Contents
Multiple sclerosis ...................................................................................................................... 2
Lecture 1 Multiple Sclerosis ............................................................................................................................. 2
Immunological processes in multiple sclerosis ...................................................................................... 10
Pathology of Multiple sclerosis ..................................................................................................................... 16
Lecture Body fluid biomarkers for MS ....................................................................................................... 18
Lecture a transcriptomic view: Molecular and cellular changes in MS .......................................... 22
Lecture animal models ..................................................................................................................................... 27
Coeliac Disease ........................................................................................................................ 32
Clinical aspects of coeliac disease ............................................................................................................... 32
Animal models for Coeliac disease ............................................................................................................. 35
Molecular basis of celiac disease and diagnostics ................................................................................ 40
Systemic lupus Erythematosus (SLE) .................................................................................... 43
Lecture SLE introduction ................................................................................................................................. 43
Failing maternal-fetal tolerance in SLE ...................................................................................................... 50
Inflammatory Bowel Disease ................................................................................................. 55
Immunology of IBD ........................................................................................................................................... 55
Crohn’s Disease................................................................................................................................................... 60
Immunodeficiencies and immunotherapies ........................................................................ 63
Translational aspects of primary immunodeficiency research .......................................................... 63
HIV............................................................................................................................................ 68
Immunological aspects of AIDS and vaccin development ................................................................. 68
HIV-1 transmission by Dendritic Cells ........................................................................................................ 73
Role of autophagy in HIV-1 transmission ................................................................................................. 79
Immunity ................................................................................................................................. 83
Trained immunity a program of innate memory in health and diseases ...................................... 83
Immunotherapy in daily practice ................................................................................................................. 86
1
,Multiple sclerosis
Lecture 1 Multiple Sclerosis
1. Basics
Multiple Sclerosis (MS)
Made up of scars in your CNS (brain and spinal cord). Both white and grey
matter. Auto-immune reaction that attacks the myelin sheets.
- Prevalence 1:1000 in the NL
- Starts between 20-40 years
- Man : woman = 1 : 2 à 3
- Almost normal life expectancy
Contributing factors
- Vitamin D levels
o Low sun exposure is one of the biggest risk factors of MS
- Diet
o Mediterranean diet is the best diet for MS patients
- Smoking
- Epstein-Barr virus
o Everyone with MS has been tested positive with EBV
- Ethnicity
- genes
Anatomy
Grey matter → cell bodies
White matter → with myelin surrounded axons
- Myelin is necessary to have fast signalling.
o Improves conduction
o Oligodendrocytes make the myelin
Pathophysiology
‘chronic inflammatory demyelinating disease of the central nervous system’
Pathological hallmarks:
- Inflammation
o Blood brain barrier (BBB)
o Immune cells enter brain
- Demyelination
o Conduction slows down
- Remyelination
- Gliosis (scarring)
2
,Picture of the white matter → a lot of myelin in the tissue (blood
vessel In the middle). Green is the myelin, red is the axons. In an
active lesion, the immune (blue) cells travel through the blood vessel
and surround it, and you see how few myelin there is now. (not a
real picture) In a chronic active lesion, you see that is being tried to
remyelinate, however the myelin doesn’t really come back. Later it
will become a scar.
Immune system
- CD4 T cells
- CD8 T cells
- B cells
o antibodies
- Cytokines
The cross the BBB and enter the CNS
2. Clinical symptoms
Clinical symptoms
The symptoms are linked to the location of a lesion. So every patient
has a different clinical picture.
- Visual problems
o Optic neuritis (lesion on the optic nerve)
▪ Pain behind the eye
▪ Decreased colour vision
▪ Decreased visual acquity, especially central visual fields
o Diplopia (other nerves)
▪ Double vision
▪ Intranuclear ophthalmoplegia
• INO left
• Lesion in the left fasciculus longitunialis
• Your eyes don’t coordinate together.
- Pyramidal symptoms (motor symptoms)
o Paresis
o Spasticity
o Abnormal reflexes
▪ In MS, the reflexes are also higher than normal (so not that you don’t
have a reflex anymore)
- Sensory disturbances
o Tingling / painful sensations
o Numbness
o Symptom of Lhermitte
▪ If you have a lesion in your cervical spinal cord, you get a numb feeling
in the rest of your body when you put your head down.
- Bladder-/bowel-/sexual problems
o Incontinence
3
, ▪ Urine
▪ Faeces
o Urine retention / constipation
o Frequent urinary tract infections
o Sexual problems
- Coordination problems
o Ataxia → you want to move your limbs, but they don’t do what you want them
to do
o Tremor
o Balance
- Cognitive disturbances
o Memory
o Concentration
o Attention
o Difficulties organising
- Fatigue.
o High prevalence
o No good treatment
o Unknown cause
o Less visible
Other less visible symptoms are depression, suicide relationship and independent walking.
Case
A female, 25 years old, has a slowly progressive weakness in the left leg, 2 weeks, now stable.
She has a history of migraine. No / paresis left leg, increased reflexes left leg. Is this MS?
3. Diagnosing MS
Diagnosis
- Clinical features
o 2/3 fault diagnosis, based on exclusion
- Radiological characteristics (MRI)
- Abnormalities in CSF
The diagnosis is based on
DIT → Dissemination in Time
- Multiple symptoms at multiple timepoints is necessary
DIS → Dissemination in Space
- More lesions in several spaces are necessary for diagnosis.
Clinical features
- What symptoms do we see in MS?
- Vary widely
o Different locations
o Different severity
- New neurological symptoms – relapses
o Slowly progressive symptoms (hours to days)
o Lasting > 24 hours
o Not attributable to other causes than MS
4
,Radiological characteristics: MRI in MS
- Lesions in the brain and spinal cord
o Ovoid shaped
- Number, size and distribution vary widely
- Specific MS localisations
o Periventricular
o Juxtacortical/cortical
o Infratentorial
o Spinal cord
Different sequences of lesions
Typical lesions on a T2 sequence.
‘black hole’ lesion
Contrast can be induced with gadolinium
DIS → lesions in 2 of 4 locations
DIT → combination of T2 lesions and contrast enhancing lesions. New T2 lesions over time
Degeneration: Over time you see signs that the nerves of the brain are less.
Atrophy
- Widening ventricles
- Later disease stages
- Both brain and spinal cord
- Partially independent from white matter lesion load
Exclusion of differential diagnosis
Monitoring disease activity, treatment efficacy and pharmacovigilance
Cerebrospinal fluid (CSF)
- Dissemination in Time
- Oligoclonal bands
- White blood count or protein count
McDonald criteria
The reason behind the criteria, is because it is a
heterogenous disease so you need to have a proper
guideline.
5
,Two lesions can be enough, however they don’t often do this.
There have been some changes → next to juxtacortical, it can
now also be cortical and the oligoclonal bands in CSF can
also be a criteria point right now.
The diagnosis is much more precise now.
They want to revise the criteria again in 2024! Here they
further want to add the optic nerve as a 5th topography (DIS). They also want to incorporate
new MRI techniques and use biomarkers (sNFL).
Back to the case!
There should be done an MRI and do a follow up for the symptoms!
Clinically isolated syndrome (CIS) → if you have some MS-like symptoms but are not
diagnosed yet for MS, you get diagnosed with CIS.
- Monosymptomatic clinical presentation of demyelination
o Optic neuritis
o Myelum syndrome
o Brainstem syndrome
- Could evolve into MS! (63-85% develops into MS eventually)
So, first episode → clinically isolated syndrome, suggestive of a demyelinating disease
1. Consultation with neurologist
2. MRI & lumbar punction
3. If (possible) MS: counselling on prognosis & treatment
Conclusion
- Wait and see
- Wait and scan
4. Disease course and subtypes
Different MS subtypes
- Relapsing-remitting
o Most common symptoms: optic neuritis, sensory
symptoms
- Secondary progressive → the relapses are not that often
anymore, but still the patient progresses gradually
(walking ability often symptom), comes after relapsing-
remitting
- Primary progressive → no relapses at all, just a
progressive worsening.
o Usually walking disabilities
- Progressive-relapsing
6
,Radiological isolated syndrome (RIS)
➔ More MRI scans are made generally, so people that do a scan without the search for
MS, can sometimes find a lesion. These are then diagnosed with RIS
5. Prognosis
6. Treatment
In the case, the woman has no wish for treatment, as there is a pregnancy wish. However,
after a while, she has an episode of visual disturbances, unable to see using one eye.
- Six months later she has difficulties with walking, suddenly present and progressive
- Back at the clinic
o Paresis upper legs. Hyperreflexia in the arms and legs. Difficulties walking due
to loss of strength in muscles and sensory
disturbances
Should we now treat her? → YES
Treatment options
Sometimes, CIS patients can also already get treatment
Approaches
- Acute symptom management
- Disease-modifying therapies (DMTs)
- Symptomatic treatment (medication, (cognitive)
rehabilitation)
DMTs (Tablets, infusion therapies, injections)
No treatment
First-line DMT →
Second-line DMT →
- Is done if you have more disease load on the MRI scans.
7
, Men have more risk of
having active disease,
if diagnosed with MRI.
And therefore get
second line DMT.
1st line:
- Interferon and glatirameracetate injections → make it more anti-inflammatory
- Teriflunomide and dimethylfumarate → make it more anti-inflammatory
- S1P modulators (-mod) → receptor on your lymph node. In MS they cross the BBB,
these medications prevent the immune cells from leaving the lymph node.
2nd line:
- S1P modulator → “ “
- Natalizumab → VLA-4 receptor antagonist, that prevents immune cells from crossing
the BBB. People get an infusion every month.
- Anti-CD20 (B cell therapy) (ocrelizumab/rituximab) → infusions that deplete the B
cells and kill the B cells.
- Cladribine / alemtuzumab / stemcell therapy → wipe out your whole immune system
and you get a new one.
Side effects
- Injectables often have skin reactions (rash). But
also have flu-like symptoms.
- Tablets often induce thinning hair, or hypertension.
- Gastrointestinal symptoms.
- Cardial arrythmia
- Brain-infection, haemorrhages, auto-immune
diseases.
- Lymphopenia (decrease in white blood cell count)
- Primary multifocal leukoencephalopathy (PML)
because of JCV virus. This virus can enter the
brain, but if because of treatment of MS you don’t
have a good immunity, you can get PML
8
,6 months later
- Started with dimethylfumarate (anti-inflammatory mediator) due to personal
preference
- She does not do so well, cannot walk anymore, needs a wheelchair to mobilize
o Turns out she has a lot of lesions!
- Second line treatment: natalizumab.
1 year later
- Clinically fully stabilized
- Can walk again, 1 km
- However, JCV positive, so they calculate an index to see if it will progress to
PML disease. This was high..
- They decided to switch to ocrelizumab and now she is doing ok.
7. Challenges on the road ahead
Rising costs MS medication
Cost effectivity
- Delayed dosage of biologicals based on blood levels
- Research on possibilities of stopping treatment
- Biosimilars / generics
9
, Immunological processes in multiple sclerosis
Part 1: multiple sclerosis
You can have relapsing remitting MS (RRMS) or progressive MS.
MS lesions in time
Some lesions stay, however, some go away over time. The lesion activity is a lot around the
ventricles, saying that maybe the CSF has a role in the pathophysiology of MS.
Challenges
Biomarkers
Biomarkers can serve at different time points
- Predictive biomarkers (genetic relatives)
- Diagnostic biomarkers (CIS/RIS)
- Disease activity biomarkers (relapsing/progressive)
o Markers for this tipping point of RRMS to progressive are necessary
- Treatment biomarkers
o To see if the treatment works, so you save time and money because if it
doesn’t work, you can then always switch treatments
10
Multiple sclerosis ...................................................................................................................... 2
Lecture 1 Multiple Sclerosis ............................................................................................................................. 2
Immunological processes in multiple sclerosis ...................................................................................... 10
Pathology of Multiple sclerosis ..................................................................................................................... 16
Lecture Body fluid biomarkers for MS ....................................................................................................... 18
Lecture a transcriptomic view: Molecular and cellular changes in MS .......................................... 22
Lecture animal models ..................................................................................................................................... 27
Coeliac Disease ........................................................................................................................ 32
Clinical aspects of coeliac disease ............................................................................................................... 32
Animal models for Coeliac disease ............................................................................................................. 35
Molecular basis of celiac disease and diagnostics ................................................................................ 40
Systemic lupus Erythematosus (SLE) .................................................................................... 43
Lecture SLE introduction ................................................................................................................................. 43
Failing maternal-fetal tolerance in SLE ...................................................................................................... 50
Inflammatory Bowel Disease ................................................................................................. 55
Immunology of IBD ........................................................................................................................................... 55
Crohn’s Disease................................................................................................................................................... 60
Immunodeficiencies and immunotherapies ........................................................................ 63
Translational aspects of primary immunodeficiency research .......................................................... 63
HIV............................................................................................................................................ 68
Immunological aspects of AIDS and vaccin development ................................................................. 68
HIV-1 transmission by Dendritic Cells ........................................................................................................ 73
Role of autophagy in HIV-1 transmission ................................................................................................. 79
Immunity ................................................................................................................................. 83
Trained immunity a program of innate memory in health and diseases ...................................... 83
Immunotherapy in daily practice ................................................................................................................. 86
1
,Multiple sclerosis
Lecture 1 Multiple Sclerosis
1. Basics
Multiple Sclerosis (MS)
Made up of scars in your CNS (brain and spinal cord). Both white and grey
matter. Auto-immune reaction that attacks the myelin sheets.
- Prevalence 1:1000 in the NL
- Starts between 20-40 years
- Man : woman = 1 : 2 à 3
- Almost normal life expectancy
Contributing factors
- Vitamin D levels
o Low sun exposure is one of the biggest risk factors of MS
- Diet
o Mediterranean diet is the best diet for MS patients
- Smoking
- Epstein-Barr virus
o Everyone with MS has been tested positive with EBV
- Ethnicity
- genes
Anatomy
Grey matter → cell bodies
White matter → with myelin surrounded axons
- Myelin is necessary to have fast signalling.
o Improves conduction
o Oligodendrocytes make the myelin
Pathophysiology
‘chronic inflammatory demyelinating disease of the central nervous system’
Pathological hallmarks:
- Inflammation
o Blood brain barrier (BBB)
o Immune cells enter brain
- Demyelination
o Conduction slows down
- Remyelination
- Gliosis (scarring)
2
,Picture of the white matter → a lot of myelin in the tissue (blood
vessel In the middle). Green is the myelin, red is the axons. In an
active lesion, the immune (blue) cells travel through the blood vessel
and surround it, and you see how few myelin there is now. (not a
real picture) In a chronic active lesion, you see that is being tried to
remyelinate, however the myelin doesn’t really come back. Later it
will become a scar.
Immune system
- CD4 T cells
- CD8 T cells
- B cells
o antibodies
- Cytokines
The cross the BBB and enter the CNS
2. Clinical symptoms
Clinical symptoms
The symptoms are linked to the location of a lesion. So every patient
has a different clinical picture.
- Visual problems
o Optic neuritis (lesion on the optic nerve)
▪ Pain behind the eye
▪ Decreased colour vision
▪ Decreased visual acquity, especially central visual fields
o Diplopia (other nerves)
▪ Double vision
▪ Intranuclear ophthalmoplegia
• INO left
• Lesion in the left fasciculus longitunialis
• Your eyes don’t coordinate together.
- Pyramidal symptoms (motor symptoms)
o Paresis
o Spasticity
o Abnormal reflexes
▪ In MS, the reflexes are also higher than normal (so not that you don’t
have a reflex anymore)
- Sensory disturbances
o Tingling / painful sensations
o Numbness
o Symptom of Lhermitte
▪ If you have a lesion in your cervical spinal cord, you get a numb feeling
in the rest of your body when you put your head down.
- Bladder-/bowel-/sexual problems
o Incontinence
3
, ▪ Urine
▪ Faeces
o Urine retention / constipation
o Frequent urinary tract infections
o Sexual problems
- Coordination problems
o Ataxia → you want to move your limbs, but they don’t do what you want them
to do
o Tremor
o Balance
- Cognitive disturbances
o Memory
o Concentration
o Attention
o Difficulties organising
- Fatigue.
o High prevalence
o No good treatment
o Unknown cause
o Less visible
Other less visible symptoms are depression, suicide relationship and independent walking.
Case
A female, 25 years old, has a slowly progressive weakness in the left leg, 2 weeks, now stable.
She has a history of migraine. No / paresis left leg, increased reflexes left leg. Is this MS?
3. Diagnosing MS
Diagnosis
- Clinical features
o 2/3 fault diagnosis, based on exclusion
- Radiological characteristics (MRI)
- Abnormalities in CSF
The diagnosis is based on
DIT → Dissemination in Time
- Multiple symptoms at multiple timepoints is necessary
DIS → Dissemination in Space
- More lesions in several spaces are necessary for diagnosis.
Clinical features
- What symptoms do we see in MS?
- Vary widely
o Different locations
o Different severity
- New neurological symptoms – relapses
o Slowly progressive symptoms (hours to days)
o Lasting > 24 hours
o Not attributable to other causes than MS
4
,Radiological characteristics: MRI in MS
- Lesions in the brain and spinal cord
o Ovoid shaped
- Number, size and distribution vary widely
- Specific MS localisations
o Periventricular
o Juxtacortical/cortical
o Infratentorial
o Spinal cord
Different sequences of lesions
Typical lesions on a T2 sequence.
‘black hole’ lesion
Contrast can be induced with gadolinium
DIS → lesions in 2 of 4 locations
DIT → combination of T2 lesions and contrast enhancing lesions. New T2 lesions over time
Degeneration: Over time you see signs that the nerves of the brain are less.
Atrophy
- Widening ventricles
- Later disease stages
- Both brain and spinal cord
- Partially independent from white matter lesion load
Exclusion of differential diagnosis
Monitoring disease activity, treatment efficacy and pharmacovigilance
Cerebrospinal fluid (CSF)
- Dissemination in Time
- Oligoclonal bands
- White blood count or protein count
McDonald criteria
The reason behind the criteria, is because it is a
heterogenous disease so you need to have a proper
guideline.
5
,Two lesions can be enough, however they don’t often do this.
There have been some changes → next to juxtacortical, it can
now also be cortical and the oligoclonal bands in CSF can
also be a criteria point right now.
The diagnosis is much more precise now.
They want to revise the criteria again in 2024! Here they
further want to add the optic nerve as a 5th topography (DIS). They also want to incorporate
new MRI techniques and use biomarkers (sNFL).
Back to the case!
There should be done an MRI and do a follow up for the symptoms!
Clinically isolated syndrome (CIS) → if you have some MS-like symptoms but are not
diagnosed yet for MS, you get diagnosed with CIS.
- Monosymptomatic clinical presentation of demyelination
o Optic neuritis
o Myelum syndrome
o Brainstem syndrome
- Could evolve into MS! (63-85% develops into MS eventually)
So, first episode → clinically isolated syndrome, suggestive of a demyelinating disease
1. Consultation with neurologist
2. MRI & lumbar punction
3. If (possible) MS: counselling on prognosis & treatment
Conclusion
- Wait and see
- Wait and scan
4. Disease course and subtypes
Different MS subtypes
- Relapsing-remitting
o Most common symptoms: optic neuritis, sensory
symptoms
- Secondary progressive → the relapses are not that often
anymore, but still the patient progresses gradually
(walking ability often symptom), comes after relapsing-
remitting
- Primary progressive → no relapses at all, just a
progressive worsening.
o Usually walking disabilities
- Progressive-relapsing
6
,Radiological isolated syndrome (RIS)
➔ More MRI scans are made generally, so people that do a scan without the search for
MS, can sometimes find a lesion. These are then diagnosed with RIS
5. Prognosis
6. Treatment
In the case, the woman has no wish for treatment, as there is a pregnancy wish. However,
after a while, she has an episode of visual disturbances, unable to see using one eye.
- Six months later she has difficulties with walking, suddenly present and progressive
- Back at the clinic
o Paresis upper legs. Hyperreflexia in the arms and legs. Difficulties walking due
to loss of strength in muscles and sensory
disturbances
Should we now treat her? → YES
Treatment options
Sometimes, CIS patients can also already get treatment
Approaches
- Acute symptom management
- Disease-modifying therapies (DMTs)
- Symptomatic treatment (medication, (cognitive)
rehabilitation)
DMTs (Tablets, infusion therapies, injections)
No treatment
First-line DMT →
Second-line DMT →
- Is done if you have more disease load on the MRI scans.
7
, Men have more risk of
having active disease,
if diagnosed with MRI.
And therefore get
second line DMT.
1st line:
- Interferon and glatirameracetate injections → make it more anti-inflammatory
- Teriflunomide and dimethylfumarate → make it more anti-inflammatory
- S1P modulators (-mod) → receptor on your lymph node. In MS they cross the BBB,
these medications prevent the immune cells from leaving the lymph node.
2nd line:
- S1P modulator → “ “
- Natalizumab → VLA-4 receptor antagonist, that prevents immune cells from crossing
the BBB. People get an infusion every month.
- Anti-CD20 (B cell therapy) (ocrelizumab/rituximab) → infusions that deplete the B
cells and kill the B cells.
- Cladribine / alemtuzumab / stemcell therapy → wipe out your whole immune system
and you get a new one.
Side effects
- Injectables often have skin reactions (rash). But
also have flu-like symptoms.
- Tablets often induce thinning hair, or hypertension.
- Gastrointestinal symptoms.
- Cardial arrythmia
- Brain-infection, haemorrhages, auto-immune
diseases.
- Lymphopenia (decrease in white blood cell count)
- Primary multifocal leukoencephalopathy (PML)
because of JCV virus. This virus can enter the
brain, but if because of treatment of MS you don’t
have a good immunity, you can get PML
8
,6 months later
- Started with dimethylfumarate (anti-inflammatory mediator) due to personal
preference
- She does not do so well, cannot walk anymore, needs a wheelchair to mobilize
o Turns out she has a lot of lesions!
- Second line treatment: natalizumab.
1 year later
- Clinically fully stabilized
- Can walk again, 1 km
- However, JCV positive, so they calculate an index to see if it will progress to
PML disease. This was high..
- They decided to switch to ocrelizumab and now she is doing ok.
7. Challenges on the road ahead
Rising costs MS medication
Cost effectivity
- Delayed dosage of biologicals based on blood levels
- Research on possibilities of stopping treatment
- Biosimilars / generics
9
, Immunological processes in multiple sclerosis
Part 1: multiple sclerosis
You can have relapsing remitting MS (RRMS) or progressive MS.
MS lesions in time
Some lesions stay, however, some go away over time. The lesion activity is a lot around the
ventricles, saying that maybe the CSF has a role in the pathophysiology of MS.
Challenges
Biomarkers
Biomarkers can serve at different time points
- Predictive biomarkers (genetic relatives)
- Diagnostic biomarkers (CIS/RIS)
- Disease activity biomarkers (relapsing/progressive)
o Markers for this tipping point of RRMS to progressive are necessary
- Treatment biomarkers
o To see if the treatment works, so you save time and money because if it
doesn’t work, you can then always switch treatments
10
