited number of JAKs and STATs lead to a plethora of different responses to receptor activation?
JAKs and STATs can be combined, giving rise to a higher number of possibilities
41
What are the main JAK/STAT pathways involved in RA? (2)
1. IL-6R -> JAK1/JAK2 -> STAT3/STAT3 -> Th17 phenotype
2. IL-2R -> JAK1/JAK3 -> STAT5/STAT5 -> blocking of Th17 phenotype by blocking of STAT3
42
What is the main effect of JAK/STAT mutations?
Auto-immune disease
43
How can knowledge of JAK/STAT signalling be used to control auto-immune disease?
JAK-inhibitors can block downstream receptor signalling
44
Into which rough groups can auto-immune disease be grouped?
1. Organ-specific
2. Systemic
45
What are the antigens of organ-specific auto-immune disease? What are examples of such diseases?
Organ-specific antigens
Examples: DM1, thyroid disease
46
What are the antigens of systemic auto-immune disease? What are examples of such diseases?
Antigens that occur throughout the body (such as blood vessels, collagens)
Examples: SLE, RA, vasculitis
47
What are the three main processes preventing auto-immunity?
1. Central tolerance -> deletion of auto-reactive T-cells
2. Peripheral tolerance -> anergy & Tregs
3. Seclusion of auto-antigens
48
What is the main cause of a disruption in central tolerance?
AIRE mutations
49
Which mechanisms may cause breakdown in peripheral tolerance? (7)
1. Activation by superantigens
2. Polyclonal activation
3. Molecular mimicry
4. Bystander activation
5. Neoantigens
6. Release of secluded auto-antigens
7. Drugs (immune checkpoint inhibitors)
50
Which four groups of vasculitis can be distinguished, based on the size of the vessels involed?
1. Large artery
2. Medium artery
3. Small artery
4. Arteriole/capillary venule
51
Why is a classification of vasculitis based on vessel size useful? (3)
1. Different clinical presentation
2. Different pathogenic mechanism
3. Different treatment
52
What are examples of diseases in the category of large artery vasculitis? (2)
1. Takayasu
2. Giant cell arteritis
53
What are examples of diseases in the category of medium artery vasculitis? (2)
1. Polyarteritis nodosa
2. Kawasaki
54
What are examples of diseases in the category of small artery vasculitis? (3)
1. Wegener's granulomatosis
2. Microscopic polyangiitis
3. Churg-Strauss
55
What are examples of diseases in the category of arteriole/capillary venule vasculitis? (2)
1. Cryglobulinaemia
2. Henoch-Schönlein
56
Which group of vasculitis is most common?
Small vessel vasculitis
57
What is the target of large vessel vasculitis?
Vessel wall of the vasa vasorum
58
What is the pathological process leading to large vessel vasculitis? (3)
1. DCs in the vasa vasorum in the adventitia of the large vessels become activated
2. DCs don't migrate to the lymph node, but locally activate passing lymphocytes
3. Local auto-immune reaction against the vessel wall
59
What is the effect of the local immune reaction against the vessel wall in large artery vasculitis? (2)
1. Internal bleeding due to weakening of the vessel wall
2. Ischaemia due to oblitteration of blood vessels
60
Why are small vessels exempt from the pathological process occurring in large vessel vasculitis?
These vessels don't have DCs in their adventitia -> no possibility of local activation
61
What are the two possible pathogeneses of small vessel vasculitis?
1. Immune complex deposition
2. ANCA-associated vasculitis
62
What can lead to immune complexes being deposited in small vessels?
High numbers of immune complexes cannot be sufficiently cleared by phagocytes in the bloodstream, leading to deposition in the vessels with the slowers blood flow
63
How does deposition of immune complexes in small vessels lead to an inflammatory reaction (vasculitis)?
Complement activation
64
What are the main treatment strategies that can be considered in case of auto-immune disease? (6)
1. Replace function of the damaged organ
2. General immune suppression
3. Specific eradication of cells involved in the disease
4. Drugs that block involved cytokine pathways
5. Blocking pathogenic cells from reaching target organs
6. Bone marrow transplant (last resort)
65
What is the most frequently used form of general immunosuppression in auto-immune disease?
Corticosteroids
66
Why is myositis paired with an elevated creatine kinase (CK)?
CK is highly present in muscles -> muslce damage causes release into the circulation
67
What is the first-line treatment of myositis? What are second line treatments?
First line: corticosteroids
Second line: IVIG and/or JAK-inhibitors
68
True or false: myositis is one disease
False: myositis is a heterogeneous group of disorders
69
Which organs can be involved in myositis (5)? How can this present itself?
1. Muscles: weakness/myositis
2. Skin: rash
3. Joints: arthritis
4. Lungs: ILD
5. Systemic: fever
70
True or false: the different auto-antibodies that are characteristic for certain types of myositis are used for diagnostics
False: while most types of myositis are characterized by specific auto-antibodies, only one of these is actually used in diagnostics
71
Which four groups of myositis can be identified?
1. Overlap myositis, including anti-synthetase syndrome
2. Dermatomyositis
3. Immune-mediated necrotizing myositis
4. Inclusion body myositis
72
On which criteria is myositis classification based? (6)
1. Age of onset
2. Type of muscle weakness
3. Type of skin manifestations
4. Other clinical manifestations
5. Laboratory measurements
6. Muscle biopsy features
73
What are the laboratory measurements used in myositis diagnostics? (4)
1. Elevated creatine kinase (CK)
2. Elevated lactate dehydrogenase (LDH)
3. Elevated transaminases (ASAT/ALAT)
4. Anti-Jo-1 auto-antibodies
74
What is the target of anti-Jo-1-antibodies? Of which type of myositis are they characteristic?
Histidyl-tRNA synthetase
Characteristic of anti synthetase syndrome
75
What are MSAs, and how do they differ with MAAs? (in the context of myositis)
MSA = myositis-specific antibody
MAA = myositis-associated antibody
76
In how many % of myositis is anti-Jo-1 positive?
15-25%
77
What is the result of anti-Jo-1 antibodies?
Target histidyl-tRNA synthetase -> interference with protein synthesis
78
How are anti-Jo-1 antibodies detected? (2)
1. Enzyme immune-assay (EIA)
2. Immunoblot
79
What is ANA immunofluorescence?
Testing patient serum for anti-nuclear antibodies, which are present in many auto-immune diseases
80
What can MSAs and MAAs be associated with, in addition to myositis? (3)
1. Malignancy
2. ILD
3. Other diseases
81
True or false: all auto-antibodies in myositis give prognostic information
False: some auto-antibodies do give prognostic information, but most do not
82
What is the main challenge in the use of antibodies to detect/diagnose myositis?
Interpretation of clinically less/non-relevant antibody types or titres -> how to interpret these?
83
What is the main way to estimate whether detected auto-antibodies are clinically relevant in myositis?
If no characteristic pattern in indirect immunofluorescence assays -> likely not clinically relevant
84
Anti-synthetase syndrome is a myositis variant. What the possible presentations of this disease? (4)
1. Myositis
2. ILD
3. Non-erosive arthritis
4. Raynaud phenomenon
85
True or false: muscle involvement is always part of myositis
False: muscle involvement is not always present and/or clear
86
What is the hallmark of sarcoidosis?
Formation of granulomas
87
How are granulomas built up?
Core of epithelioid cells & macrophages, surrounded by T-lymphocytes
88
Granulomas can produce hormones and enzymes. Which are the two main ones, and what is their effect?
1. Active vitamin D -> increased Ca2+ in blood
2. ACE -> increased blood pressure
89
What is the trigger for sarcoidosis?
Haha, got you there: the trigger is unknown!
90
What are the stages of sarcoidosis, and the pathological processes during these stages?
Early stage: inflammatory response - (temporary) organ dyfunction
Late stage: fibroblast triggering -> fibrosis -> tissue damage
91
Sarcoidosis is a multi-organ disease. What is the main target organ, and which other organs can be involved (4)?
Main target: lungs
Manifestations can also occur in:
1. Eyes
2. Skin
3. Heart
4. Brain/CNS
92
What is the treatment of sarcoidosis?
Immunosuppression
93
What are the treatment lines of immunosuppression for sarcoidosis? (3)
1. Prednisone
2. Methotrexate
3. Anti-TNF (adalimumab, infliximab)
94
Hypogammaglobulinaemia is [typical/atypical] for sarcoidosis
Atyptical -> usually (clonally) increased hypergammaglobulinaemia
95
What causes hypergammaglobulinaemia in sarcoidosis?
Elevated levels of BAFF
96
True or false: sarcoidosis is related to an increased risk of infections
False, sarcoidosis patients typically do not have an increased risk of infections
97
Which pathogen forms an exception to the rule that sarcoidosis patients typically do not have an increased infection risk?
Cryptococcus
98
What can cause sarcoidosis patients to have a higher risk of opportunistic infections?
Immunosuppression (steroids)
99
What are primary antibody deficiences? (definition)
Antibody deficiency with low IgG, IgM & IgA
100
What are important antibody deficiencies? (2)
1. X-linked agammaglobulinaemia
2. Common variable immunodeficiency (CVID)
101
What is the cause of X-linked agammaglobulinaemia (XLA)?
BTK mutations, causing a complete block in B-cell maturation
102
True or false: XLA is always diagnosed during childhood
True; XLA causes such a severe increase in infection risk that it is (nearly) always diagnosed during childhood
103
True or false: CVID is always diagnosed during childhood
False; CVID does not necessarily cause such an increased infection risk that it is always diagnosed during childhood
104
What are the main complications of CVID? (4)
1. Recurrent infections
2. Auto-immune complications
3. Auto-inflammatory complications
4. Increased risk of haematological malignancies
105
What are the main types of infections commonly seen in CVID patients? (2)
1. Gastrointestinal
2. Respiratory
106
What is the main determinant of prognosis in CVID patients?
Non-infectious complications such as auto-immunity and haematological malignancy
107
Why are infections not the factor determining prognosis in CVID?
Can be effectively prevented/treated using (prophylactic) antibiotics & IVIG
108
True or false: the majority of CVID patients have granulomatous disease
False: granulomatous disease occurs in 8-25% of CVID patients
109
In CVID patients with granulomatous disease, granulomatous disease often presents [before/after] presentation of antibody deficiency
Before -> granulomatous presents before antibody deficiency
110
Granulomatous disease [does/does not] affect prognosis in CVID patients
Does -> granulomatous severely worsens prognosis of CVID patients
111
Granulomas in CVID patients typically form in [different/the same] locations as in sarcoidosis patients
Same locations
112
What is the trigger of granuloma formation in granulomatous disease in CVID?
Haha, got you again! This is also unknown, although it is kikely infectious
113
What is the treatment of granulomatous disease in CVID?
No standardized treatment
114
What makes treatment of granulomatous disease in CVID difficult?
Immunosuppression is necessary to decrease granuloma formation, but this severely increases the risk of infection in these already immunodeficient patients
115
How can histological characteristics of granulomas be used to develop treatments?
Differences in size, structure & involved cells generally give information about the origin of the granuloma, which can be used to target treatment
