Neurological infections and neuro-immunology I

Question 1

What are the characteristic features of anti-MAG neuropathy? (3)

Answer 1

1. Diffuse
2. Sensory
3. Upper limbs

Question 2

What are the characteristic features of multifocal motor neuropathy (MMN)? (3)

Answer 2

1. Multifocal
2. Motor
3. Lower limbs

Question 3

Which immune-mediated neuropathies have intermediate characteristic figures? (2)

Answer 3

1. CIDP
2. Lewis-Sumner syndrome

Question 4

How many new CIDP patients are diagnosed per year in NL?

Answer 4

~50

Question 5

What are the clinical features of CIDP? (6)

Answer 5

1. Similar presentation as GBS
2. Symptoms progress > 8 weeks
3. Chronic progressive/relapsing disease course
4. Some patients have acute onset
5. No association with infection
6. Typical and atypical variants

Question 6

CIDP/GBS has more severe symptoms

Answer 6

GBS

Question 7

What can maken CIDP diagnosis in the clinic difficult?

Answer 7

2-16% of cases have an acute onset -> similar to GBS

Question 8

Describe the pathogenesis of CIDP

Answer 8

Combined cellular and humoral autoimmune response to Schwann cell or myelin antigens -> leads to demyelination

Question 9

Why is the immune system considered to play a pivotal role in CIDP?

Answer 9

You can find inflammation in the nerves

Question 10

What treatment works for CIDP patients?

Answer 10

Immunomodulatory treatments

Question 11

Which immunomodulatory treatments are used to treat CIDP patients? (3)

Answer 11

1. Immunoglobulins
2. Corticosteroids
3. Plasma exchange

Question 12

Why do CIDP patients need multiple treatments?

Answer 12

It’s a chronic disease

Question 13

What are the pathological hallmarks of CIDP? (4)

Answer 13

1. Demyelination
2. Schwann cell proliferation -> Onion bulbs
3. Myelin phagocytosis
4. Remyelination

Question 14

What are the immunological T cell observations in CIDP? (2)

Answer 14

1. T cells present in nerve -> clonal expansion
2. %CD8+ and %HLA-DR(more activated) CD8 T cells increased in CSF

Question 15

What are the B cell immunological observations in CIDP? (3)

Answer 15

1. Elevated BAFF levels
2. Expanded B cell clones in blood
3. IgM and IgG to diverse glycolipids (or complexes) and complement deposition

Question 16

CIDP: Proteins where the auto-antibodies are directed to are important for?

Answer 16

Firm attachment of these proteins to the myelin loop

Question 17

Why is this firm attachment important?

Answer 17

To keep all the sodium channels in the node of ranvier -> depolarization

Question 18

Novel antibodies to paranodal antigens in CIDP are associated with..? (5)

Answer 18

1. Ataxia
2. Tremor
3. Aggressive onset
4. Poor response to IVIg
5. HLADRB1*15 alleles

Question 19

What are the properties of IgG4 antibodies? (4)

Answer 19

1. No complement activation
2. Reduced Fc-receptor binding
3. Half-molecule exchange
4. Related to chronic immune activation

Question 20

What structural difference in IgG4 ensures half-molecule exchange?

Answer 20

Disulfide bridges are within the heavy chains (as opposed to between+linked the heavy chains)

Question 21

What is meant with “monovalent binding” in the context of half-molecule exchange of IgG4?

Answer 21

Can only bind with one of their arms to a specific antigen

Question 22

What does monovalent binding prevent? (3)

Answer 22

1. Immune complex formation
2. Cross-linking and endocytosis of transmembrane antigens
3. Complement activation

Question 23

Why does monovalent binding prevent complement activation?

Answer 23

IgG4 does not bind C1q

Question 24

How do IgG4 antibodies disrupt the paranoidal architecture in CIDP?

Answer 24

They cause retraction of the myelin from the axon

Question 25

What is an example of a parameter used to determine efficacy of treatment in CIDP?

Answer 25

Grip strength

Question 26

Why do intravenous immunoglobulins not work properly in combatting CIDP?

Answer 26

IgG4 antibodies can't bind to complement --> effector functions not as important in this disease

Question 27

What are the characteristical clinical features of MMN? (6)

Answer 27

1. Asymmetric distal weakness 2. Muscle atrophy 3. Mean age of onset 40 years 4. No association with infection 5. Anti-GM1 IgM ~50% of cases 6. Associated with HLADR1*15

Question 28

MMN is often confused with another disease, which disease?

Answer 28

ALS -> starting ALS resembles MMN

Question 29

What are the properties of anti-GM1 antibodies MMN? (3)

Answer 29

1. Activate complement in vitro 2. Most likely monoclonal 3. IgM paraprotein found in peripheral blood of a subset of patients

Question 30

What are the molecular features of anti-GM1 antibodies in MMN? (3)

Answer 30

1. Contain mutations 2. Low affinity 3. Concentration of recombinant IgG needs to be 100 times higher for the same signal (ELISA)

Question 31

Antibodies containing mutations is indicative for what?

Answer 31

They've gone through the germinal center

Question 32

A 100 times higher concentration of recombinant IgG is suggestive of? (MMN)

Answer 32

The pentameric shape of the IgM being important for mediating the pathogenic effect in MMN patients

Question 33

What is the main treatment of MMN patients?

Answer 33

IVIg -> induction AND maintenance

Question 34

What is the main challenge of treating MMN patients?

Answer 34

IVIg does not prevent axonal degeneration

Question 35

True or false: plasma exchange and corticosteroids have been shown to be ineffective or even exacerbate the symptoms (MMN)

Answer 35

True

Question 36

If MMN patients have really bad symptoms, you can also treat with?

Answer 36

High-dose cyclophosphamide -> but side effects

Question 37

What are the characteristical (clinical) features of anti-MAG neuropathy? (5)

Answer 37

1. Prevalence 1 in 100,000 2. Age of onset mostly > 50 years 3. IgM paraprotein -> kappa or lambda 4. IgM recognizes carbohydrates on MAG or glycolipid SGPG

Question 38

What does the myelin-associated glycoprotein (MAG) bind? (2)

Answer 38

1. GD1a ganglioside 2. GT1b ganglioside

Question 39

True or false: MAG is highly glycosylated

Answer 39

True

Question 40

The Interaction between the MAG and ganglioside is important for?

Answer 40

Mediating the space between myelin and axon

Question 41

Pathogenesis of anti-MAG neuropathy is different than other neuropathies. What can you detect in the bone marrow?

Answer 41

Abberant B cells with clonal expansions

Question 42

Which rearrangement is most prominent in patients with anti-MAG neuropathy?

Answer 42

IGHV4-34

Question 43

In what kind of diseases in the L265P mutation also found?

Answer 43

Diffuse large B-cell lymphoma's

Question 44

Which mutation is found in ~60% of anti-MAG neuropathy patients?

Answer 44

L265P mutation in MyD88

Question 45

How does the L265P mutation result in a gain-of-function?

Answer 45

NFkB activation and cytokine signaling -> clones with this mutation have a survival advantage (deregulation)

Question 46

In short, describe different mechanisms how antibodies can cause peripheral neuropathies (3)

Answer 46

1. IgG4 antibodies disrupt paranodal architecture (CIDP) 2. IgM antibodies to glycolipids/proteins bind motorneurons 3. Oncogenic mutations in Myd88 (anti-MAG)

Question 47

With what disease are anti-Yo antibodies associated?

Answer 47

Cerebellar degeneration

Question 48

What are the auto-immune disease postulates adapted from Koch? (6)

Answer 48

1. Antibody found in patients, not healthy controls 2. Antibody interacts with target antigen 3. Passive transfer 4. Active transfer 5. Reduction of antibody titer = reduction clinical symptoms 6. Comparable to genetic and pharmacological models

Question 49

When were the anti-NMDA receptor antibodies found?

Answer 49

2007