Immunology

Question 1

What is the ligand of CD28?

Answer 1

CD80/CD86

Question 2

What are two key differences between CD28 and ICOS?

Answer 2

-CD28 is involved in initial activation, whereas ICOS helps maintain activity of differentiated T cells
-CD28 is expressed on all naive T cells and some memory cells while ICOS is expressed on memory and effector cells

Question 3

What are the 3 signals and what do they do?

Answer 3

Signal 1: antigen-specific -> TCR activation
Signal 2: Co-stimulation -> proliferation and differentiation
Signal 3: Cytokines -> T cell differentiation

Question 4

What happens when there is no signal 2?

Answer 4

T cell becomes anergic. This happens when there is an antigen but no APC presenting it

Question 5

How may a self-reactive T cell develop?

Answer 5

A T cell isn’t screened against a peripheral self-antigen during development

Question 6

What causes anergy, and why is it benefitial?

Answer 6

Anergy happens when there is no co-stimulatory signal (signal 2). This helps provide tolerance, especially in the periphery. An APC must present the antigen for signal 2 to occur.

Question 7

What is 4-1BB?

Answer 7

A co-stimulatory receptor that can act as CD28 when it is induced

Question 8

What are two important inhibitory receptors?

Answer 8

CTLA4 and PD1

Question 9

When is CTLA4 expressed?

Answer 9

Starting a few days after the start of an immune reaction due to it needing an accumulation of transcription factors

Question 10

How does CTLA4 work?

Answer 10

It binds CD80/CD86 with a higher affinity than CD28 to prevent signal 2 co-stimulation (receptor competition) and gives a negative signal by dephosphorylating pathways via phosphatases

Question 11

What does PD1 bind to?

Answer 11

PD-L1 and PD-L2 on APCs and tumor cells

Question 12

Why is tumors expressing PD-L1 and PD-L2 significant?

Answer 12

It can prevent T cells from attacking it by preventing co-stimulation (since they also express antigens a.k.a signal 1)

Question 13

In what conditions does T cell exhaustion occur?

Answer 13

During persistent antigen presentation: Chronic viral infections, cancer/tumors, autoimmunity

Question 14

What happens to T cells when they become exhausted?

Answer 14

They start gradually gaining inhibitory receptors, starting with PD-1.
They start losing their ability to make pro-inflammatory cytokines and lose their ability to prolifirate while also gradually becoming pro-apoptotic.

Question 15

What is the 3 signal model in T cell exhaustion?

Answer 15

1: Persistent antigen presentation
2: Negative co-stimulation
3: Chronic inflammation

Question 16

What happens with transcription factors during T cell exhaustion?

Answer 16

TCF1 (helps proliferate) goes down at first as TOX goes up. TOX is supposed to go back down (as TCF1 goes back up) but doesn’t, making T cells TCF1 and TOX positive. Eventually they lose TCF1 and become terminally exhausted, losing the ability to proliferate.

Question 17

Why is T cell exhaustion benefitial?

Answer 17

It dampens immunopathology in i.e chronic infections, and prevents autoimmunity

Question 18

What does CART stand for?

Answer 18

Chimeric antigen receptor T cell. It contains Both TCR (signal 1) as well as 4-1BB and CD28 for strong co-stimulation (signal 2)

Question 19

What is checkpoint inhibition?

Answer 19

Antibodies against inhibitory receptors CTLA4 and PD-1

Question 20

What route do T cells leave the lymph nodes and spleen?

Answer 20

Through the efferent lymph

Question 21

How do APCs leave the lympph nodes?

Answer 21

They don’t! They die there

Question 22

What regulates T cell exit?

Answer 22

Not chemokines, but lipids called S1P. Lymph nodes upregulate S1PR during dwell time in

Question 23

What cells synthesize S1P?

Answer 23

Endothelial cells and red blood cells. This makes S1P concentration high in bodily fluids and low in tissues, creating a gradient for T cells to follow.

Question 24

How do T cells ensure they don’t leave the lymph node too soon?

Answer 24

They express CD69 as an early activation marker, which prevents re-expression of S1PR. CD69 is expressed less after a few divisions, allowing S1PR upregulation and exit after some time.

Question 25

How does rolling work for T cells?

Answer 25

L-selectin weakly interacts with integrins, so glycoproteins on HEVs, causing slowing.

Question 26

How does sticking work for T cells?

Answer 26

CCL21 expressed by HEVs interact with CCR7 on T cells now that it is slowed down. This interaction causes a conformational change in LFA-1, which can then bind to ICAM-1 with high affinity.

Question 27

What happens after rolling?

Answer 27

Diapedesis (Transmigration)

Question 28

What is inside out signaling?

Answer 28

CCR7-CCL21 interaction causes a change in LFA-1 conformation on the T cell

Question 29

What is outside in signaling?

Answer 29

LFA-1 (after a conformational change) on T cells binds to ICAM-1 on HEVs

Question 30

What are peripheral Node Addressins?

Answer 30

Integrins. “postal code” sugars expressed by HEV

Question 31

What homeostatic chemokines attract B cells and T cells, respectively, and what cells produce them and where?

Answer 31

CXCL13 is expressed by stromal cells in the B cell follicles.
CCL21 is produced by stromal cells in the paracortex and promotes T cell and dendritic cell migration.

Question 32

What are the three mechanisms of attraction?

Answer 32

Chemotaxis, haptotaxis and chemo/haptokinesis

Question 33

What is more common, chemotaxis or haptotaxis?

Answer 33

Haptotaxis

Question 34

Why is chemotaxis not as effective as haptotaxis?

Answer 34

Diffusion

Question 35

Where are integrins mainly expressed?

Answer 35

Endothelial cells

Question 36

What determines the location at which a T cell can move into tissue after activation? Explain the process and name an example

Answer 36

When dendritic cells from a certain part of the body migrate to the lymph node and activate T cells, it ensures that the T cell expresses homing molecules specific for that location.. This ensures that the T cell only enters that area and in an efficient manner.

Question 37

What are the two blood supplies of the liver and what are their characteristics?

Answer 37

Portal vein - from the intestines, oxygen-poor and nutrient rich
Hepatic artery - oxygen rich

Question 38

What are sinusoidal endothelial cells?

Answer 38

They line the vascular ducts in the liver and allow nutrients through to hepatocytes

Question 39

What are the 3 main functions of the liver?

Answer 39

Metabolism
Detoxification
Synthesis

Question 40

What biomolecules does the liver synthesize?

Answer 40

MBL and other complement system components
C-reactive protein
Soluble PRRs
Antimicrobial peptides
Clotting factors
Acute phase proteins

Question 41

How is acute phase protein production initiated?

Answer 41

When macrophages detect a threat, they secrete cytokines IL6, IL1, TNFa. These lead to an increase of acute phase proteins such as c-reactive protein.

Question 42

What is a marker used to detect inflammation?

Answer 42

C-reactive protein

Question 43

What forms does CD14 have?

Answer 43

Bound on macrophages in the liver and soluble

Question 44

In what ways can liver tolerance become a problem?

Answer 44

Hepatitis B & C virus, malaria spores, tumor metastases and autoimmune reactions

Question 45

Why are liver transplants more often successful than other transplants?

Answer 45

HLA-matching is not required

Question 46

What does LSEC stand for?

Answer 46

Liver sinusoidal endothelium

Question 47

Where do immune cells of the liver reside?

Answer 47

In the blood vessels between the portal and central veins

Question 48

How are waste products removed from the liver?

Answer 48

Liver sinusoidal endothelial cells remove waste using scavenger receptors and carbohydrate receptors -> endocytosis -> lysosomal degradation

Question 49

What are the properties of LSECs as APCs?

Answer 49

-Weak with tolerogenic properties
-MHC I - non-productive activation of CD8 T cells
-MHC II - usually leads to Tregs
-Anti-inflammatory cytokine secretion: IL-10, TGF-ß
-PDL-1
-Large tolerizing surface

Question 50

Why does activation through LSECs usually lead to induction of Tregs?

Answer 50

Liver sinusoidal endothelial cells mainly produce anti-inflammatory cytokines IL-10 and TGF-ß

Question 51

Why is MHCI cross-presentation in LSECs non-productive?

Answer 51

There is a low level of co-stimulation (signal 2) and no inflammatory cytokines (signal 3)

Question 52

What do the Fcy and Fcα receptors on Kupffer cells do?

Answer 52

Clear immune complexes and IgA-antigen complexes

Question 53

What do complement receptors on macrophages do?

Answer 53

Allow for clearance of C3b-coated bacteria

Question 54

What is Poly:I:C?

Answer 54

Synthetic dsRNA used to mimic TLR3 stimulation

Question 55

What are the properties of Kupffer cells as APCs?

Answer 55

-Not very potent with tolerogenic properties
-Activation causes co-stimulatory molecule expression
-Induce expansion of Tregs
-Secrete IL-10, TGFß and prostaglandins

Prostaglandins can for example reduce IL-2 receptor expression

Question 56

What type of phenotype do lymphocytes have in the liver?

Answer 56

Mostly HLA-DR+, so activated.
Also 35% are gamma-delta T cells and there are also NKT cells, so more innate T cell phenotype

Question 57

What kind of infection is Hep A infection?

Answer 57

Acute, infectious hepatitis

Question 58

What kind of infection is Hep B infection?

Answer 58

Persistent, serum hepatitis

Question 59

What kind of infection is Hep C infection?

Answer 59

Persistent, non-A and non-B

Question 60

Where do you normally see immune infiltration/inflammation during Hep B infection?

Answer 60

Around the portal tract area. Mostly T and B cells. There is very little liver damage until very late stage.

Question 61

What type of virus is Hep A?

Answer 61

Picornavirus, RNA + sense

Question 62

What type of virus is Hep B?

Answer 62

Hepadnavirus, DNA (partial double strand)

Question 63

What type of virus is Hep C?

Answer 63

Flavivirus, RNA - sense

Question 64

Which of the 3 main Hep viruses have no envelope?

Answer 64

A

Question 65

What age group usually gets chronically infected with Hep B and recovers less often?

Answer 65

Newborns

Question 66

What age group usually develops chronic infection via Hep C?

Answer 66

Adults (20-40%)

Question 67

When is the clinical outcome of HCV infection determined?

Answer 67

Within 24 weeks.

Question 68

What is ALT?

Answer 68

An enzyme released into the blood during liver damage. Higher levels coincide with measured viral load of HCV

Question 69

What is peculiar about the adaptive response during HCV infection?

Answer 69

Delay. T cell proliferation starts after 10 weeks.

Question 70

What inhibits killing of infected cells by NK?

Answer 70

HCV

Question 71

What is peculiar about the adaptive response during HBV infection?

Answer 71

Most chronic HBV patients have a weak or absent HBV-specific T cell response. It comes up late and goes back down and stays low.
The relationship between viral load and T cells is inverse. Also liver infiltrating B cells are observed in active phases of chronic HBV.

Question 72

What is a characteristic of T cells during chronic Hep B and C infection?

Answer 72

T cell exhaustion. High PD-1 expression.

Question 73

What can restore T cell responses in HBV infection?

Answer 73

Nucleoside analogues - mimic nucleotides that get incorporated into growing DNA strands, impairing DNA polymerase

Question 74

What are 4 ways to restore T cell responses in HBV infection?

Answer 74

1. Reduce antigen load
2. Block inhibitory receptors
3. Block inhibitory pathways (IL-10, etc)
4. Immunotherapeutic boosting of T cells (vaccines, cytokines, TLR agonists)

Question 75

What is a parenchyma?

Answer 75

The functional structure of a tissue distinguished from the connective and supporting tissues

Question 76

What is spot necrosis?

Answer 76

A small area of necrosis

Question 77

What are characteristics of an apoptotic hepatocyte?

Answer 77

Shrinkage and pyknosis

Question 78

What are characteristics of balloon degeneration?

Answer 78

Swollen cytoplasm, eosinophilic enlarged nucleus -> karyoreksis

Question 79

What are characteristics of bridging necrosis?

Answer 79

necrosis that extends between lobules, such as portal-portal or central-central bridging

Question 80

What are two histopathological characteristics of a chronic HBV infection?

Answer 80

Ground glass (light eosinophilic cytoplasm, clear halo) and sanded nuclei (pale eosinophilic, finely granular)

Question 81

What is the main difference between acute and chronic hepatitis?

Answer 81

The chronic component is in the portal area

Question 82

What is the order of the segments of the small intestine?

Answer 82

1. duodenum
2. jejunum
3. ileum

Question 83

What is the order of the parts of the large intestine?

Answer 83

1. cecum
2. ascending colon
3. transverse colon
4. descending colon
5. sigmoid colon
6. rectum
7. anus

Question 84

Where do secretions from the liver and pancreas empty into?

Answer 84

Duodenum

Question 85

How come stomach acid doesn’t affect the small intestine?

Answer 85

Duodenum’s brunner’s glands secrete bicarbonate which neutralizes it, and pancreatic juices and bile mixed in dilute it.

Question 86

Where are the majority of nutrients absorbed?

Answer 86

Jejunum

Question 87

What parts of the intestine absorb water?

Answer 87

The ascending and transverse colon

Question 88

What are M cells?

Answer 88

They are highly selective recognition cells that take up antigen to present to dendritic cells in the Peyer’s patches

Question 89

What types of immune cells are in the mucosa outside of the lymhpoid structures?

Answer 89

Memory T and B cells, macrophages, dendritic cells and inter-epithelial lymphocytes

Question 90

What lymphoid organs in the intestines are not structured?

Answer 90

Colonic patches or isolated lymhoid follicles

Question 91

Where are intestinal goblet cells most numerous?

Answer 91

The colon

Question 92

Where can Paneth cells?

Answer 92

In the crypts of the small intestines

Question 93

What is the function of Paneth cells?

Answer 93

They contain antimicrobial granules that, when secreted, keep the crypts clear of bacteria. It also functions as a signaling cell to surrounding cells/

Question 94

WHat are GALTs?

Answer 94

Gut-associated lymphoid tissue

Question 95

What undergoes regional adaptation and why

Answer 95

Mesenteric lymph nodes, since they drain from different areas of the intestines, which are all different

Question 96

Where is the highest microbiota diversity in the intestines?

Answer 96

The colon

Question 97

What are two ways commensal bacteria can limit pathogen colonization?

Answer 97

1. Pathogens are poorly adapted to compete for nutrients
2. Commensals stimulate immune responses against pathogens

Question 98

In what 5 ways is the intestinal epithelium a barrier?

Answer 98

1. Microvillar extensions prevent attachment
2. Epithelial tight junctions
3. Secreted mucins
4. Epithelial transcytosis of IgA
5. Antimicrobial peptides

Question 99

In what 5 ways is the intestinal epithelium a barrier?

Answer 99

1. Microvillar extension prevent attachment
2. Epithelial tight junctions
3. Secreted mucins
4. Epithelial transcytosis of IgA
5. Antimicrobial peptides

Question 100

In what 5 ways is the intestinal epithelium a barrier?

Answer 100

1. Microvillar extension prevent attachment
2. Epithelial tight junctions
3. Secreted mucins
4. Epithelial transcytosis of IgA
5. Antimicrobial peptides

Question 101

What types of mucus layers are there in the intestines?

Answer 101

Small: single thin
Colon: Two (inner and outer)

Question 102

What is a histopathological hallmark of spontaneous colitis?

Answer 102

Very long crypts

Question 103

What does idiopathic mean?

Answer 103

A disease that arises spontaneously or for which the cause is unknown

Question 104

What is it called when something moves across a cell?

Answer 104

Transcytosis

Question 105

How do Paneth cells differ in their antimicrobial function from other epithelial cells?

Answer 105

They have a higher diversity of AMPs and have vesicles already ready to go

Question 106

What is microbial sampling?

Answer 106

Controlled testing by M cells of bacteria present in the lumen of the intestine

Question 107

In what three ways microbes are sampled?

Answer 107

1. Passive diffusion
2. Transcellular transport
3. Macrophage uptake

Question 108

What type of antibodies are produced in the Peyer’s patches?

Answer 108

Mostly IgA but also IgG. Especially IgG is someone is IgA-deficient

Question 109

What cells can disrupt tight junctions for antigen sensing and uptake?

Answer 109

Macrophages

Question 110

How does microbial sensing by PRRs work?

Answer 110

Through TLRs

Question 111

Why is sensing important?

Answer 111

So we can discern between harmless and harmful bacteria

Question 112

How is sensing like a piano?

Answer 112

Microbes have many different structures that can be sensed by different PRRs, like fingers on a piano that hit keys in different strengths, creating unique cytokine cocktails. The microbiome interacting with us is the music.

Question 113

How does NF-kB maintain intestinal mucosal integrity?

Answer 113

Through its roles in regulating inflammation, promoting cell survival against inflammation (anti-apoptitic genes like Bcl-2) and proliferation, maintaining barrier function (ie. Upregulation of tight junction proteins and adherins), and regulating mucin production.

Question 114

Does NF-kB mean activation?

Answer 114

Not necessarily. It is essential for homeostasis in the intestines

Question 115

What happens when you delete NF-kB in the intestinal epithelium?

Answer 115

Apoptosis and activation of macrophages underneath (due to infiltration), which leads to chronic intestinal inflammation

Question 116

How are TLRs situated in the intestinal epithelium?

Answer 116

Mostly on the baso-lateral side, except for at the peyers patches. TLRs in the small intestine are also different than in the colon for example. TLR4 and 2 are also expressed a bit low.

Question 117

What is the TLR5 ligand?

Answer 117

flagella

Question 118

What regulates the epithelial response pattern?

Answer 118

Inhibitory proteins

Question 119

How do intestinal epithelial cells respond?

Answer 119

They downregulate different cells using anti-inflammatory cytokines unless necessary (hopefully)

Question 120

What is a consequence of mucosal tolerance regarding treatment?

Answer 120

Vaccination is very hard if you want to do a mucosal vaccination.

Question 121

What do adjuvants do?

Answer 121

Danger triggers that overcome homeostatic tolerance

Question 122

Do dendritic cells or macrophages drain more to the LN?

Answer 122

DCs

Question 123

What do dendritic cells do in the lymphoid tissue in the intestines?

Answer 123

Present to Naive T cells so they can eventually differentiate

Question 124

What is another term for Th1/Th17?

Answer 124

Tr1

Question 125

What types of T cells are in the lamina propria?

Answer 125

Effector memory T cells

Question 126

What adhesion molecule is required for cells to

Question 127

What do resident DCs in the mesenteric LN do?

Answer 127

They take up and present antigens that have diffused and drained in the lymph

Question 128

What do subcapsular macrophages do?

Answer 128

They seave macromolecules out of the molecules that have drained with the lymph to the mesenteric LNs, digest them and transfer them to resident DCs

Question 129

How do differentiated T cells in the mesenteric LNs go back into the intestines?

Answer 129

Imprinting: They are imprinted to go back through chemokine receptors like CCR9, that respond to CCL25 from small intestines and adhere using α4ß7 to bind to MADCAM1.

Question 130

What is α4ß7?

Answer 130

An adhesion molecule that allows cells that express CCR9 to enter the intestinal tissue

Question 131

Where do Tregs differentiate in the intestines?

Answer 131

Peyers patches and mesenteric LNs

Question 132

What function do CD103+ DCs have?

Answer 132

They can convert vitamin A derived retinol into retinoic acid. In combination with TGFß from the environment, Treg induction occurs: Foxp3, CCR9, α4ß7, Treg.

Question 133

What is necessary for Treg induction in the intestines?

Answer 133

Vitamin A (retinol) -> retinoic acid by CD103+ DCs plus environmental TGFß

Question 134

What type of branching system does the lungs have?

Answer 134

Dichotomous

Question 135

What does the respiratory unit consist of?

Answer 135

The respiratory bronchioles and alveolar ducts

Question 136

What do the conducting airways consist of?

Answer 136

Trachea, segmental bronchi and nonrespiratory bronchioles

Question 137

What is found in the submucosa of the bronchus?

Answer 137

Cartilage and glands

Question 138

What type of epithelium is that of the bronchus?

Answer 138

Pseudostratified

Question 139

What is BALT?

Answer 139

Bronchus-associated lymphoid tissue

Question 140

Does BALT have germinal centers?

Answer 140

Yes

Question 141

What is the difference between BALT and lymph nodes?

Answer 141

LNs are more well defined and have a capsule with afferent and efferent lymphatic vessels for fluid circulation

Question 142

What are club cells?

Answer 142

Clara cells. They are nonciliated bronchiolar secretory cells that secrete surfactants, and are progenitors for other cells

Question 143

Is the beating of cilia ATP dependent?

Answer 143

Yes

Question 144

What causes ciliary dyskinesia?

Answer 144

Disorder of motor proteins within cilia

Question 145

What does ciliary dyskinesia lead to?

Answer 145

Mucus buildup with dirt and bateria

Question 146

What influences mucus production?

Answer 146

DNA of damaged cells

Question 147

What causes cystic fibrosis?

Answer 147

Mutations that affect chloride ion channels, preventing them from getting to the cell surface, leading to thick sticky buildup and flattening of cilia

Question 148

What is metaplasia?

Answer 148

A change of one cellular phenotype to another

Question 149

What is a risk factor for tumorlets?

Answer 149

Chronic or repeated inflammation, causing consistent increase in neuroendocrine bundles aka hyperplasia

Question 150

What is the CTFR?

Answer 150

Ion transporter that regulates mucus viscosity

Question 151

What does surfactant do?

Answer 151

Lower surface tension to be able to breathe more easily

Question 152

How many type 2 pneumocytes are there per type 1 pneumocyte?

Answer 152

2

Question 153

What is the stem cell for type 1 pneumocytes?

Answer 153

Type 2 pneumocytes

Question 154

Why is the pleura being so thin important?

Answer 154

Negative pressure between the lung and the thorax

Question 155

Why is pulmonary infection the most common type of infection?

Answer 155

Exposure/interface with the environment

Question 156

What is a typical infection dynamic of viral pneumonia?

Answer 156

Usually self-limiting, but dominated by secondary bacterial infection in severe cases

Question 157

What is one problem with histological diagnosis of viral pneumonia?

Answer 157

Limited morphological specificity

Question 158

What group is most likely to get ill from CMV infection?

Answer 158

Immunocompromised people

Question 159

What is histologically characteristic for DNA virus infections?

Answer 159

Large nuclei due to replication

Question 160

What predicts the type of bacterial pneumonia?

Answer 160

The setting (community acquired, nosocomial, immunocompromised, etc)

Question 161

What are the two pathological patterns in bacterial pneumonia?

Answer 161

Bronchopneumonia and lobar pneumonia

Question 162

Species from which fungal phylum can cause disease in individuals with impaired immunity?

Answer 162

Mucormycetes

Question 163

What is the definition of sarcoidosis?

Answer 163

A granulomatous disorder of unknown cause affecting multple organs

Question 164

What organ is mostly involved in sarcoidosis?

Answer 164

Lungs, but generally more often organs more exposed to the air

Question 165

How often do sarcoidosis patients develop progressive disease?

Answer 165

1/3 of patients

Question 166

What surrounds granulomas?

Answer 166

T cells

Question 167

What is the epidemiological pattern of sarcoidosis?

Answer 167

High rate in scandinavia but low morbidity, lower rates in other places but worse prognosis

Question 168

What is the prevalence of chronic development of sarcoidosis in non-LS patients?

Answer 168

50%, about 20% with fibrosis

Question 169

What are triggers of sarcoidosis?

Answer 169

Anorganic exposure, antigen exposure

Question 170

What drives a granuloma?

Answer 170

Ongoing cytokine production by T helper cells around a trigger

Question 171

What type of Th cells are present in pulmonary sarcoidosis?

Answer 171

Th17.1 cells

Question 172

What is a biomarker of patients who develop chronic sarcoidosis?

Answer 172

Higher Th17.1 proportion to other Th cells

Question 173

What is CTLA4?

Answer 173

A co-inhibitory receptor with higher affinity for CD80/CD86 than CD28

Question 174

What is the CTLA4 expression level in memory Th cells in sarcoidosis, and what type of Th cells?

Answer 174

Reduced, Tregs and Th17

Question 175

What does an increase in Th17 with reduced CTLA4 expression do?

Answer 175

Enhanced pro-inflammatory activity

Question 176

What is double trouble in sarcoidosis?

Answer 176

Reduced expression of CTLA4 in Tregs (less inhibition) and Th17 (enhanced pro-inflammatory response)

Question 177

What drug classes are associated with sarcoid-like reaction?

Answer 177

Checkpoint inhibitors

Question 178

What is ICOS?

Answer 178

The memory and effector T cell version of CD28, which sustains proliferation and activation

Question 179

What is 4-1BB?

Answer 179

It can be activated in place of CD28 when absent

Question 180

Is CD80/CD86 constitutive or induced?

Answer 180

Induced: only expressed by activated APCs

Question 181

What does JAK inhibition do?

Answer 181

Targets multiple cytokines involved in sarcoidosis, since JAK is a kinase in many pathways involved with cytokine signaling

Question 182

Is ICOS constitutive or induced?

Answer 182

Induced

Question 183

What happens when T cells become exhausted?

Answer 183

They slowly gain inhibitory receptors, starting with PD-1, and start losing their ability to make cytokines, proliferate and maintain. They end apoptotic.

Question 184

In what conditions does T cell exhaustion occur?

Answer 184

Chronic viral infections, cancer/tumors, autoimmunity

Question 185

What is the underlying cause of disease of interstitial lung disease?

Answer 185

Highly variable, over 200 known, including autoimmune disease, exposure-related, sarcoidosis, idiopathic, etc.

Question 186

What is the initial site of damage in ILD associated with environmental factors or exposure?

Answer 186

Epithelial cell

Question 187

What happens initially in ILD when associated with autoimmunity?

Answer 187

Immune complex formation and vascular blockage

Question 188

What is the late phase of ILD?

Answer 188

Fibrosis

Question 189

Can ILD be reversible?

Answer 189

Only in the early phase

Question 190

What is a major clinical need in fibrotic ILD?

Answer 190

To distinguish inflammation from fibrosis

Question 191

What is a histological hallmark of ILD fibrosis?

Answer 191

Honeycombing

Question 192

What is hypersensitivity pneumonitis?

Answer 192

Immune-mediated response by susceptible and sensitized individuals to inhaled environmental antigens

Question 193

What is Acute HP?

Answer 193

Intermittent high level exposure to inducing antigen

Question 194

What is chronic HP?

Answer 194

Chronic low level exposure to inducing antigen, which can be stable non-fibrotic but can sometimes progress to fibrotic

Question 195

How do connective tissue diseases play a role in ILD?

Answer 195

Autoimmune diseases like RA and SLE can lead to immune-mediated damage to lung tissue such as autoantibodies forming immune complexes and blocking and damaging capillaries

Question 196

What is the pathogenic cytokine in pulmonary fibrosis?

Answer 196

IFNy, in the sense that it should inhibit Th2 but somehow doesnt

Question 197

What cells are pro-fibrotic?

Answer 197

Th2

Question 198

What is the dominant profile in pulmonary fibrosis?

Answer 198

Th2, but Th17 is also a bit pro-fibrotic

Question 199

What are idiopathic pulmonary fibrosis risk factors?

Answer 199

50-70 years of age, predominantly men, often smokers, genetic predisposition

Question 200

What is a very pro-fibrotic cytokine?

Answer 200

TGFß

Question 201

How is fibrosis induced?

Answer 201

Through TGFß:
-signals fibroblasts or epithelial cells to differentiate into myofibroblasts, which leads to production of extracellular matrix.
-Inhibits ECM degradation
-Inhibits lymphocyte proliferation and macrophage activation

Question 202

What categories are genes associated with IPF subdivided into?

Answer 202

Telomere biology (telomerase) and surfactant metabolism and Muc5B

Question 203

What removes senescent cells?

Answer 203

NK cells usually, however they are dysfunctional in IPF

Question 204

What predicts IPF outcome?

Answer 204

Telomere length

Question 205

Where are biologicals derived from?

Answer 205

Biological sources

Question 206

What is the efficacy of biologicals?

Answer 206

Overall much greater than other therapeutics

Question 207

What are the two main modes of action of biologicals

Answer 207

Soluble mediator binding or binding of cell surface molecules

Question 208

What are ways cell surface molecules binding biologicals can help in a disease?

Answer 208

Cell elimination and receptor blocking

Question 209

How can soluble mediator binding by biologicals help in a disease?

Answer 209

Neutralization: cytokines, growth factors, etc

Question 210

Are checkpoint inhibitors biologicals?

Answer 210

Yes

Question 211

What is the mechanism of checkpoint inhibitors?

Answer 211

Anti-PD-1 prevent binding of co-inhibitory binding allowing T cells to bind

Question 212

Where can checkpoint inhibitors act?

Answer 212

During the priming phase and effector phase

Question 213

Where is the priming phase and how can checkpoint inhibitors act there?

Answer 213

Prevent development of inhibitory receptors on T cells

Question 214

What is -omab

Answer 214

Mouse derived mAb

Question 215

What is -ximab

Answer 215

Chimeric mAb

Question 216

What is -zumab

Answer 216

Humanized mAb

Question 217

What is -umab?

Answer 217

Human mAb

Question 218

What is the possible negative impact of ADA on disease activity?

Answer 218

Rapid clearance and loss of response, which can later have an impact on disease severity, which is why monitoring is really important

Question 219

What is the biologic trough level?

Answer 219

The amount needed of a biological to be effective

Question 220

What is it called when you analyze ADA presence or biologic trough level?

Answer 220

Therapeutic drug monitoring

Question 221

What does bioavailablity depend on?

Answer 221

Distribution, degradation and neutralization

Question 222

How are trough levels determined?

Answer 222

ELISA

Question 223

Are all ELISA assays the same?

Answer 223

No

Question 224

What can anti-thyroid antibodies predict?

Answer 224

Efficacy of anti PD-1 antibodes

Question 225

What are biosimilars?

Answer 225

B brand unpatented biologicals

Question 226

What is the risk of treating humans with gene therapy?

Answer 226

Introduction into the environment

Question 227

What’s the difference between DM and ML?

Answer 227

DM involves an animal plus a genetically modified organism, whereas ML only involves a genetically modified organism

Question 228

What is needed to be allowed to treat patients with gene therapy?

Answer 228

An IM-VM permit

Question 229

Look up the 8 pillars of biosecurity

Answer 229

Awareness, personnel reliability, …

Question 230

What are the three ladder steps of psoriasis?

Answer 230

Topical, photo, systemic

Question 231

What is important for pathogenesis in psoriasis?

Answer 231

Inflammatory cytokines, most notably IL23 (and IL17)

Question 232

What is a potential side effect of biologics use?

Answer 232

Infections

Question 233

What type of adalunimab used in EMC?

Answer 233

Biosimilar

Question 234

Why can you rebound with biological use?

Answer 234

Immune reaction against the biological: ADAb

Question 235

What is ADAb

Answer 235

Anti-drug antibodies, the change the bioavailability of a drug

Question 236

What is necessary for long antibody halflife?

Answer 236

High affinity binding to the FcRn receptor

Question 237

Why is it no use to give more of a drug than necessary?

Answer 237

No increased improvement

Question 238

Why could an Ab gradually become less effective over long periods of time?

Answer 238

Changes in the disease

Question 239

What if you have a low trough level and no to low anti antibodies?

Answer 239

The patient is likely not taking the drug

Question 240

What do you do if you don’t find a drug in nonresponders but do find ADAb?

Answer 240

Switch to a less immunogenic drug

Question 241

What are immunogenic drugs?

Answer 241

Drugs against which a patient has an immune response

Question 242

What do you do when you have a nonresponder and find a high enough trough level?

Answer 242

Change to a different mode of action

Question 243

What is a calcineurin inhibitor

Answer 243

Tacrolimus

Question 244

What is the main immunosuppressive drug

Answer 244

Tacrolimus

Question 245

What is a pro of tacrolimus

Answer 245

Low level of rejection

Question 246

What are 5 problems with tacrolimus

Answer 246

Narrow therapeutic window, nephrotoxicity, neurotoxicity, incidence of diabetes, a specific (infections)

Question 247

What does belatacept do?

Answer 247

Blocks both CD80/86 (polyclonal) -> costimulation

Question 248

Imlifidase mode of action

Answer 248

Cleaves IgG

Question 249

What are three new forms of immunosuppression?

Answer 249

Anti IL-6, imlifidase and CAR-T cells

Question 250

In what way is tacrolimus better than cyclosporin?

Answer 250

Better kidney function

Question 251

What is surfactant produced by?

Answer 251

Type II pneumocytes

Question 252

What was the PANTHER trial?

Answer 252

They used prednisone and two other therapeutics to try to knock out the immune system of IPF patients, causing many people to die

Question 253

Does anti-microbial therapy improve IPF symptoms?

Answer 253

No. You take away the trigger but not the immune response and damage already done

Question 254

Is there antifibrotic therapy and (how) does it work?

Answer 254

Yes, Ninedanib (also other ILD types): and Pirfenodone (only IPF). Both kinase inhibitors for certain cytokines such as TGFß. Quality of life is still not great once already fibrotic

Question 255

What is the most prominent type of asthma?

Answer 255

Type 2 asthma

Question 256

What are two ways to treat asthma?

Answer 256

Corticosteroids and Bronchodilators (ß2-agonists)

Question 257

What do corticosteroids target?

Answer 257

Almost every immune cell

Question 258

What do bronchodilators target?

Answer 258

Smooth muscle cells of the airway walls

Question 259

What are two down sides to corticosteroid use against asthma?

Answer 259

Can cause severe side effects, and sensitivity and response is highly dependent on disease phenotype

Question 260

What causes disease exacerbations in asthma?

Answer 260

Respiratory viral infections

Question 261

What is a doenside of ß2 agonist use?

Answer 261

It only targets one symptom and does not treat the inflammation

Question 262

What happens to tissues in chronic asthma?

Answer 262

Irreversible tissue remodelling, goblet cell hyperplasia

Question 263

What causes the rapid constriction of the airway in asthma?

Answer 263

Mast cell degranulation (histamine)

Question 264

What time of onset of asthma is Th2-associated and which is non-Th2 associated?

Answer 264

Childhood is Th2 (T2 high), usually allergy driven.
Adult is non-Th2 (T2 low), obesity and smoking associated, the later neutrophilic. Also smooth muscle mediated

Question 265

What cytokines and adaptive and innate cells does T2 high asthma involve?

Answer 265

IL-4, IL-5, IL-13 and IL-9, Th2 and ILC2 and honestly almost every immune cell, even B cells

Question 266

What does IL-5 lead to?

Answer 266

Tissue eosinophilia

Question 267

What does IL-4 lead to?

Answer 267

IgE

Question 268

What do Th17 cytokines lead to in asthma?

Answer 268

T2 low asthma -> neutrophil recruitment

Question 269

What cells are involved in T2 low asthma?

Answer 269

Th1, Th17, macrophages and ILC1

Question 270

What type of asthma is characterized by neutrophilic inflammation and involved IFNy and IL-17?

Answer 270

T2 low

Question 271

What type of asthma is characterized by eosinophilic inflammation, type 2 cytokines and allergen-specific B cells and IgE?

Answer 271

T2 high

Question 272

What type of receptor do mast cells have?

Answer 272

Igε

Question 273

What are alarmins?

Answer 273

Innate cytokines produced by epithelial cells that affect DCs and activate ILCs

Question 274

What do dendritic cells do in T2 high astghma?

Answer 274

Take up allergen, migrate to LN, active naive T cells, which proliferate and differentiate into Th2 cells.

Question 275

What are the two ways type 2 cytokine production is induced in T2 high asthma?

Answer 275

DCs to Th2 and alarmins to ILC2

Question 276

What does IL-13 do?

Answer 276

Disturb epithelial homeostasis by affecting the tight junctions and causing goblet cell hyperplasia, cause activation and migration of DCs

Question 277

Where are neuroendocrine cells mostly found?

Answer 277

Bronchioles

Question 278

Where are goblet cells mainly found?

Answer 278

Trachea and bronchi, a bit in bronchioles

Question 279

Where are submocosa glands found?

Answer 279

Trachea and bronchi

Question 280

Where are club cells found?

Answer 280

Trachea, bronchi and bronchioles

Question 281

What do ILC2 cells respoind to?

Answer 281

alarmins produced by the epithelium

Question 282

What cells do ILC2s interact with?

Answer 282

Almost everything you can think of

Question 283

What cell makes the most IL-25?

Answer 283

The tuft cell

Question 284

What is IL-13 essential for?

Answer 284

DC activation andmigration in protease-induced allergic airway inflammation

Question 285

What is a marker for activated ILC2s?

Answer 285

CD-45RO

Question 286

What is high levels of CD-45RO+ ILC2 associated with?

Answer 286

Asthma severity and unresponsiveness to corticosteroids

Question 287

What happens with chromatin in asthma patients?

Answer 287

It is open at genes encoding for ILC2

Question 288

How can viral infections exacerbate asthma symtpoms?

Answer 288

They can turn into cytotoxic T cells that produce Th2 type cytokines. It’s weird because type 1 cytokines usually surpress Th2 responses.

Question 289

What is the cytokine production pattern of CD8 T cells in severe asthma patients?

Answer 289

Type 2 cytokine production by CD8 T cells is highest in severe asthma patients

Question 290

What is the paradox in CD8 T cells responses in asthma?

Answer 290

After viral infections, CD8 T cells, which usually produce IFNy which counteracts Th2 responses, can produce type 2 cytokines, also in patients that are unresponsive to corticosteroids

Question 291

What is inflammatory bowel disease?

Answer 291

An intolerance to microbiota in the intestines

Question 292

What is dysbiosis?

Answer 292

There are large shifts in the microbiota present in the GI tract

Question 293

What are 4 factors that can contribute to dysbiosis?

Answer 293

Genetics, lifestyle (diet, stress), early colonization (during birth), medical practices (vaccination, antibiotics, hygiene)

Question 294

What part of the intestines does UC affect?

Answer 294

The colon, always one adjacent superficial area

Question 295

What part of the intestines does Crohn’s disease affect?

Answer 295

Can affect any area in the GI tract with healthier areas and areas with lesions

Question 296

What are cobblestones and what are they a hallmark of?

Answer 296

Crohns. They are healthy pieces of tissue buldging out due to scar tissue that pushes softer tissue out

Question 297

What is transmural?

Answer 297

Affecting all layers (of the bowel wall in Crohn’s)

Question 298

Do you see granulomas in IBD?

Answer 298

In 60% of Crohn’s patients

Question 299

What are two big histological distinguisher sbetween Crohn’s and UC?

Answer 299

Granulomas (though only in 60% of patients) and transmural vs superficial

Question 300

What are typical histological signs in Crohn’s?

Answer 300

Patchy, transmural, lymphocyte infiltratin, Granuloma presence (60%), ulcer formation

Question 301

What are typical histological signs of UC?

Answer 301

Superficial, lymphocyte infiltration, empty goblet cells, presence of ulcerations and crypt absesses (cells within crypt lumen)

Question 302

SNPs in what types of genes are involved in IBD?

Answer 302

Immune-related (Innate, adaptive, HLA, epithelium, etc)

Question 303

How can we classify IBD to battle heterogeneity in IBD?

Answer 303

Genetic susceptibility in groups of genes associated with the same pathways. This way we can see what pathways are essential, what type of inflammation emerges from particular defects and what microbial changes can we relate to this?

Question 304

What is Chronic Granulomatous Disease?

Answer 304

Defective neutrophil function which leads to IDB caused by defective defense.

Question 305

What is IL-10 RA deficiency?

Answer 305

Defective regulation of IL-10 signaling which leads to IBD cause by hyperactive host defense

Question 306

Do IBD patients usually only have one SNP?

Answer 306

No, it often is SNPs in multiple genes which makes treatment very difficult

Question 307

What is NOD2?

Answer 307

A NOD-like receptor (PRR) expressed by monocytes, macrophages, DCs and gut epithelial cells. Activation leads to NF-kB activation.

Question 308

What is NOD2 polymorphisms associated with?

Answer 308

Crohn’s disease in the ileum.

Question 309

How does NOD2 affect Paneth cells?

Answer 309

Promotes the production of AMPs

Question 310

How does NOD2 affect stem cells?

Answer 310

Induces survival through resistance to oxidative stress

Question 311

How does chronic NOD2 stimulation affect APCs?

Answer 311

Downregulates pro-inflammatory cytokine production through reduced TLR2 signals

Question 312

How does NOD2 affect macrophages?

Answer 312

Inhances killing through inflammasome mediated caspase-1 activation

Question 313

What type of signalling is crucial for epithelial barrier function in the gut?

Answer 313

NF-kB

Question 314

What happens if NF-kB is knocked out?

Answer 314

Chronic severe intestinal inflammation and increased TNF-mediated cell death (apoptosis), leading to infiltration

Question 315

What drives colitis in IL-10 deficient mice?

Answer 315

Helicobacter (microbiota in general)

Question 316

What drives small intestine inflammation in IL-10 deficient mice?

Answer 316

Dietary antigens

Question 317

Why does IL-10 deficiency in Tregs mainly affect the colon and not the small intestines?

Answer 317

There are other cells in the small intestine that can produce IL-10 such as Tr1, so there is more of a division of labor.

Question 318

What is celiac disease?

Answer 318

Gluten induced inflammation of the GI tract

Question 319

What is inflammed in celiac disease?

Answer 319

The proximal intestines, causing perturbation of nutrient uptake

Question 320

Is there a cure for celiac?

Answer 320

No

Question 321

Does celiac have genetic susceptibility?

Answer 321

Yes, HLA-DQ2 (95% of cases) or HLA-DQ8.

Question 322

Does HLA-DQ2 lead to celiac?

Answer 322

No, only a minority get celiac, though 95% of celiac cases have HLA-DQ2

Question 323

What are histological hallmarks of celiac disease?

Answer 323

Duodenal crypt hyperplasia and duodenal villous atrophy

Question 324

What types of T cells can be found in by gluten-inflammed intestinal tissue?

Answer 324

CD8 intraepithelial lymphocytes and gliadin-specific IFNy-secreting CD4 T cells in the lamina propria

Question 325

What can be found in the serum of celiac patients?

Answer 325

autoantibodies against tissue transglutaminase 2

Question 326

What drives celiac disease chronicity?

Answer 326

Gliadin-specific memory CD4 T cells

Question 327

Why is HLA-DQ2 associated with celiac?

Answer 327

Deamidated gluten peptides fit in HLA-DQ2

Question 328

How is celiac diagnosed?

Answer 328

anti-tissue transglutaminase 2 antibodies in the serum combined with a positive HLA-DQ2 or 8 test

Question 329

Explain pathogenesis of celiac.

Answer 329

1. Gluten is ingested
2. Gluten passes the epithelial barrier, possibly through diffusion
3. Deamidation by tissue transglutaminade 2
4. Presentation by HLA-DQ2 of 8 to T cells
5. Inflammatory T cell differentiation

Question 330

Do anti-tissue transglutaminase 2 antibodies contribute to celiac?

Answer 330

No

Question 331

Why are anti-tissue transglutaminase 2 antibodies produced?

Answer 331

The gliadin-tissue transglutaminase 2 complex is likely no longer seen as “self”

Question 332

What is the most important cytokine in celiac disease?

Answer 332

IL-15 (but there is also IFNα and IL-21)

Question 333

What are possible inducers of IL-15?

Answer 333

Virus/intracellular pathogens, IFNα, gliadin peptides

Question 334

What are two adaptive responses during celiac disease?

Answer 334

1. Inflammatory gliadin-specific HLA-DQ-restricted CD4 T cells secrete IFNy
2. Plasma B cells secrete anti-tissue transglutaminase 2 (TG2) antibodies

Question 335

What are two innate responses during celiac disease?

Answer 335

1. Innate epithelial cells are stressed and secrete IL-15 and express NK-ligands
2. CD8 MHCI intraepithelial lympocytes (IELs) lyse epithelium

Question 336

How does the pathogenesis of celiac work regarding IELs?

Answer 336

1. CD4 T cell derived IFNy causes epithelial cell stress and activates cytotoxic IEL
2. IL-15 production by stressed epithelial cells co-stimulates cytotoxic IEL
3. Cytotoxic IELs kill epithelial cells

Question 337

What is the role of IL-10 in mice regarding celiac?

Answer 337

Mice require IL-10 to maintain tolerance against gluten-derived gliadin

Question 338

What does the mucosa refer to?

Answer 338

Everything from the lumen to the muscularis mucosa

Question 339

What is the normal villi-crypt ratio?

Answer 339

3:1 (to 5:1) in adults, 2:1 in children

Question 340

What is the normal amount of intraepithelial lymphcytes in the villi of the duodenum and jejunum?

Answer 340

Up to 1 in 4 (25 per 100)

Question 341

Where are biopsies to test for celiac taken from?

Answer 341

Duodenal bulb and the distal portion of the duodenum

Question 342

What are 2 pre-requisites for accurate diagnosis with celiac via biopsy?

Answer 342

The tissue fragments need to be well-oriented and they must be performed when the patients consumes a gluten-containing diet

Question 343

What are the 4 cardinal histological markers for celiac disease?

Answer 343

1. lower villi:crypt ratio (atrophy of the villi)
2. crypt hyperplasia
3. increase of interepithelial lymphocytes (IE lymphocytosis)
4. chronic inflammatory cell infiltration in the lamina propria

Question 344

What does atrophy mean?

Answer 344

To waste away due to degeneration of cells

Question 345

How is celiac severity scored?

Answer 345

Proportion of lymphocytes and levels of crypt hyperplasia and villous atrophy

Question 346

What two things are part of normal ileum architecture?

Answer 346

1. Increased proportion of goblet cells compared to other parts of the small intestine
2. Presence of Peyer’s Patches

Question 347

What 3 things are part of normal colon architecture?

Answer 347

1. Crypts lined with columnar cells
2. Crypts oriented parallel to one another and perpendicular to muscularis mucosa
3. Lamina propria is mostly lymphocytic and plasmacytic, with varying numbers of eosinophils and mast cells

Question 348

What are differential diagnoses?

Answer 348

Possible diagnoses

Question 349

How should a pathologist assess the colon for IBD?

Answer 349

Between different sites, between biopsies from the same site and within each biopsy

Question 350

What are three patterns of inflammation in an intestinal biopsy?

Answer 350

Diffuse, patchy, focal

Question 351

How can you determine whether there is evidence of basal lymphoplasmacytosis?

Answer 351

Infiltration of cells in an area between the crypts and the muscularis mucosa (there should not be space between those)

Question 352

What does a crypt abcess look like?

Answer 352

Immune cells in the lumen of crypts

Question 353

What is it called when there is space between the crypts and the muscularis mucosa filled with immune cells?

Answer 353

Basal lymphoplasmacytosis

Question 354

What do crypts look like in Crohn’s disease?

Answer 354

Distorted: splitting or loss, etc

Question 355

What is it called when there are immune cells between the epithelial cells of the crypts?

Answer 355

Cryptitis

Question 356

Are paneth cells usually found in the crypts of the colon?

Answer 356

No. If they are it is called Paneth cell metaplasia

Question 357

Should mucus (goblet) cells be present or visible in the colon?

Answer 357

Yes. If not it’s called mucin depletion

Question 358

In summary, what are the 4 things to look for in IBD (histologically?)

Answer 358

1. Architectural changes
2. Chronic inflammation of the lamina propria
3. Acute inflammation
4. Epithelial changes

Question 359

What is found only in Crohn’s disease and not in ulcerative colitis?

Answer 359

Granulomas

Question 360

How long does it take for pedriatric IBD to resolve?

Answer 360

It’s incurable and lifelong

Question 361

Is Adult IBD or pediatric IBD more severe?

Answer 361

Pediatric

Question 362

What is the inflammation pattern in Crohn’s versus UC?

Answer 362

Crohn’s: whole GI, transmural
UC: Colon only, diffuse, mucosal inflammation

Question 363

What is the first diagnostic tool to be used to diagnose IBD?

Answer 363

Endoscopy

Question 364

What are four things to measure for in blood for Crohn’s disease diagnosis?

Answer 364

CRP (acute inflammation), Erythrocyte sedimentation rate (ESR, marker of systemic inflammation), low albumin (protein loss/malnourishment), high calprotectin

Question 365

What can you find in UC patients in the blood?

Answer 365

Low iron/hemoglobin (anemia) due to bleeding

Question 366

What are 4 procedures to diagnose IBD?

Answer 366

1. Endoscopy
2. Bloodwork
3. Stool analysis
4. Maybe ultrasound (constriction in Crohn’s)

Question 367

What does infliximab do?

Answer 367

Anti-TNF antibody

Question 368

How can Infliximab be used in Crohn’s and what does it do?

Answer 368

Infliximab is best used right after diagnosis to prevent further irreversible destruction of the intestines.
It induces mucosal healing by blocking TNF.

Question 369

How can we predict whether patients will be able to switch to dietary intervention after Infliximab or have to maintain Infliximab use?

Answer 369

Patients with low pre-treatment levels of Infliximab-modulated proteins are more likely to be able to stop Infiliximab treatment after remission and switch to dietary intervention

Question 370

What is autografting?

Answer 370

Transfer of living cells, tissues or organs from one part of the (same) body to another

Question 371

What is allografting?

Answer 371

Transfer of living cells, tissues or organs from one individual to another

Question 372

What is xenografting?

Answer 372

Transfer of living cells, tissues or organs from one species to another

Question 373

What is the allo-immune response?

Answer 373

An immune response to non-self antigens from members of the same species (allo-antigens)

Question 374

What two types of rejection are there?

Answer 374

Cellular rejection and antibody-mediated rejection

Question 375

In what two ways can antigens be presented to B cells?

Answer 375

Directly to the B cell, or through helper T cells

Question 376

What 3 types of allo-antigens are there?

Answer 376

1. Major histocompatibility complex (MHC) (or HLA) antigens
2. Minor histocompatibility complex antigens (miHA/non-MHC antigens)
3. Blood group antigens

Question 377

What type of antigen causes the strongest and fastest rejection?

Answer 377

MHC. It is the main cause of grant rejection

Question 378

What type of antigen causes slow and weak graft rejection?

Answer 378

miHA or non-MHC antigens. It requires different antigen processing.

Question 379

What mismatched cells can be recognized by CD8 cells?

Answer 379

All nucleated cells

Question 380

What mismatched cells can be recognized by CD4 cells?

Answer 380

Antigen presenting cells and activated CD4 cells

Question 381

How are minor allo-antigens presented?

Answer 381

They are taken up and presented by recipient HLA molecules to recipient T cells, like all other peptides

Question 382

What are minor-allo antigens?

Answer 382

All non-MHC proteins that differ in amino acid composition between toe donor and recipient outside of MHC due to mutations or genetic polymorphisms

Question 383

Does presentation of red blood cell antigens require T cell help?

Answer 383

No, they immediately activate B cells

Question 384

What types of antibodies do you have if you are blood group A?

Answer 384

Anti-B

Question 385

What type of antibodies do you have if you are blood group B?

Answer 385

Anti-A

Question 386

What type of antibody do you have if you are blood group AB?

Answer 386

None against blood groups

Question 387

What type of antibody do you have if you are blood group O

Answer 387

Both Anti-A and Anti-B

Question 388

What is the most important allo-antigen recognition pathway?

Answer 388

Direct allo-recognition, of intact foreign HLA molecules on donor APCs by recipient T cells

Question 389

What is cross-reactivity in allo-recognition?

Answer 389

When T cell receptors can recognize peptides presented by intact foreign HLA molecules, causing an immune response

Question 390

What is peptide-independent binding?

Answer 390

When the recipient TCR recognizes the donor MHC but not the peptide

Question 391

What is peptide-dependent binding?

Answer 391

When the recipient TCR recognizes only the peptide but not the donor MHC presenting it

Question 392

What is foreign peptide:self MHC binding?

Answer 392

When the recipient TCR recognizes a foreign peptide on the recipient (own) MHC

Question 393

What is indirect allo-recognition?

Answer 393

When a donor peptide is taken up by a recipient APC and presented to the recipient TCR (through self-MHC)

Question 394

What is the semi-direct recognition pathway?

Answer 394

When an APC of the recipient presents a donor peptide on a donor HLA to a recipient TCR

Question 395

How can donor matching be tested in the lab?

Answer 395

Mixed lymphocyte reaction with T cell activation or cytokine production as read-outs

Question 396

What are two signs of kidney transplant rejection?

Answer 396

A rise in creatinine and descreased urine production

Question 397

What is done after creatininine and urine tests to prove kidney rejection?

Answer 397

Biopsy and histology

Question 398

What are measurable signs of liver rejection?

Answer 398

Rise in serum aminotransferases (ASAT, ALAT), alkaline phosphatase, bilirubin

Question 399

How is heart rejection tested?

Answer 399

Biopsy. There is no other biochemical way.

Question 400

What is a 4th target for organ transplant rejection?

Answer 400

Injury

Question 401

What happens when there is a blood group mismatch?

Answer 401

Blockages of capillaries, hyperacute rejection within minutes or hours. Causes severe damage by antibodies of the recipient

Question 402

What is hyperacute rejection?

Answer 402

Blood group mismatch causes severe damage to the transplant, causing organ loss within minutes or hours

Question 403

Can there already be pre-existing anti-donor HLA antibodies?

Answer 403

Yes, due to pregnancy, blood transfusions or earlier transplantations

Question 404

What are the 2 requirements for organ transplantation?

Answer 404

1. ABO system compatibility
2. Negative cross match (except for liver)

Question 405

How does tissue injury play a role in rejection?

Answer 405

reactive oxygen species, cellular damage, imflammatory cytokines, immune cell attraction and attachment of immune cells to inflamed endothelium

Question 406

Why can’t cardiac death donors donate?

Answer 406

Stopped circulation leads to lack of oxygen supply to the organ

Question 407

Why can’t brain dead donors donate?

Answer 407

Cytokine storm

Question 408

How can tissue injury be minimized?

Answer 408

Machine preservation

Question 409

What is the type of rejection based on?

Answer 409

The type of immune cells involved and how quickly rejection occurs

Question 410

What is hyperacute rejection?

Answer 410

Immediate lysis of donor cells due to ABO or donor HLA specific antibodies

Question 411

What type of rejection can take weeks or years?

Answer 411

Humoral rejection: B cell-mediated (antibody-mediated) rejection

Question 412

How can humoral rejection be detected?

Answer 412

C4d staining in capillaries

Question 413

What is CMV seropositivity a risk factor for?

Answer 413

Antibody-mediated rejection

Question 414

How can you treat acute cellular rejection?

Answer 414

High doses of methylprednisolone, otherwise T cell depletion

Question 415

How can you treat acute antibody-mediated rejection?

Answer 415

Plasmapheresis (antibody depletion), IVIg, otherwise Rituximab (anti-CD20) therapy

Question 416

What is rituximab?

Answer 416

Anti-CD20 therapy, so B cell depletion

Question 417

What are signs of chronic kidney rejection?

Answer 417

Increase of serum creatinine, proteinuria, hypertension

Question 418

What are two reasons chronic organ rejection happens?

Answer 418

1. Low levels of immune attack against the organ
2. Chronic calcineurin inhibitor (Tacrolimus) nephrotoxicity

Question 419

What is needed for improved immunosuppressive therapy?

Answer 419

Something as effective or more effective than Tacrolimus, but less nephrotoxic

Question 420

What Class I HLAs are mostly looked at in transplants?

Answer 420

A and B

Question 421

What Class II HLAs are mostly looked at in transplants?

Answer 421

DR

Question 422

When is Class I C and Class II DQ and DP also looked at for matching?

Answer 422

Stem cell transplants

Question 423

Why is strict stem cell matching important?

Answer 423

Because there is a huge risk of rejection but also that the new immune system also attacks the recipient body

Question 424

What are two clinical consequences of mismatching in solid organ transplant?

Answer 424

1. Host versus graft (HvG) -> rejection
2. Graft versus host (GvH) -> GvHD

Question 425

In what setting can you get host versus graft and thus rejection?

Answer 425

Usually HLA mismatching in solid organ transplants

Question 426

In what setting can you get graft-versus-host and this graft versus host disease?

Answer 426

In hematopoetic stem cell transplation when the stem cells differentiate into immune cells that attack the recipient immune system due to HLA mismatching

Question 427

What can cause sensitization before transplantation?

Answer 427

Pregnancy, previous transplants and blood transfusion

Question 428

What is sensitization in transplantation?

Answer 428

Formation of anti-HLA antibodies such as against paternal HLA molecules during pregnancy, making it more difficult to find a suitable donor

Question 429

What happens when anti-HLA antibodies encounter a mismatched organ?

Answer 429

Hyperacute rejection, which happens within minutes or hours

Question 430

What has reduced the incidence of hyperacute rejection?

Answer 430

Serological crossmatching

Question 431

What causes de novo antibody formation after transplantation?

Answer 431

Humoral alloimmune responses

Question 432

What can de novo antibody formation after transplantation lead to?

Answer 432

Acute humoral rejection and chronic transplant dysfunction

Question 433

What are 4 HLA screening methods used in the lab?

Answer 433

HLA typing, HLA antibody screening, crossmatching and donor search

Question 434

What is a luminex platform?

Answer 434

A multiplex ELISA with color-coded beads with specific HLA oligonucleotides

Question 435

What types of samples are used in crossmatching assays?

Answer 435

Patient serum and donor cells from the blood or spleen + complement

Question 436

What is flow crossmatch?

Answer 436

Same as normal crossmatching, but with an anti-IgG label instead of complement to measure using flow cytometry

Question 437

What are 5 reasons to do a renal biopsy?

Answer 437

1. Provides a diagnosis (toxicity, rejection, viral, donor disease)
2. Guides treatment (changes in more than half of the cases)
3. Predicts prognoses
4. Reveals pathogenesis
5. Validates outcome (as endpoint result in clinical trials)

Question 438

What are 6 pitfalls in nephropathology?

Answer 438

1. Morphology not specific
2. Sample size
3. Sample location might not show primary lesion
4. Chronic changes can obscure origin or pathology
5. Differences in pathologist experience
6. Sampling error (might miss lesion)

Question 439

Name 4 examples of clinical information that is important to know when looking at nephropathology?

Answer 439

Anti-donor HLA antibodies
Original disease
Drug therapy
Time post transplant

Question 440

What is the Banff classification?

Answer 440

Standardized grading system to grade severity and type of rejection

Question 441

What is needed for an accurate classification according to Banff?

Answer 441

A minimum of 7 glomeruli and 2 arteries, but depends on the disease

Question 442

What are the two main types of rejection in the Banff classification?

Answer 442

Antibody-mediated rejection and T-cell mediated rejection

Question 443

What are the three levels of TCMR (histologically)

Answer 443

-bTCMR (borderline)
-I Tubulo-interstitial
-II Vascular rejection

Question 444

What can be found in AMR?

Answer 444

Antibodies, monocytes, neutrophils, and NK cells

Question 445

What morphological change is found in AMR?

Answer 445

Microvascular inflammation

Question 446

What is needed for an AMR diagnosis?

Answer 446

C4d+ and donor-specific antibodies (DSA+)

Question 447

What is BK nephrology?

Answer 447

Nephropathology caused by a polyomavirus, characterized histologically by enlarged nuclei (caused by viral replication in the nucleus)

Question 448

What is being done to improve diagnosis of transplant rejection?

Answer 448

microRNA profiling

Question 449

What 3 types of immunosuppression are there?

Answer 449

Induction therapy, maintenance therapy and anti-rejection therapy

Question 450

When is induction therapy given?

Answer 450

Shortly before and after the transplant surgery to fully knock out the immune system

Question 451

What type of induction therapy is given in a standard kidney transplantation?

Answer 451

Signal 3-blocking antibody (cytokines)

Question 452

What is blocked by the induction therapy used in The Netherlands?

Answer 452

Anti-CD25, which clocks the IL-2 receptor

Question 453

Why not use signal 1 antibodies?

Answer 453

A lot of side effects due to complete T cell depletion (infection susceptibility)

Question 454

What are 3 standard maintanence drugs given?

Answer 454

Tacrolimus (chronic calcineurin inhibitor), mycophenolate mofotil (MPA/MMF) and prednisolon

Question 455

What does Tacrolimus do?

Answer 455

Blocks downstream of signal 1

Question 456

How does prednisolon work?

Answer 456

It works anti-inflammatory and immuniosuppressive by inhibiting mRNA expression when interacting with corticosteroid receptor, mimicing cortisol. It inhibits T cell growth and differentiation.

Question 457

What is the standard immunosuppressive regimen in kidney transplantation in The Netherlands?

Answer 457

1. High dose immunosuppression: Induction with Anti-CD25 (basiliximab), Prednisolon, Tacrolimus and MMF
2. Taper down prednisolon for 3 months, also tacrolimus and MMF
3. Tacrolimus and MMF only, no more prednisolon

Question 458

What are 3 additional immunosuppressive therapies in case of rejection?

Answer 458

1. Methylprednisolon (always, high dose intravenously)
2. Alemtuzumab (T and B depletion)
3. IVIg (little evidence that it works)

Question 459

What are 3 major adverse effects of immunosuppressive drugs?

Answer 459

Infections, malignancies and cardiovascular disease

Question 460

Which immunosuppressive drug needs to be monitored closely and why?

Answer 460

Tacrolimus due to the small therapeutic window and interactions with other drugs

Question 461

How can drugs be monitored?

Answer 461

Measuring trough levels

Question 462

Which drug affects antiviral immunity the most?

Answer 462

Prednisolon

Question 463

What are 3 advantages of cellular therapies?

Answer 463

1. Less side effects
2. Long term effects (cells stick around)
3. Cellular therapy may create a balance between activation and suppression, potentially in a donor antigen specific manner

Question 464

What cells have regulatory properties?

Answer 464

Myeloid cells, Mesenchymal stem cells (MSC) and lymphoid cells

Question 465

In what two ways can myeloid regulatory cells play a role in homeostasis?

Answer 465

Either directly or by affecting Tregs

Question 466

What is pharmacokinetics?

Answer 466

What a body does to a drug

Question 467

What is pharmacodynamics?

Answer 467

What a drug does to the body

Question 468

What does ADME stand for?

Answer 468

Absorption, distribution, metabolism and elimination

Question 469

What is the absorption in an infusion?

Answer 469

almost 100%

Question 470

What is oral absorption dependent on?

Answer 470

How much the medication is absorbed and the form of the medicine (delayed-response, enteric-coating, etc.)

Question 471

What is bioavailability?

Answer 471

The fraction of an administered dose of an unchanged drug that reaches the systemic circulation. It is stated as a percentage in respect to intravenous form.

Question 472

What is F or BB?

Answer 472

Bioavailability

Question 473

What is Vd?

Answer 473

The volume of distribution

Question 474

How do you calculate the Vd?

Answer 474

Ab (drug quantity in the body)/C (blood concentration) or F*Dose/plasma concentration

Question 475

Where can a drug be distributed into?

Answer 475

Hydrophilic tissues (blood, muscles), lipophilic tissues (dermis, nerves, fat), brain (through BBB), placenta/breastmilk

Question 476

What does the volume of distribution mean?

Answer 476

The apparent or hypothetical volume in which the drug is dispersed

Question 477

Is the Vd of plasma high or low?

Answer 477

Low, around 5 liters

Question 478

What kind of drugs do you need if it has to be in the plasma?

Answer 478

High molecular weight or those that bind to plasma proteins exclusively

Question 479

What kind of drugs will distribute in the extracellular fluid?

Answer 479

Low molecular weight but hydrophilic

Question 480

What types of drugs will distribute in the intracellular fluid?

Answer 480

Those that bind strongly to tissues.

Question 481

What is the extracellular fluid Vd?

Answer 481

Equal to total water volume: ~42 L

Question 482

What is the water proportion of newborns compared to adults?

Answer 482

Much higher, around 80%. For Male adults 60 and Female adults 50

Question 483

What is metabolism?

Answer 483

Chemical conversion in the body (biotransformation)

Question 484

Why must a drug be metabolised?

Answer 484

To be converted into a water soluble form to be excreted by the kidneys

Question 485

What can genetic polymorphisms of CYP enzymes do?

Answer 485

They can speed up, slow down or otherwise change the normal breakdown of a drug

Question 486

What can drug-drug interactions do?

Answer 486

They can speed up, slow down or otherwise change the normal breakdown of a drug

Question 487

What happens when a fast metabolizer takes codeine and why?

Answer 487

Codeine is a pro-drug, which means it needs to metabolized into morphine before it can take effect. High metabolizers thus have a faster and stronger morphine effect, since more morphine goes into the system faster

Question 488

What happens when a fast metabolizer takes codeine and why?

Answer 488

Codeine is a pro-drug, which means it needs to metabolized into morphine before it can take effect. Slow metabolizers thus have a slower and weaker morphine effect, since more morphine goes into the system much slower

Question 489

How can a drug be excreted?

Answer 489

Via the urine, bile or feces

Question 490

What do you do with drug administration if someone has a decreased kidney function?

Answer 490

Dose must be decreased, since the drug will stay in the system longer.

Question 491

What are intrapatient reactions?

Answer 491

Differences in reactions of a patient to the same medication in multiple or repeated dosings

Question 492

What are interpatient reactions?

Answer 492

Differences between a group in how individuals react to a medication

Question 493

What is Tmax?

Answer 493

The time at which the blood concentration is at its highest

Question 494

What is Cmax?

Answer 494

The maximum concentration

Question 495

What is clearance?

Answer 495

The volume of plasma cleared of the drug per unit time

Question 496

What is renal clearance?

Answer 496

Via the kidneys

Question 497

What is hepatic clearance?

Answer 497

Out of the liver

Question 498

What is T1/2?

Answer 498

The time necessary to decrease the blood concentration of a medication by 50%

Question 499

What can prolong T1/2?

Answer 499

renal impairment of intoxification

Question 500

What is the general rule of when a medication is out of the blood?

Answer 500

4-5x T1/2

Question 501

When is a drug level steady?

Answer 501

3-5x T1/2

Question 502

What is AUC and when can it increase?

Answer 502

The area under the curve when concentration is plotted against time. It can increase when clearaqnce is decreased, which leads to accumulation and increases chances of side effects and toxicity

Question 503

What is the therapeutic range?

Answer 503

The window of time during which a drug is effective but not (as) toxic

Question 504

What is pharmacogenetics?

Answer 504

DNA analysis to explain or predict the response of a patient to drug therapy

Question 505

What are three main factors that determine how fast a drug is metabolized?

Answer 505

The dose, kidney function and liver metabolizing capacity (through CYP450 enzymes)

Question 506

Cytochrome P450 enzymes are responsible for the metabolism of what drugs?

Answer 506

80% of all drugs

Question 507

What causes someone to be an ultrarapid metabolizer?

Answer 507

3 copies of the CYP450 enzyme in question

Question 508

When is someone an intermediate metabolizer?

Answer 508

Usually one allele has a polymorphism associated with poor metabolism

Question 509

What causes poor metabolism?

Answer 509

Both alleles have polymorphisms associated with poor metabolism

Question 510

What CYP450 enzyme metabolizes antidepressants among many other drugs?

Answer 510

CYP2D6

Question 511

What do you have to be careful of when as patient does not react to prescribed medication?

Answer 511

They might not be adhering, it does not necessarily mean they are ultra-rapid metabolizers

Question 512

What effect can CYP2D6 polymorphisms have on codeine or tramadol?

Answer 512

They can make it so the patient has no pain relief

Question 513

What is voriconazol?

Answer 513

Antifungal

Question 514

What enzyme metabolizes Voriconazol?

Answer 514

CYP2C19

Question 515

Why are CYP polymorphisms important in transplant patients?

Answer 515

Some polymorphisms can cause poor or fast metabolism or Tacrolimus, causing either acute rejection when metabolized too fast (low concentration) or nephrotoxicity when metabolized too slow (high concentration). This is especially important since Tacrolimus has such a small therapeutic window.

Question 516

What does CYP2C19 do to voriconazol?

Answer 516

It inactivates it

Question 517

What CYP inactivates Tacrolimus?

Answer 517

CYP3A5 when expressed, most people are non-expressers

Question 518

What are the three meningeal layers that envelop the brain and spinal chord, from apical to basal?

Answer 518

Dura, arachnoid mater and pia mater

Question 519

What is the subarachoid space?

Answer 519

It is the space between the arachoid mater and pia mater that contains the cerebral spinal fluid (CSF) and blood vessels, the latter of which penetrates into the brain and spinal chord tissues as the blood-brain barrier.

Question 520

What does it mean when you can find inflammatory cells in the CSF?

Answer 520

The patient has meningitis

Question 521

Where is CSF produced?

Answer 521

In the choroid plexus

Question 522

What is cerebritis?

Answer 522

Inflammation of the brain tissue (encephalitis)

Question 523

What can cause brain abcesses?

Answer 523

Endocarditis, lung infections, abdominal infections (i.e. peritonitis)

Question 524

What is the first most fatal aspect of meningitis?

Answer 524

Brain swelling -> compressed vessels, leaking and infarctions

Question 525

What is a brain abcess?

Answer 525

A non-preformed space in the body that contains (dead) leukocytes, encapsulated by fibroblasts

Question 526

What is alzheimers disease characterized by?

Answer 526

Accumulation of amyloid-beta plaques and tau tangles

Question 527

What role do microglia play in alzheimers?

Answer 527

They can clear amyloid-beta plaques through phagocytosis, releasing IL-10 and TGFß for anti-inflammatory purposes, but can also lead to chronic inflammation and degeneration by releasing pro-inflammatory IL-12 and IL23

Question 528

What happens in gliomas?

Answer 528

An immunosupressive microenvironment is created that gliomas exploit to be able to evade and continue growing. TILs are recruited but impaired, microglia and macrophages polarize to M2 and accidentally support growth and supress immune responses, Tregs are involved, and gliomas express PD-L1.

Question 529

Is the optic nerve part of the CNS or PNS?

Answer 529

CNS

Question 530

What are 5 ways tumors avoid the immune system?

Answer 530

1. Low immunogenicity (low receptor expression)
2. Tumor treated as self antigen (no co-stimulation)
3. Antigenic modulation
4. Tumor-induced immune supression
5. Tumor-induced privilged site

Question 531

What can pass the blood brain barrier?

Answer 531

Small molecules, and large molecules only in a very controlled way

Question 532

What is the glia limitans?

Answer 532

A second tight border on the other side of the perivascular space from the BBB that tightly controls entry and exit of cells and molecules into the parenchyma

Question 533

What is the phenotype of CNS T cells?

Answer 533

Generally more inhibitory, such as Tregs

Question 534

What is the natural habitat of CNS T cells?

Answer 534

The perivascular space

Question 535

Why doesn’t the parenchyma iliccit immune responses?

Answer 535

Microglia are much less able to express traits necessary for T cell activation (tolerogenic)

Question 536

What 3 things causes this tolerogenic phenotype in microglia?

Answer 536

They require multiple cytokines for activation, are moderate APCs and express few co-stimulatory molecules

Question 537

What can neurons do to prevent inflammation?

Answer 537

They express high levels of CD200R (the perivascular space is loaded with anti-inflammatory CD200)

Question 538

What is one of the main points of entry of T cells?

Answer 538

The choroid plexus

Question 539

What controls diapedesis of activated immune cells?

Answer 539

Inflamed endothelium

Question 540

What are the 5 ways the CNS is immune priviliged?

Answer 540

1. Parenchymal APCs cannot provide effective activation
2. Parenchyma produces anti-inflammatory signals
3. Lymphocyte presence is strictly compartimentalized
4. BBB
5. T cells need to be re-activated after crossing BBB

Question 541

What viral infection is a prerequisite for developing MS?

Answer 541

Epstein-Barr virus

Question 542

What cells are affected by Epstein-Barr Virus?

Answer 542

Memory B cells

Question 543

What are 4 risk factors of MS?

Answer 543

Female (2:1)
Genetics
MHCII HLA-DRB1 variant
Environmental risks (vitamin D, smoking, EBV)

Question 544

Is MS similar across the lifespan?

Answer 544

No. Even babies can get MS. Most common age of onset is in early 30s though

Question 545

What does MS look like in younger people?

Answer 545

Attacks that people can recover from.

Question 546

What is the dominant phenotype of MS in older people?

Answer 546

Slow progression of disability, steady accumulation of neurological dysfunction, resistant to almost all drugs that are given to people that get attacks.

Question 547

What can be tested to monitor MS or learn about it?

Answer 547

Genetics, Blood, CSF, brain biopsies, autopsies

Question 548

Do you normally have B cells in your brain?

Answer 548

No, hardly any

Question 549

Are there naive T cells in the CNS?

Answer 549

No, no reason to search for antigens there

Question 550

WHat types of T cells do you see in the CSF?

Answer 550

Memory and effector CD4 cells, and some memory CD8 cells

Question 551

What is the dominant phenotype of T cells in the perivascular space compared to in the CSF?

Answer 551

CD69+ (early activation marker)

Question 552

Where are CD69- CD103- CD8 T cells mainly found with regards to the CNS?

Answer 552

The border organs (blood, choroid plexus and meninges

Question 553

Where are CD69+ CD103- and CD69+ CD103+ CD8 T cells mostly found with regards to the CNS?

Answer 553

CSF and white matter

Question 554

What could be the initiator of an MS attack?

Answer 554

Can be several mechanisms including:
1. peripheral antigens without presentative activation of CNS patrolling cells, or
2. presentation of CNS antigens in the periphery
3. Tregs are less functional and cannot control immune activation

Question 555

What do disease modifying therapies in MS act on?

Answer 555

Processes in the lymph nodes, such as T cell activation, clonal expansion, migration, cell depletion or blocking from crossing barriers

Question 556

What is the general lymphocyte phenotype in the blood of people with MS compared to healthy patients?

Answer 556

CD4s have a more cytotoxic phenotype, more memory B cells with a CSF infiltrating phenotype (CXCR3 expression -> CCR10, highly expressed in CSF)

Question 557

What is the most immunogenic region in the CNS?

Answer 557

The perivascular space

Question 558

When can cells enter the parenchyma?

Answer 558

Once they have interacted with an APC in the perivascular space

Question 559

What is found in white matter lesions of early in MS?

Answer 559

A lot of T cells, B cells and myeloid cells

Question 560

Where is inflammation mostly found in early MS

Answer 560

Far more in white matter than grey matter

Question 561

What is characteristic of lesions in the brain of most people who have died due to MS?

Answer 561

The lesions are still populated by MHCII cells that are demyelinating and expanding, tissue resident memory T cells and B cells

Question 562

What is interesting about B cells at end stage MS?

Answer 562

There is still continuous production of IgG, which may contribute to the progression of MS

Question 563

What does the presence of follicle-like structures in the meninges tell you about the disease progression?

Answer 563

These B and T cell interaction hotspots (where IgG synshtesis is stimulates) is associated with early onset of MS, faster accumulation of disability and earlier death

Question 564

When are grey matter lesions more or a problem in MS?

Answer 564

Later stages

Question 565

What are the three different MS patterns?

Answer 565

1. Relapsing-remitting MS
2. Secondary progressive MS
3. Primary progressive MS

Question 566

What precedes secondary progressive MS?

Answer 566

Relapsing-remitting MS

Question 567

What are the three pathological hallmarks of MS?

Answer 567

1. Influx of peripheral immune cells
2. Demyelination
3. Neurodegeneration

Question 568

What is a permanent aspect of MS?

Answer 568

Neurodegeneration. Myelin can be restored.

Question 569

What happens to microglia in MS lesions?

Answer 569

They become activated and turn into macrophages, that then damage the myelin

Question 570

What is the EAE model?

Answer 570

A mouse model in which an autoimmune response is induced against myelin, by injecting myelin protein with immune activators

Question 571

What are the 2 stages of axonal degeneration?

Answer 571

1: Focal swelling and 2: fragmentation

Question 572

What predicts axonal fate?

Answer 572

Ca2+

Question 573

What is the source of increased Ca2+?

Answer 573

Extracellular influx

Question 574

How does extracellular Ca2+ enter the axon?

Answer 574

Physical membrane damage (loss of integrity), so leaky

Question 575

How is membrane integrity (or disruption) tested in EAE models?

Answer 575

Injecting dyes of different sizes that may cross the membrane if there is loss of integrity

Question 576

What does the influx of Ca2+ cause?

Answer 576

Swelling and defragmentation

Question 577

What drives cortical pathology?

Answer 577

The immune cells in the meninges (meningial inflammation) that stimulate and activate the microglia

Question 578

What is the phenotype of MS2 (MS specific) microglia that is not found in other neurodegenerative diseases?

Answer 578

High branching, low homeostatic markers and low inflammatory markers (HLAII low)

Question 579

What is the CMI?

Answer 579

A chronic meningeal inflammation model to study cortical pathology in progressive MS

Question 580

What is the current hypothesis of pathogenesis of cortical pathology (in 4 steps)?

Answer 580

1. Meningeal B cells secrete inflammatory factors
2. Loss of microglia-mediated neuroprotection
3. Impaired neuronal mitochondrial transport
4. Neuronal necroptosis

Question 581

In what 4 ways does the skin act as a barrier?

Answer 581

Physical, microbiota, chemical, immune

Question 582

Why do people that suffer from food allergy also often suffer from itchiness?

Answer 582

There is a skin-gut axis due to similar homing molecules

Question 583

What are the main skin functions?

Answer 583

Protection/defense
Signal reception
Thermoregulation
Communication
Secretion
Absorption

Question 584

How does the skin thermally regulate the body?

Answer 584

Sweating, vasoconstriction/dilation

Question 585

What is sebum?

Answer 585

A sticky, oily substance produced by the sebaceous glands

Question 586

What can skin absorb?

Answer 586

Light, pharmaceutics

Question 587

What are the three main layers of the skin?

Answer 587

Epidermis, dermis, hypodermis

Question 588

What does the epidermis consist of?

Answer 588

Keratinocytes in 5 stratum layers:
Corneum
Lucidum
Granulosum
Spinosum
Basale

Question 589

What does the stratum basale consist of?

Answer 589

Basal cells (stem-cell like keratinocyte precursors), Merkel cells and melanocytes

Question 590

Where are langerhans cells located?

Answer 590

The stratum spinosum

Question 591

What do lamellar granules do in the skin?

Answer 591

Play a role in keratinization

Question 592

What is the function of the stratum lucidum?

Answer 592

Water resistance and barrier

Question 593

What does the stratum corneum consist of?

Answer 593

Dead cells

Question 594

What is the site of entry of microbiota?

Answer 594

The glands and hair follicles

Question 595

What prevents invasion of microbiota into the hair follicles and glands?

Answer 595

Monocytes and Tregs

Question 596

How do keratinocytes attach to the basal lamina?

Answer 596

Hemidesmosomes

Question 597

What does the basal lamina consist of?

Answer 597

Type IV collagen, laminin and proteoglycans

Question 598

What do desmosomes do?

Answer 598

They interconnect keratinocytes to each other, provide structural integrity but still allow passage of substances

Question 599

How is transport of substances limited in the epidermis?

Answer 599

Tight junctions, particularly in the stratum granulosum, enforcing cytoplasmic uptake

Question 600

Is all keratin expressed in skin cells the same?

Answer 600

No, different cells have different types of keratin made up of heterodimers of keratin with different functions (barrier, metabolism, differentiation, etc)

Question 601

How is photoprotection provided?

Answer 601

Melanocytes produce melanin and form melanosomes
Melanosomes are exocytosed
Melanosomes are endocytosed by keratinocytes
Exposure to sunlight causes migration of melanosomes to apical side of keratinocytes to protect

Question 602

What do Merkel cells do?

Answer 602

They are specialized epithelial cells especially present in thick skin. They are in close contact with sensory nerves and aid in perception of light touch

Question 603

What are the two dermis layers?

Answer 603

Papillary dermis and reticular dermis

Question 604

What is the papillary dermis?

Answer 604

It is highly vascularized and made up of a lot of loose connective tissue

Question 605

What is the reticular dermis?

Answer 605

Makes up the bulk of the dermis, made up of tight connective tissue

Question 606

What is the dermis populated by?

Answer 606

Next to collagen and elastic fiber, also fibroblasts, endothelial cells and innate and adaptive immune cells

Question 607

What is the vascularization pattern in the dermis?

Answer 607

Capillaries in papillary, arterioles and venules to arteries and veins in reticular dermis (thickest towards basal lamina)

Question 608

Is the skin a passive barrier?

Answer 608

No

Question 609

How is homeostasis maintained in the skin by the microbiota?

Answer 609

They themselves produce AMPs and they interact with keratinocytes and immune cells

Question 610

How do keratinocytes aid in innate immunity of the skin?

Answer 610

They express TLRs, signal for AMPs, produce inflammatory cytokines and chemokines to facilitate direct killing and recruit and modulate immune cells

Question 611

What does CCR7 do?

Answer 611

Aids in migration of langerhans cells to the lymph nodes

Question 612

What does CCR6 do?

Answer 612

It has CCL20 as a ligand, whch is produced by keratinocytes and other langerhans cells during inflammation to attract langerhans cells to the site

Question 613

What do langerhans cells do?

Answer 613

They have a sentinel function

Question 614

What are inflammatory reactions of langerhans cells?

Answer 614

Cytokine secretion (IL-1ß, TNF-α, IL-6, IL-12)
Chemokine secretion (recruitment)
IL-23: Th17 development

Question 615

What are tolerance reactions of langerhans cells?

Answer 615

IL-10 and TGFß
Co-stimulatory receptor downregulation

Question 616

How does TGFß play a role in skin homeostasis?

Answer 616

Wound healing: promotes keratinocyte proliferation, activates fibroblasts to produce ECM
Immune regulation: T cell differentiation into Tregs

Question 617

What do langerhans cells do in steady state?

Answer 617

They respond to commensals and self antigens by producing TGFß and IL-10 to induce antigen-specific Tregs
They also upregulate AXL to interact with apoptotic keratinocytes to facilitate clearance and trigger anti-inflammatory signaling and supress inflammatory signaling

Question 618

What cells represent the vast majority of dermal cells?

Answer 618

Phagocytes, mostly macrophages, but also dermal DCs and migrating and resident langerhans cells

Question 619

What is CGRP?

Answer 619

It is a neurotransmitter produced by nerves in the skin that is produced when sensing fungi or bacteria.

Question 620

What does CGRP do?

Answer 620

Downregulates langerhans APC function, increases IL-10 and IL-23 production in langerhans cells and downregulates production of pro-inflammatory cytokines by langers hans cells and dermal macrophages

Question 621

When is TAFA4 produced?

Answer 621

UV exposure by sensory neurons around hair follicles

Question 622

What does TAFA4 do?

Answer 622

Induces macrophage survival, induces IL-10 production which limits inflammatory response by newly arriving macrophages and induces healing

Question 623

Do mast cells have homeostatic functions or inflammatory functions?

Answer 623

Both!

Question 624

What plays a role in vaso-dilation and constriction?

Answer 624

TNFa produced by phagocytes and mast cells

Question 625

What do mast cells do in the skin?

Answer 625

-Vaso-dilation and activation
-Recruit inflammatory cells
-induce emigration and activation of resident leukocytes
-Peptide degradation
-Scratch reflex

Question 626

What do mast cells do in severe allergies?

Answer 626

Massive degranulation and prolonged inflammation, systemic reaction and tissue remodeling

Question 627

Can mast cells phagocytose?

Answer 627

Yes

Question 628

How can mast cells facilitate viral dissemination?

Answer 628

They can get infected and they can cause vascular leakage and thus viremia

Question 629

What do mast cells recruit during viral infections?

Answer 629

T cells and NK cells

Question 630

What do mast cells recruit during bacterial infection?

Answer 630

Neutrophils

Question 631

What do mast cells recruit during parasitic infection?

Answer 631

DCs

Question 632

What are extracellular traps?

Answer 632

The NETs of mast cells (against parasites)

Question 633

What are the transcription factors of ILCs?

Answer 633

Same as their helper counterparts

Question 634

What do CCR10+ ILCs do?

Answer 634

Facilitate effector and Treg homeostasis

Question 635

What do CCR6 ILCs do?

Answer 635

Facilitate barrier and microbiome homeostasis

Question 636

What ILC is involved in tissue repair?

Answer 636

ILC2

Question 637

What ILC plays a role in psoriasis?

Answer 637

ILC3 (Th17 does too)

Question 638

What cells play a role in contact hypersensitivity?

Answer 638

NKs and ILC1

Question 639

What is the host response (skin) against S. aureus?

Answer 639

TLR2 -> infl. cytokines -> NFkB -> AMPs and neutrophil recruitment
TLR2 -> inf. cytokines -> Th17, ydTcell, NK(T) -> AMPs and neutrophil recruitment

Question 640

Who produces AMPs in the skin?

Answer 640

Keratinocytes, leukocytes, adipocytes and commensals

Question 641

AMP production is increased or decreased in certain skin diseases, which ones?

Answer 641

Psoriasis: increased -> seldom bacterial infections
Atopic dermatitis: decreased -> higher susceptibility to infection and commensal imbalance

Question 642

How do AMPs work?

Answer 642

Lysis or sequestering iron

Question 643

Which T cell subsets are involved in the development of psoriasis and atopic dermatitis?

Question 644

What is the link between T cell transcription and cell plasticity?

Question 645

What are novel therapies for psoriasis and atopic dermatitis?

Question 646

What facilitates adhesion during T cell homing to the skin?

Answer 646

CLA and selectins on endothelial cells

Question 647

What is a chemokine receptor of T cells, B cells and DCs for homing to the skin?

Answer 647

CCR10

Question 648

What does TGFß help differentiate T cells into?

Answer 648

If also IL-6 -> Th17
If also IFNy -> Treg

Question 649

What makes T cells plastic?

Answer 649

They can be manipulated into changing their phenotype (fully or partially) to other T cell types through still available transcription factors associated with other types. It depends on the environment.

Question 650

What is the macroscopic hallmark of psoriasis?

Answer 650

Plaque formation

Question 651

What are the 4 histological features of psoriasis?

Answer 651

Acanthosis: thickening of the skin
Papillomatosis: Elongation of the epidermis into the papillary dermis
Hypogranulosis: Loss of stratum granulosum
Parakeratosis: Nuclei still present in stratum corneum cells
Also influx of T cells and neutrophils

Question 652

What are munro’s microabscesses?

Answer 652

Collections of neutrophils in the stratum corneum during psoriasis

Question 653

What happens during pre-psoriasis?

Answer 653

Innate and adaptive cell activation and recruitment, Th1, Th22 and Th17 -> AMP production

Question 654

What do epithelial cells do during psoriasis?

Answer 654

Hyperproliferation

Question 655

What triggers psoriasis?

Answer 655

Microorganisms, trauma, drugs combined with genetic susceptibility

Question 656

What cytokines are important in psoriasis plaque formation?

Answer 656

IL-23 and IL-17

Question 657

What type of treatment is effective against psoriasis?

Answer 657

Biologics targetting p19 subunit of IL-23, since p19 is specific for that cytokine and/or anti-p40 (IL-12 inhibitor) and/or anti-TNF. Some treatment is anti IL-17 or anti-IL-17

Question 658

What is atopic dermatitis initiated by?

Answer 658

Defective skin barrier in combination with genetic susceptibility

Question 659

What happens when the skin of an AD susceptible person is disrupted?

Answer 659

Activation -> Th2 type reaction including ILC2 (Th22 is also there) -> mast and eosinophil activation (histamines), IgE producing B cells.

Question 660

What T cells dominate the acute stage of atopic dermatitis?

Answer 660

Th2/Th22

Question 661

What T cells are activated as atopic dermatitis prgresses?

Answer 661

More Th2 and Th22 cells, but also Th1 and Th17 (though the question is if this is not just plasticity instead of recruitment)

Question 662

What types of itching pathways are there?

Answer 662

Histamine dependent and histamine-independent

Question 663

How is the histamine-dependent pathway initiated?

Answer 663

Histamines interact directly with histamine receptors on sensory neurons

Question 664

How is the histamine-independent pathway initiated?

Answer 664

Cytokines produced by Th2 cells (IL-4, IL-13 and IL-31) interact with their respective receptors on sensory neurons

Question 665

What is the synovial membrane made up of?

Answer 665

Type A (mAcrophage) and type B (fibroBlast) synoviocytes

Question 666

What are the layers of the joint lining?

Answer 666

The sublining, lining (fibroblast and barrier-forming macrophages) and the synovial fluid)

Question 667

How are type A synoviocytes connected?

Answer 667

Tight junctions

Question 668

What happens to the Type A lining during arthritis?

Answer 668

The lining is disrupted, enabling infiltration of myeloid cells

Question 669

What is the sublining composed of?

Answer 669

Different types of macrophages and fibroblasts (than those of the lining). There are many different fibroblast types in the sublining with different roles like proliferation, proinflammatory, and adhesion).

Question 670

What happens (diseasewise) in early RA?

Answer 670

Immune infiltration and proliferation of the synovial lining, blood vessel formation.

Question 671

What happens (diseasewise) in established RA?

Answer 671

Synovial lining is overlaying the cartilage, produced enzymes lead to cartilage and bone destruction

Question 672

What are chondrocytes?

Answer 672

Cartilage cells

Question 673

What do macrophages do in arthritis?

Answer 673

They release a lot of inflammatory cytokines as well as IL-10 and TGFß (to try to dampen the whole thing) and interact with T and B cells through soluble factors and direct contact

Question 674

What causes RA?

Answer 674

We don’t know, but environmental factors (smoking, stress, microbes) and genetic predisposition is involved

Question 675

What happens before clinical symptoms?

Answer 675

Pre-arthritis, which is a bit auto-immunelike but not yet arthritis. It might need an extra trigger (neurological, biochemical or microvascular events?) to progress.

Question 676

Can pre-arthritis be detected?

Answer 676

Yes, there are some antibodies that can be detected in some patients, such as IgG-RF and/or anti-CCP

Question 677

What are ACPAs directed against and what does binding do?

Answer 677

Citrullinated protein on osteoclast precursors. This causes further activation and maturation of osteoclasts and IL-8 production

Question 678

What do osteoclasts usually do?

Answer 678

Bone resorption which is necessary for maintenance, repair and remodeling

Question 679

How do ACPAs induce pain?

Answer 679

IL-8 produced by mature osteoclasts can interact with (sensory) nociceptor.
Recruitment of neutrophils can lead to inflammation and progression, which is also painful

Question 680

What does knocking out IL-12 in RA patients do, and why does knocking out IFNy not have the same effect?

Answer 680

Dampens symptoms, while knocking out IFNy makes symptoms worse. This is because knocking out IL-12 also knocks out IL-23 (due to the p40 subunit they share, so actually IL-23 is important here

Question 681

So what is driving RA autoimmune processes?

Answer 681

IL-17/IL-23 (so Th17), not Th1

Question 682

What does Th17 have an effect on?

Answer 682

Monocytes, B cells and fibroblasts

Question 683

What is the proportion of IL-17 in early RA patients, and why?

Answer 683

Higher compared to healthy controls, due to a CCR6 polymorphism

Question 684

What is the pro-inflammatory loop in RA?

Answer 684

Th17 ->TNFα and L-17 ->fibroblast ->IL6 and IL8 which act on Th17 and so on.

Question 685

Is Th17 plastic?

Answer 685

Ya

Question 686

What are possibel treatments?

Answer 686

Rituximab, CD80/86 inhibitors, JAK inhibitors, TNF inhibitors, IL6R inhibitors

Question 687

What are the two kinds of RA?

Answer 687

Antibody-mediated (70%) and non-antibody mediated (30%)

Question 688

How can antibodies contribute to inflammation?

Answer 688

Activating complement and binding to Fc receptors on macrophages

Question 689

What is RF?

Answer 689

Rhematoid factors are autoantibodies directed against IgG Fc that can form enormous immune complexes

Question 690

What is ACPA?

Answer 690

Antibodies (general) against Citrullinated Protein antigens. It is a general term for different autoantibodies against citrullinated epitopes than can be inside or outside the joint

Question 691

What is anti-CCP?

Answer 691

Anti-cyclic citrullinated Peptide, which is an artificial peptide used to measure ACPA using ELISA (so anti-ACPA)

Question 692

What is citrullination?

Answer 692

Totally normal. Post-translational amino acid modification (arginine -> citrulline), can occur in every protein

Question 693

Why is smoking a risk factor?

Answer 693

Inflammation (lungs) results an increase citrullination and breakdown of tolerance in genetically predisposed individuals

Question 694

What 3 clinical outcomes are there in RA?

Answer 694

Self-limiting, presistent non-erosive and persistent-erosive. It is important to be able to determine who is who for treatment (or not)

Question 695

What are strong predictors of presistent RA?

Answer 695

IgM-RF and Anti-CCP

Question 696

What are the 3 roles of B cells in RA pathogenesis?

Answer 696

Antibody production, antigen presentation to T cells and cytokine production via cell-cell interaction

Question 697

What joints are involved in RA?

Answer 697

Small joints of hands and feet, symmetrical

Question 698

What are inflammation markers in the lab for RA?

Answer 698

C reactive protein (acute inflammation) and ESR (chronic inflammation)
Also RA and ACPA

Question 699

The earlier you treat a disease…

Answer 699

the better the outcome!
Window of opportunity

Question 700

What are glucocorticoids, what is the downside and how to go about that?

Answer 700

Part of initial RA treatment that can prevent radiological progression. They work very fast.
Downside: They cannot be taken for a long time, so they are used as bridging therapy until other therapies kick in

Question 701

What is Methotrexate?

Answer 701

The most important initial RA treatment. They inhibit IKK-NFkB pathway and thus TNF

Question 702

Where is the cell body of the sensory neurons?

Answer 702

Dorsal root ganglia

Question 703

Where it the cell body of the motor neurons

Answer 703

In the brain stem or spinal cord

Question 704

What part of the motor neuron is part of the PNS?

Answer 704

Only the axon

Question 705

What is the outside layer of connective tissue around a nerve?

Answer 705

The epineurium

Question 706

What surrounds the nerve fiber veriscles?

Answer 706

The perineurium

Question 707

What surrounds the individual nerve fibers?

Answer 707

Endoneurium

Question 708

Are all axons myelinated, and who produces myelin?

Answer 708

No, not all. Schwann cells are present in all nerve fibers but only some produce myelin. Unmyelinated cells are present in both the CNS and PNS

Question 709

What is myelin?

Answer 709

A lipid-rich sheath that is essential for fast and efficient transmission of signals. It is interrupted by Nodes of Ranvier which aid in transmission via action potential

Question 710

What cells are unmyelinated?

Answer 710

Cells important for regulating smooth muscles. These signals don’t need to be as fast

Question 711

What cells are myelinated?

Answer 711

Sensory and motor neurons involved in (acute) sensation and muscle contraction

Question 712

What is the difference between the CNS and PNS regarding Schwann cells?

Answer 712

in the PNS, one Schwann cell myelinates only one axon

Question 713

What happens when there is damage in the myelin or Nodes of Ranvier?

Answer 713

Conductions are slowed which leads to sensation or movement problems

Question 714

What are characteristics of the blood-nerve barrier regarding the immune system?

Answer 714

Endothelial cells create a tight barrier using tight junctions, but are leaky at nerve roots, ganglion cells and nerve terminals to allow for the passage of activated T cells, macrophages and antibodies

Question 715

What cells in the PNS can act as APCs?

Answer 715

Schwann cells and endothelial cells can express MHCII, also endoneurial macrophages

Question 716

What are endoneurial macrophages?

Answer 716

Specialized macrophages important for regulation of inflammation and promotion of healing such as during Wallerian degeneration

Question 717

What is Wallerian degeneration?

Answer 717

The degeneration of the part of an axon that is severed from the neuron cell body after injury, allowing for new space for the proximal part of the nerve to sprout and make new connections

Question 718

What makes peripheral nerves so vulnerable?

Answer 718

They are extremely large and require proper alignment of the membrane and myelin to work correctly

Question 719

What type of disease is GBS?

Answer 719

An acute peripheral nerve specific immune-mediated neuropathy?

Question 720

What are paraproteins?

Answer 720

A very prominent clone of antibody present in the serum, usually IgM but can also be IgG or IgA

Question 721

What age-group has highest incidence of GBS?

Answer 721

Higher usually, except in M. pneumoniae

Question 722

What are the neurological deficits in GBS? (4)

Answer 722

-Muscle paralysis
-Sensory deficits
-Autonomic dysfunction
-Areflexia

Question 723

What is areflexia?

Answer 723

Loss or absence of reflexes

Question 724

What is ataxia?

Answer 724

Lack of voluntary coordination of muscle movements, such as balance, coordination and speech

Question 725

What are the symptoms of autonomic deficits in GBS?

Answer 725

Tension fluctuations and cardiac arrhythmia

Question 726

Two categories of diagnostic criteria for GBS

Answer 726

-Clinical features
-Additional examinations

Question 727

What are the clinical features to look out for when considering GBS?

Answer 727

-Rapidly progressive (<4 weeks)
-Symmetrical paresis of arms and legs
-Reduced or absent reflexes

Question 728

What are the additional examinations you can perform when considering GBS?

Answer 728

-Blood (no abnormalities that may explain symptoms)
-Cerebrospinal fluid (no cells, increased protein level)
-Electrophysiology (demyelination, axonal degeneration)

Question 729

Sequence of events in GBS

Answer 729

1. Progression
2. Plateau phase
3. Recovery phase
4. Disability

Question 730

What are the two histological classifications of GBS?

Answer 730

-Demyelination
-Axonal degeneration

Question 731

How is demyelinating GBS called disease wise?

Answer 731

Acute inflammatory demyelinating polyneuropathy (AIDP)

Question 732

How is axonal degenerating GBS called disease wise?

Answer 732

Acute motor axonal neuropathy (AMAN)

Question 733

How can macrophages attack the myelin? (3)

Answer 733

-Phagocytosis of myelin debris and myelin sheaths
-Pro-inflammatory cytokines
-Antigen-presentation of myelin derived antigens to T cells

Question 734

How does complement activation work in GBS?

Answer 734

Antibodies are directed against glycolipids/gangliosides, which are present in membranes of all of your cells BUT highly enriched in the nerve system. Antibody::antigen complex activate complement.

Question 735

Where does compliment activation occur during GBS?

Answer 735

Along Schwann cell surfaces

Question 736

Describe the concept of molecular mimicry in GBS

Answer 736

Generation of an immune response against the infectious agent generates anti-ganglioside antibodies that cross-react with glycolipids present in peripheral nerves and nerve roots

Question 737

Which antibodies are associated with GBS?

Answer 737

IgM, IgG1

Question 738

Which ganglioside is most often attacked?

Answer 738

GM1

Question 739

Where is GM1 present?

Answer 739

-Myelin
-Axolemma
-Paranodes
-Nodes of Ranvier (peripheral motor nerves)

Question 740

What are the three categories of treatments in GBS?

Answer 740

Specific treatment
Supportive treatment
Rehabilitation

Question 741

What are the options for specific GBS treatment?

Answer 741

-Plasma exchange or plasma pheresis
-Intravenous immunoglobulins

Question 742

What are the options for supportive GBS treatment?

Answer 742

-Artificial respiration
-Prevention and treatment of complications (infections, pain)
-Physiotherapy

Question 743

Why is GBS not a typical classic auto-immune disease? (5)

Answer 743

-No predominance in females
-No association with other auto-immune diseases
-No relapsing-remitting or chronic disease course
-No association with specific HLA haplotypes
-No improvement after corticosteroids

Question 744

Why is GBS a typical post-infectious disease?

Answer 744

-2/3 of patients have symptoms of a recent respiratory or GI-infection
-Antibodies to glycolipids in serum are detected in 50-60% of the cases
-Association type of infection and clinical features
-Association type of infection and prognosis
- >95% has a monophasic disease course, which is typical for post-infeciton diseases

Question 745

What is the most common clinical and electrophysiological phenotype of GBS related to a preceding C.jejuni infection?

Answer 745

Pure motor clinical variant and the acute motor axonal neuropathy

Question 746

Which infections are associated with GBS?

Answer 746

C.jejuni
CMV
EBV
Mycoplasma pneumoniae
HEV

Question 747

Which infections commonly precede sensory motor GBS? What is their electrophysiological phenotype?

Answer 747

M. pneumoniae, CMV and EBV. Demyelinating (AIDP)

Question 748

True or False: “Clinical outcome is better if you had a preceding C.jejuni infection than if you had a preceding M.pneumoniae infection.”

Answer 748

False. You actually have a worse outcome

Question 749

What kind of data can you use to investigate an association between infections and GBS?

Answer 749

Epidemiological data
Case-control study

Question 750

What do you look for in a case-control study to study an association between Zika infection and GBS?

Answer 750

-Zika virus positive cases vs Zika virus negative cases –> compare %GBS cases
-GBS cases vs control cases –> compare % Zika virus positives

Question 751

How long do lymphocytes spend in the lymph nodes?

Answer 751

approximately 12 hours

Question 752

What to T cells do in the lymph nodes?

Answer 752

They move around along stromal cells and scan DCs to see if there are peptides that are being presented

Question 753

What if a T cell doesn’t find an antigen-presenting DC in the lymph node?

Answer 753

It goes into the efferent lymph and drains back into circulation

Question 754

What is the life cycle of a macrophage or DC?

Answer 754

They are formed in the bone marrow and move to the tissues directly. They scan peripheral tissues and take up whatever is there, move to the lymph nodes and present to T cells. They do not exit, they die in the lymph nodes.

Question 755

What regulates T cell exit?

Answer 755

soluble lipids: S1P

Question 756

What produces S1P?

Answer 756

Endothelial cells and red blood cells

Question 757

What prevents T cells from leaving the lymph nodes too soon?

Answer 757

Once in the lymph node, they will express CD69, which is often used as an early activation marker. CD69 prevents re-expression of S1PR, which prevents activated cells from leaving the lymph node too soon. After a few divisions, CD69 will be expressed less and allow for the upregulation of S1PR, allowing exit.

Question 758

How do B cells organize themselves into B cell follicles?

Answer 758

Marginal reticular cells express CXCL13, which is a homeostatic chemokine to promote B cell migration

Question 759

What do follicular dendritic cells do?

Answer 759

They express Fc receptors, complement receptors and CXCL13 for B cell migration and assist in germinal center development

Question 760

What do fibroblastic reticular cells do and where are they located?

Answer 760

FRCs are located in the cortical sinus where they express CCL21 and CCL19. These are homeostatic chemokines that promote T cell and dendritic cell migration (which express CCR7). They also express IL-7 for resting T cell survival.

Question 761

What are HEVs?

Answer 761

High endothelial venules express adhesion molecules for naive T cell migration from blood into the lymph nodes. Naive T and B cells can ONLY leave the blood through those. They are also found in Peyer’s patches

Question 762

How do HEVs facilitate lymphocyte entry into the LNs?

Answer 762

1. They express LN homing molecules GlyCAM-1, ICAM-1 and CD34, and secrete CCL21.
2. GlyCAM1 and CD34 weakly interact with L-selectin (LFA-1) on the surface of naive T cells.
3. LFA-1 (already present) changes conformation through inside-out signalling (this necessity prevents inappropriate interactions elsewhere)
4. New conformation of LFA-1 can now bind with high affinity to ICAM-1 (outside-in signalling), making the T cell stop rolling.
5. Diapedesis (extravasation).

Question 763

What attracts T cells to the lymph nodes?

Answer 763

CCL21 and CXCL12

Question 764

What are the two chemokine classes?

Answer 764

Homeostatic and Inflammatory

Question 765

What do homeostatic chemokines do?

Answer 765

They attract immune cells and are always expressed by the lymphoid organs, which is why lymphocyte entry into the LNs is continuous. They ensure lymphoid organ maintenance and attract cells.

Question 766

What do inflammatory chemokines do?

Answer 766

Attract activated lymphocytes. Expression is induced by activated cells and can happen anywhere.

Question 767

When are inflammatory cytokine receptors expressed?

Answer 767

Only after activation

Question 768

What is chemo/haptokinesis?

Answer 768

It is not a gradient-mediated movement of cells, it is simply movement of cells independent of chemokines

Question 769

What is cell migration regulated by?

Answer 769

Chemokines and adhesion by integrins

Question 770

What are integrins?

Answer 770

Multimeric proteins made of α- and ß- chains. You always have combinations of αs and ßs.

Question 771

What are the 4 integrin classes?

Answer 771

Collagen-binding
RGD receptors
Laminin receptors
Leukocyte receptors

Question 772

Where are leukocyte receptor integrins mainly expressed?

Answer 772

Vascular cells

Question 773

Why are integrins important?

Answer 773

Homing of cells from the blood into tissues

Question 774

How do leukocytes know where to go?

Answer 774

When a DC comes from a certain location, a T cell activated by that DC expresses the homing molecule (i.e CCR9 for intestine) that correlated with the tissue of DC origin. This ensures that the T cell only enters that tissue and not other organs, as this would be highly inefficient when an immune response is necessary in a specific location.

Question 775

What are the molecules involved in T cell homing to the intestines?

Answer 775

CCL25 (CCR9 on T cells), P-selectin, MADCAM1

Question 776

What are the molecules involved in homing to the skin?

Answer 776

CCL17 (CCR4), E-selectin, P-selectin, ICAM1, VCAM1

Question 777

What is CCR10?

Answer 777

Binds to CCL27, which is produced by keratinocytes in the skin. This receptor-ligand interaction is important for the migration of T cells to the skin, particularly in the context of inflammatory skin diseases.

Question 778

What is CCR6?

Answer 778

Interacts with CCL20 (MIP-3α), expressed by epidermal keratinocytes and some dermal cells. CCR6 is found on various immune cells, including Th17 cells, contributing to their migration to the skin, especially in conditions like psoriasis.

Question 779

What is CCR4?

Answer 779

Expressed on Th2 cells, Tregs, and skin-homing memory T cells. Its ligands, CCL17 (TARC) and CCL22 (MDC), are expressed in the skin and play roles in attracting cells involved in allergic inflammation and maintaining tolerance.

Question 780

What cells express Fc receptors?

Answer 780

Every immune cell

Question 781

Does every Fc receptor bind to every Fc with the same affinity?

Answer 781

No, they differ per antibody subclass

Question 782

What does Fc stand for

Answer 782

Fragment crystallizable

Question 783

What does FCyRI bind to and what affinity?

Answer 783

Monomeric IgG, high

Question 784

What do FcyRIIA, B, C and FCRIIIA and B bind to and what affinity?

Answer 784

medium to low affinity
Recognize IgG, but require immune complexes for activation

Question 785

What FcyRs have an activating motif?

Answer 785

All but FCyRIIB, which is the only one expressed by B cells

Question 786

What are the 9 roles of Fc receptors in immune responses?

Answer 786

1. Clearance of Immune complexes
2. Phagocytosis and antigen presentation
3. Production of cytokines
4. Antibody dependent cellular toxicity (ADCC)
5. Modulation of cellular activation
6. Mast cell degranulation
7. Generation of high affinity antibodies
8. Prevent autoimmunity by forming late auto-immune checkpoint
9. Transportation/recycling of imunoglobulins

Question 787

In what ways can FcR binding lead to antigen presentation?

Answer 787

1. Internalization, increased endosomal maturation, processing and loading on MHCII
2. Immune complexes are protected from degradation in the early endosome, degraded by the proteosome and loaded onto MHCI in the ER

Question 788

How do FcRs deal with immune complexes with viruses that manage to escape vesicles?

Answer 788

FcRs such as TRIM21 detect them and target them for proteosomal breakdown to be loaded onto MHCI

Question 789

How long does it take for FcR activation to lead to cytokine production?

Answer 789

Can take hours

Question 790

What is antibody-dependent cellular cytotoxicity?

Answer 790

ADCC is a mechanism initiated by FcRs on NK cells.

Question 791

How does ADCC work?

Answer 791

1. Antibodies bind antigens on the surface of target cells such as tumor cells or microbes
2. FcRs on NK cells (FCyIII/CD16) recognize bound antibody
3. Crosslinking of FcRss signals the NK cell to kill the target cell
4. NKs release granzymes and perforin which killes the cell through apoptosis

Question 792

When is ADCC especially important?

Answer 792

Biological use such as anti-CD20 (Rituximab) which depletes B cells

Question 793

What is glycosylation?

Answer 793

A carbohydrate expressed on Fc is required for FcR binding.

Question 794

How does glycosylation affect Fc-FcR binding affinity?

Answer 794

Low fucose = higher binding

Question 795

What affects glycosylation?

Answer 795

Age, changes after immunization, during pregnancy and in some autoimmune disease

Question 796

How does glycosylation play a role in severe COVID-19 patients?

Answer 796

Afucosylated IgGs are a result of strong BCR cross-linking due to repetitive expression of spike. A lack of fucose leads to a >50x higher affinity for FcyRIII (NKs, macrophages, neutrophils, some T cells). This signal, combined with recognition of dsRNA by TLR3, create very strong activation and TLR3 response and thus alveolar macrophage response, leading to ARDS.

Question 797

What is meant by net effect in FcR interactions?

Answer 797

In case of immune complexes, activatory and inhibitory receptors can be activated at the same time. One pathway counteracts the other. When multiple receptors are involved, the net effect determines whether there is activation or inhibition. Cytokines or bacterial molecules like LPS influence the expression of these receptors, shifting the balance to activation or inhibition.

Question 798

How does mast cell degranulation by FcRs work?

Answer 798

Cross-linking via immune complexes leads to release of vasoactive substances such as histamines and chemoattractants. This is a really fast process.

Question 799

How do FcRs help in generation of high affinity antibodies?

Answer 799

Through expression on follicular DCs in germinal centers

Question 800

What 3 things affect Fcy binding affinity?

Answer 800

Glycosylation, polymorphisms and expression levels

Question 801

Most people have a stop codon in what FcR?

Answer 801

FcyRIIC, but some people have a mutation where there is an open reading frame

Question 802

What is FcyRIIB important for?

Answer 802

Peripheral tolerance. It has an inhibitory reaction. Activated B cells upregulate IIB to prevent it from going haywire (feedback loop). Only B cells with very strong affinity will have the necessary activation threshold to be selected for, and the added competition for growth factors and antigens prevents autoimmunity

Question 803

What do neonatal FcRs do?

Answer 803

Recycle IgG and transport them through mucosa and placenta

Question 804

What is FcE for and what does it do?

Answer 804

It is important for allergies. When cross-linked with IgE complexes, it results in degranulation which causes allergic symptoms

Question 805

How are fetuses sensitized for allergens?

Answer 805

IgE can be present in the amniotic fluid

Question 806

How does food allergy work?

Answer 806

IgE is internalized by binding to CD23 in the gut. Binding of IgE to FcERI on mast cells and DCs cause allergic inflammation and further IgE synthesis after B cell class switching. Inflammation mediated by IgE damages the intestinal epithelium, disrupts tight junctions, allowing allergens to pass and bind to sensitized mast cells and DCs, exacerbating the food allergy.

Question 807

What does FCαR do?

Answer 807

It is expressed by myeloid cells and binds only monomeric IgA. It results in a similar response to IgG: Phagocytosis, endocytosis, ADCC and respiratory burst (ROS)

Question 808

What diseases can FcRs contribute to?

Answer 808

ADE
Deficiency
SLE
Autoimmunity
IBD

Question 809

How can FcRs contribute to ADE?

Answer 809

ADE is thought to be mediated by antibodies that bind but do not neutralize a virus. The virus, when internalized through FcRs, can uncoat and replicate in the cell, potentially leading to more severe outcomes by leading to altered cytokine production, immune activation and potentially supression or dysregulation.

Question 810

What happens when mice have an FcyRIIB deficiency?

Answer 810

B cells cannot be adequately inhibited, causing increased humoral responses and increased collagen-induced arthritis severity. This is also thought to be behind SLE

Question 811

What are the two sides of the FcR balance scale?

Answer 811

Pathogen clearance vs. septic shock and autoimmunity (SLE)

Question 812

What does insufficient FcR-mediated clearance lead to?

Answer 812

Sustained myeloid cell activation and induction of autoimmunity

Question 813

What is a pitfall when studying FcRs?

Answer 813

Species specificity, of mice but not men

Question 814

What is the definition of epigenetics?

Answer 814

Epigenetic mechanisms transduce the inheritance of gene expression patterns without altering the underlying DNA sequence but by adapting chromatin, which is the physiological form of our genetic information. In summary: chromatin affects gene expression

Question 815

What role does epigenetics play in myeloid cells?

Answer 815

The transcriptome contains housekeeping genes that are expressed by all of the cell types, but there is also cell type specific genes that are transcribed by some and not others, which results in a different phenotype.

Question 816

How is transcription initiated?

Answer 816

The TATA box binds to its transcription factor and recruits RNA pol II, which binds to the promoter along with one or more general transcription factors.

Question 817

Where is the promoter with respect to the transcription starting site?

Answer 817

Upstream and/or partially downstream, can have some coding region overlap.

Question 818

What do promoters do?

Answer 818

They define where transcription of a gene begins

Question 819

What happens when RNA pol II binds?

Answer 819

It unwinds around 14bp of the DNA to form the RNA-polymerase-poromoter complex, exposing the “transcription bubble”.

Question 820

What initiates transcription?

Answer 820

Enhancers (a gene can have multiple), which are non-coding DNA regions distant from the promoter.

Question 821

How do enhancers interact with the promoter?

Answer 821

Chromosome loops are formed to allow for close proximity. The loops are stabilized with anchored architectural proteins, and specific transcription factors that bind along with RNA pol II, also bind to the enhancer.

Question 822

How can epigenetics impact mice with the Agouti gene?

Answer 822

The Agouti gene should only be expressed during hair follicle development, which is influenced by ingestion of folic acid during pregnancy. Folic acid provides the building blocks with methylation, which prevents expression of the gene in cells. When this does not happen properly, the gene is not silenced and leads to obesity and a light fur color in mice.

Question 823

How can epigenetics cause tortoiseshell color in cats?

Answer 823

Cells individually inactivate one X chromosome through hypermethylation.

Question 824

What are 4 epigenetic mechanisms?

Answer 824

DNA methylation
Nucleosome positioning
Histone modification
3D genome folding

Question 825

What is DNA methylation?

Answer 825

DNA methyltransferase adds a methyl group to usually cytosine, causing some transcription factors to no longer be able to bind. When a promoter is heavily methylated, this leads to silencing.

Question 826

What can demethylate promoters?

Answer 826

TET enzymes

Question 827

What is imprinting in the context of epigenetics?

Answer 827

Mostly involved in embryonic growth. One gene copy is methylated and the other is not based on whether is was maternal or paternal, allowing for a balance of gene expression (i.e. length).

Question 828

What happens when imprinting is lost?

Answer 828

Usually life incompatibility

Question 829

What is closed chromatin?

Answer 829

DNA with a high nucleosome content.

Question 830

What are histone modifications?

Answer 830

Post-translational modifications. Acetylation mediated by HAT allows for DNA to have space, giving room for binding. The opposite is mediated by HDAC enzymes (deacetylation).
Phosphorylation and others can also modify histones.

Question 831

How does 3D genome folding contribute to epigenetics? Name 2

Answer 831

1. It determines the proximity of enhancers to promoters
2. In recombination for lymphocyte receptors and antibodies, all V genes need to have equal opportunity, so folding should be as such that they are all in close proximity to the recombination center.

Question 832

What are 2 key players in epigenetics?

Answer 832

Transcription factors and gene regulatory elements

Question 833

How many transcription factors are encoded in the genome?

Answer 833

More than 1000

Question 834

What do transcription factors do?

Answer 834

They lead to the transcription of genes

Question 835

How are transcription factors produced?

Answer 835

Through signaling iniciated by i.e cytokines

Question 836

What are gene regulatory elements?

Answer 836

They are pieces of non-coding DNA (almost all transcription is regulated by non-coding DNA): enhancers, silencers and insulators.

Question 837

What is the role of epigenetic mechanisms lymphocyte diversity? Name 2 examples

Answer 837

1. Transcription factors are required for the adaptation of different T cell phenotypes depending on what is necessary.
2. T cell exhaustion is defined by up- and downregulation of genes

Question 838

How does epigenetics shape T cell maturity?

Answer 838

Memory T cells already have their chromatin accessible through demethylation and acetylation sothat the necessary genes can immediately be transcribed.
Naive T cells still need to undergo epigenetic changes.

Question 839

How can (disturbed) epigenetics cause disease? Name 4.

Answer 839

1. Enhancer mutation of Pax5 in a B cell leads to loss. It stays alive but becomes to plastic, allowing it to change to a T or NK when exposed to different signals. The plasticity poses a high risk for leukemic transformation.
2. Loss of imprinting
3. Cancer: silencing of supressor genes and genomic instability
4. Gene misfolding can cause developmental syndromes

Question 840

How can we exploit epigenetics for therapeutics (for example)

Answer 840

Ex: To inhibit things that promote transcription of hyperexpressed genes via methylation

Question 841

What is signal transduction?

Answer 841

Any process by which the cell converts one kind of signal stimulus into another, which involves ordered sequences of biochemical reactions inside the cell

Question 842

What are the different types of receptors and signalling molecules? (5)

Answer 842

Linkers
Protein Tyrosine Kinases
Protein Tyrosine Phosphatases
Lipid-metabolizing enzymes
Guanine nucleoride exchange factors

Question 843

What are linkers?

Answer 843

They don’t have any enzymatic activity, but have components that interact with other signaling proteins

Question 844

What are Protein Tyrosine Kinases?

Answer 844

They have enzymatic activity/domain and can phosphorylate their target

Question 845

What are Protein Tyrosine Phosphatases?

Answer 845

They have enzymatic activity/domain and can dephosphorylate their target

Question 846

What are lipid-metabolizing enzymes?

Answer 846

They have enzymatic activity and can cross and bind to the cell membrane

Question 847

What are the 4 steps of signal transduction?

Answer 847

Signal perception, Intracellular transduction, Cellular response and Termination

Question 848

What is signal perception?

Answer 848

When a ligand binds to a receptor, it activates other proteins bound to the membrane by recruiting signaling proteins

Question 849

What are 3 ways proteins are activated after signal perception?

Answer 849

1. The intracellular domain is phosphorylated which creates docking sites
2. Ras proteins bound to the membrane are activated by a linked receptor, which leads to a conformational change and downstream interaction
3. Signaling proteins bind directly to the plasma membrane

Question 850

Are phosphorylation sites activating or inhibiting?

Answer 850

They can be either

Question 851

What 2 types of linkers are there?

Answer 851

Scaffolds and adaptors

Question 852

What are scaffolds?

Answer 852

Linkers that can be phosphorylated

Question 853

What are adaptors?

Answer 853

They cannot be phosphorylated but have binding sites that can connect 2 other signaling proteins so they interact

Question 854

What do kinases do?

Answer 854

They add a phosphate group from ATP (->ADP) to an amino acid residue, leading to phosphorylation

Question 855

What is a kinase cascade?

Answer 855

A cascade that can amplify signal logarithmically (Ca2+ can also do that)

Question 856

What do phosphatases do?

Answer 856

Dephosphorylate targets. They can also activate them through conformational changes, allowing binding of other proteins

Question 857

How long do cellular responses last after signalling?

Answer 857

They can take hours or days, sometimes throughout the entire lifetime of the cell.

Question 858

What (3) types of cellular responses are there?

Answer 858

Gene transcription, cytoskeleton changes (to aid in cell migration) and metabolism

Question 859

What are the 3 mechanisms by which signaling can be terminated?

Answer 859

1. (De)phosphorylation
2. Proteosomal degradation (~15aa chains can be reused)
3. Lysosomic degradation

Question 860

How does Notch signalling work?

Answer 860

1. Notch binds to stromal cell receptors
2. Intracellular part of Notch is cleaved
3. Enters nucleus with Coenzyme A
4. T cell fate is induced

Question 861

How can signalling be defective in the context of Notch?

Answer 861

Notch is oncogenic in mature T cells

Question 862

What happens when there is no BTK?

Answer 862

BTK is a kinase with a function in B cell development. When there is none, no B cells can be developed, leading to X-linked agammaglobulinemia (XLA)

Question 863

What happens when BTK is always activated?

Answer 863

Chronic lymphocytic leukemia

Question 864

What happens when BTK is increased?

Answer 864

Autoreactive cells in mice survive

Question 865

Why are there so many off-target effects in treatment involving B and T cells?

Answer 865

BCR and TCR (scaffold) pathways are extremely similar (even the same phosphorylation sites), causing cross-reactivity in used therapeutics.

Question 866

Why are there in general so many off-target effects in therapeutics?

Answer 866

Signaling molecules are often involved in more than one pathway

Question 867

Why can B cells still survive when BTK is targetted in CLL (always activated BTK)?

Answer 867

They can survive by rewiring since there is so much redundancy, so off-target effects don’t really matter. In the mean time CXCL4 inhibition in tumor cells cause the tumors to leave the LN and die.