Neurological infections and neuro-immunology I Flashcards
What are the characteristic features of anti-MAG neuropathy? (3)
- Diffuse
- Sensory
- Upper limbs
What are the characteristic features of multifocal motor neuropathy (MMN)? (3)
- Multifocal
- Motor
- Lower limbs
Which immune-mediated neuropathies have intermediate characteristic figures? (2)
- CIDP
- Lewis-Sumner syndrome
How many new CIDP patients are diagnosed per year in NL?
~50
What are the clinical features of CIDP? (6)
- Similar presentation as GBS
- Symptoms progress > 8 weeks
- Chronic progressive/relapsing disease course
- Some patients have acute onset
- No association with infection
- Typical and atypical variants
CIDP/GBS has more severe symptoms
GBS
What can maken CIDP diagnosis in the clinic difficult?
2-16% of cases have an acute onset -> similar to GBS
Describe the pathogenesis of CIDP
Combined cellular and humoral autoimmune response to Schwann cell or myelin antigens -> leads to demyelination
Why is the immune system considered to play a pivotal role in CIDP?
You can find inflammation in the nerves
What treatment works for CIDP patients?
Immunomodulatory treatments
Which immunomodulatory treatments are used to treat CIDP patients? (3)
- Immunoglobulins
- Corticosteroids
- Plasma exchange
Why do CIDP patients need multiple treatments?
It’s a chronic disease
What are the pathological hallmarks of CIDP? (4)
- Demyelination
- Schwann cell proliferation -> Onion bulbs
- Myelin phagocytosis
- Remyelination
What are the immunological T cell observations in CIDP? (2)
- T cells present in nerve -> clonal expansion
- %CD8+ and %HLA-DR(more activated) CD8 T cells increased in CSF
What are the B cell immunological observations in CIDP? (3)
- Elevated BAFF levels
- Expanded B cell clones in blood
- IgM and IgG to diverse glycolipids (or complexes) and complement deposition
CIDP: Proteins where the auto-antibodies are directed to are important for?
Firm attachment of these proteins to the myelin loop
Why is this firm attachment important?
To keep all the sodium channels in the node of ranvier -> depolarization
Novel antibodies to paranodal antigens in CIDP are associated with..? (5)
- Ataxia
- Tremor
- Aggressive onset
- Poor response to IVIg
- HLADRB1*15 alleles
What are the properties of IgG4 antibodies? (4)
- No complement activation
- Reduced Fc-receptor binding
- Half-molecule exchange
- Related to chronic immune activation
What structural difference in IgG4 ensures half-molecule exchange?
Disulfide bridges are within the heavy chains (as opposed to between+linked the heavy chains)
What is meant with “monovalent binding” in the context of half-molecule exchange of IgG4?
Can only bind with one of their arms to a specific antigen
What does monovalent binding prevent? (3)
- Immune complex formation
- Cross-linking and endocytosis of transmembrane antigens
- Complement activation
Why does monovalent binding prevent complement activation?
IgG4 does not bind C1q
How do IgG4 antibodies disrupt the paranoidal architecture in CIDP?
They cause retraction of the myelin from the axon
What is an example of a parameter used to determine efficacy of treatment in CIDP?
Grip strength
Why do intravenous immunoglobulins not work properly in combatting CIDP?
IgG4 antibodies can’t bind to complement –> effector functions not as important in this disease
What are the characteristical clinical features of MMN? (6)
- Asymmetric distal weakness
- Muscle atrophy
- Mean age of onset 40 years
- No association with infection
- Anti-GM1 IgM ~50% of cases
- Associated with HLADR1*15
MMN is often confused with another disease, which disease?
ALS -> starting ALS resembles MMN
What are the properties of anti-GM1 antibodies MMN? (3)
- Activate complement in vitro
- Most likely monoclonal
- IgM paraprotein found in peripheral blood of a subset of patients
What are the molecular features of anti-GM1 antibodies in MMN? (3)
- Contain mutations
- Low affinity
- Concentration of recombinant IgG needs to be 100 times higher for the same signal (ELISA)
Antibodies containing mutations is indicative for what?
They’ve gone through the germinal center
A 100 times higher concentration of recombinant IgG is suggestive of? (MMN)
The pentameric shape of the IgM being important for mediating the pathogenic effect in MMN patients
What is the main treatment of MMN patients?
IVIg -> induction AND maintenance
What is the main challenge of treating MMN patients?
IVIg does not prevent axonal degeneration
True or false: plasma exchange and corticosteroids have been shown to be ineffective or even exacerbate the symptoms (MMN)
True
If MMN patients have really bad symptoms, you can also treat with?
High-dose cyclophosphamide -> but side effects
What are the characteristical (clinical) features of anti-MAG neuropathy? (5)
- Prevalence 1 in 100,000
- Age of onset mostly > 50 years
- IgM paraprotein -> kappa or lambda
- IgM recognizes carbohydrates on MAG or glycolipid SGPG
What does the myelin-associated glycoprotein (MAG) bind? (2)
- GD1a ganglioside
- GT1b ganglioside
True or false: MAG is highly glycosylated
True
The Interaction between the MAG and ganglioside is important for?
Mediating the space between myelin and axon
Pathogenesis of anti-MAG neuropathy is different than other neuropathies. What can you detect in the bone marrow?
Abberant B cells with clonal expansions
Which rearrangement is most prominent in patients with anti-MAG neuropathy?
IGHV4-34
In what kind of diseases in the L265P mutation also found?
Diffuse large B-cell lymphoma’s
Which mutation is found in ~60% of anti-MAG neuropathy patients?
L265P mutation in MyD88
How does the L265P mutation result in a gain-of-function?
NFkB activation and cytokine signaling -> clones with this mutation have a survival advantage (deregulation)
In short, describe different mechanisms how antibodies can cause peripheral neuropathies (3)
- IgG4 antibodies disrupt paranodal architecture (CIDP)
- IgM antibodies to glycolipids/proteins bind motorneurons
- Oncogenic mutations in Myd88 (anti-MAG)
With what disease are anti-Yo antibodies associated?
Cerebellar degeneration
What are the auto-immune disease postulates adapted from Koch? (6)
- Antibody found in patients, not healthy controls
- Antibody interacts with target antigen
- Passive transfer
- Active transfer
- Reduction of antibody titer = reduction clinical symptoms
- Comparable to genetic and pharmacological models
When were the anti-NMDA receptor antibodies found?
2007
