Contents
01 Clinical introduction to Multiple Sclerosis
02 MS and therapy
03 Immunological processes in MS
04 Fluid biomarkers in MS
05 Molecular and cellular changes in MS
06 Animal models for MS
07 Myasthenia Gravis
08 Clinical aspects of Celiac Disease
09 Mechanisms and treatment in IBD
10 Systemic lupus erythematosus
11 Failing maternal-fetal immune tolerance
12 Autoantibodies in autoimmune disease
13 Complement-mediated disease and therapeutics
14 Molecular basis of celiac disease and diagnostics
15 Immunohematology & AIHA
16 Clinical aspects of AIDS
17 Translational aspects of primary immunodeficiency research
18 Immunological aspects of aids and vaccine development
19 HIV1 transmission by dendritic cells
20 Autophagy and HIV
21 New strategies for HIV prevention
22 Immunotherapy in daily practice
clinical immunology · study summary
, lecture 01
Clinical intr oduction to Mu ltiple Scler osis
Clinical immunology
Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system (CNS). The
name refers to multiple areas of scarring (sclerosis) in the brain and spinal cord. These scars correspond to
plaques of demyelination, typically occurring in white matter, but also in grey matter.
Neuroimaging
On T2-weighted MRI, MS lesions appear bright due to increased water content from inflammation/demyelination.
On T1-weighted MRI, chronic axonal loss appears as “black holes”, indicating irreversible tissue loss.
Gadolinium-enhancing lesions indicate active inflammation via blood–brain barrier leakage.
Epidemiology
Prevalence: 1–2 per 1000 in many Western countries, including the Netherlands. Typical onset: ages 20–40.
Female predominance: ≈ 2–3 : 1. Not typically fatal; life expectancy is near-normal, though disability burden can
be high.
The exact cause is unknown, but MS is considered a multifactorial autoimmune disease. Important contributing
factors (all mentioned on slides): vitamin D deficiency / low sunlight exposure early in life, smoking, dietary
factors, genetic susceptibility, ethnicity, EBV infection.
Basic Neuroanatomy Relevant to MS
Grey matter: neuronal cell bodies.
White matter: axons wrapped in myelin, produced by oligodendrocytes.
Function of myelin: increases conduction speed through saltatory conduction.
Pathophysiology
MS is a chronic inflammatory demyelinating disease with four key processes:
Inflammation: Immune cells cross a leaky BBB and enter the CNS.
Demyelination: Loss of myelin slows or blocks nerve conduction.
Remyelination: Partial repair by surviving oligodendrocytes—often incomplete.
Gliosis (scarring): Chronic lesions become fibrotic and cannot recover.
Importantly, no single immune cell is solely responsible—MS involves T cells (CD4+, CD8+), B cells, antibodies,
cytokines, and microglia
Clinical presentation
Symptoms vary widely depending on lesion location. Common symptoms:
Visual; Optic neuritis (inflammation of optic nerve), diplopia (double vision), loss of color, loss of contrast.
Pyramidal; paresis, spasticity, abnormal reflexes.
Sensory disturbances; tingling, burning, painful sensations, numbness, Lhermitte’s sign (electric-shock
sensation down back/limbs when neck is flexed, suggesting a cervical spinal cord lesion).
Bladder, bowel, and sexual dysfunction; incontinence, urine retention, frequent STIs, erectile dysfunction,
etc.
Coordination problems; most common. Ataxia (coordination disorder), tremor, balance difficulties.
Cognitive disturbances; memory problems, reduced concentration and attention.
Fatigue; one of the most prevalent and disabling symptoms.
clinical immunology · study summary
,Less visible symptoms; depression, increased suicide risk, relationship strain, walking independence
decreases over decades.
Diagnosis of MS
Clinical features
Slowly progressive neurological symptoms lasting >24h
Not explained by other causes
Relapses = new episodes of focal inflammation
MRI findings
Dissemination in Space (DIS); MRI must show ovoid lesions in 2 or more of the 4 typical MS locations
periventricular, juxtacortical, infratentorial (brain stem/cerebellum), spinal cord.
Dissemination in Time (DIT); Evidence of lesions occurring at different time points, demonstrated by
new T2 lesions on follow-up scans, Simultaneous presence of enhancing and non-enhancing lesions OR
oligoclonal bands in CSF.
Abnormalities in CSF
Detection of oligoclonal bands (OCBs): unique intrathecal IgG production.
Do a lumbar puncture to retract CSF. Look for Igg production in CSF that we cant see in the serum of the
patient. If this is the case, there is an immune response going on in the brain. These are called
oligoclonal bands.
Present in >90% of MS patients.
Differential Diagnosis (exclusions) – differentiate with MRI
Vascular disease (different lesion shapes/locations)
Neuromyelitis optica spectrum disorder (long spinal cord lesions)
Sarcoidosis (distinctive leptomeningeal enhancement - broad enhancement of the vessels around the
cortex)
Special Diagnostic Categories
Clinically Isolated Syndrome (CIS): First demyelinating episode; high risk of evolving into MS. Patient
only has 1 type of symptom.
Radiologically Isolated Syndrome (RIS): MRI lesions typical for MS but without symptoms.
Disease Subtypes
Relapsing–Remitting MS (RRMS) – ~85% at onset
New lesions cause symptoms. Distinct relapses with full/partial recovery.
Inflammation-driven. Most common in young people.
Secondary Progressive MS (SPMS)
Gradual worsening with fewer relapses.
Often develops after (about 15) years of RRMS
Axon degeneration and brain atrophy
Primary Progressive MS (PPMS) – 10–15%
Steady decline from onset, no relapses.
More common in older people; motor symptoms dominate.
Disease Progression
Possible trajectory: RIS → CIS → RRMS → SPMS
Progression involves both inflammatory activity and neurodegeneration.
clinical immunology · study summary
, lecture 02
MS and Ther apy
Clinical immunology
General Principles of MS Treatment
DMTs primarily work by preventing new inflammatory lesions, not by stopping neurodegeneration. Treatment
strategies fall into three major categories:
Acute symptom management – e.g., corticosteroids during relapses
Disease-modifying therapies (DMTs) – aim to reduce inflammatory activity
Symptomatic treatment – medication, physical therapy, cognitive rehabilitation
Role of DMTs
Reduce relapse rate
Reduce formation of new MRI lesions
Prevent enlargement of existing lesions
Delay disability progression (partially)
First line therapies
Interferons & Glatiramer Acetate (injectable therapies)
Examples: IFN-β (Avonex, Rebif, Betaferon), glatiramer acetate
Interfere with inflammatory cytokine signaling
Reduce immune activation and prevent immune cells from crossing the BBB. Clinical effect:
modest reduction in relapses and new MRI lesions
Common side effects: flu-like symptoms, injection-site reactions
Teriflunomide (exact mechanism not understood)
Inhibits proliferation of activated T and B cells (pyrimidine synthesis inhibitor)
Broad but mild immunosuppressive effect
Teratogenic -> relevant for patients planning pregnancy.
Dimethyl fumarate (and related fumarates)
Activates the Nrf2 pathway → reduces oxidative stress
Has broad immune-modulating effects (precise mechanism not fully understood)
Common side effects: flushing, GI complaints. Can cause lymphopenia (need monitoring).
Second line therapies (higher efficacy)
Natalizumab
Monoclonal antibody blocking VLA-4 receptors on lymphocytes. Prevents immune cells from crossing the
BBB.
Very effective at preventing new lesions, but increased risk of PML (progressive multifocal
leukoencephalopathy).
S1P Receptor Modulators (fingolimod, siponimod, ozanimod, ponesimod)
Reduce the number of circulating immune cells by trapping them in the lymph nodes → less trafficking
into CNS.
Strong anti-inflammatory activity, but can lead to bradycardia/arrhytmias and increased infection
risk.
clinical immunology · study summary
01 Clinical introduction to Multiple Sclerosis
02 MS and therapy
03 Immunological processes in MS
04 Fluid biomarkers in MS
05 Molecular and cellular changes in MS
06 Animal models for MS
07 Myasthenia Gravis
08 Clinical aspects of Celiac Disease
09 Mechanisms and treatment in IBD
10 Systemic lupus erythematosus
11 Failing maternal-fetal immune tolerance
12 Autoantibodies in autoimmune disease
13 Complement-mediated disease and therapeutics
14 Molecular basis of celiac disease and diagnostics
15 Immunohematology & AIHA
16 Clinical aspects of AIDS
17 Translational aspects of primary immunodeficiency research
18 Immunological aspects of aids and vaccine development
19 HIV1 transmission by dendritic cells
20 Autophagy and HIV
21 New strategies for HIV prevention
22 Immunotherapy in daily practice
clinical immunology · study summary
, lecture 01
Clinical intr oduction to Mu ltiple Scler osis
Clinical immunology
Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system (CNS). The
name refers to multiple areas of scarring (sclerosis) in the brain and spinal cord. These scars correspond to
plaques of demyelination, typically occurring in white matter, but also in grey matter.
Neuroimaging
On T2-weighted MRI, MS lesions appear bright due to increased water content from inflammation/demyelination.
On T1-weighted MRI, chronic axonal loss appears as “black holes”, indicating irreversible tissue loss.
Gadolinium-enhancing lesions indicate active inflammation via blood–brain barrier leakage.
Epidemiology
Prevalence: 1–2 per 1000 in many Western countries, including the Netherlands. Typical onset: ages 20–40.
Female predominance: ≈ 2–3 : 1. Not typically fatal; life expectancy is near-normal, though disability burden can
be high.
The exact cause is unknown, but MS is considered a multifactorial autoimmune disease. Important contributing
factors (all mentioned on slides): vitamin D deficiency / low sunlight exposure early in life, smoking, dietary
factors, genetic susceptibility, ethnicity, EBV infection.
Basic Neuroanatomy Relevant to MS
Grey matter: neuronal cell bodies.
White matter: axons wrapped in myelin, produced by oligodendrocytes.
Function of myelin: increases conduction speed through saltatory conduction.
Pathophysiology
MS is a chronic inflammatory demyelinating disease with four key processes:
Inflammation: Immune cells cross a leaky BBB and enter the CNS.
Demyelination: Loss of myelin slows or blocks nerve conduction.
Remyelination: Partial repair by surviving oligodendrocytes—often incomplete.
Gliosis (scarring): Chronic lesions become fibrotic and cannot recover.
Importantly, no single immune cell is solely responsible—MS involves T cells (CD4+, CD8+), B cells, antibodies,
cytokines, and microglia
Clinical presentation
Symptoms vary widely depending on lesion location. Common symptoms:
Visual; Optic neuritis (inflammation of optic nerve), diplopia (double vision), loss of color, loss of contrast.
Pyramidal; paresis, spasticity, abnormal reflexes.
Sensory disturbances; tingling, burning, painful sensations, numbness, Lhermitte’s sign (electric-shock
sensation down back/limbs when neck is flexed, suggesting a cervical spinal cord lesion).
Bladder, bowel, and sexual dysfunction; incontinence, urine retention, frequent STIs, erectile dysfunction,
etc.
Coordination problems; most common. Ataxia (coordination disorder), tremor, balance difficulties.
Cognitive disturbances; memory problems, reduced concentration and attention.
Fatigue; one of the most prevalent and disabling symptoms.
clinical immunology · study summary
,Less visible symptoms; depression, increased suicide risk, relationship strain, walking independence
decreases over decades.
Diagnosis of MS
Clinical features
Slowly progressive neurological symptoms lasting >24h
Not explained by other causes
Relapses = new episodes of focal inflammation
MRI findings
Dissemination in Space (DIS); MRI must show ovoid lesions in 2 or more of the 4 typical MS locations
periventricular, juxtacortical, infratentorial (brain stem/cerebellum), spinal cord.
Dissemination in Time (DIT); Evidence of lesions occurring at different time points, demonstrated by
new T2 lesions on follow-up scans, Simultaneous presence of enhancing and non-enhancing lesions OR
oligoclonal bands in CSF.
Abnormalities in CSF
Detection of oligoclonal bands (OCBs): unique intrathecal IgG production.
Do a lumbar puncture to retract CSF. Look for Igg production in CSF that we cant see in the serum of the
patient. If this is the case, there is an immune response going on in the brain. These are called
oligoclonal bands.
Present in >90% of MS patients.
Differential Diagnosis (exclusions) – differentiate with MRI
Vascular disease (different lesion shapes/locations)
Neuromyelitis optica spectrum disorder (long spinal cord lesions)
Sarcoidosis (distinctive leptomeningeal enhancement - broad enhancement of the vessels around the
cortex)
Special Diagnostic Categories
Clinically Isolated Syndrome (CIS): First demyelinating episode; high risk of evolving into MS. Patient
only has 1 type of symptom.
Radiologically Isolated Syndrome (RIS): MRI lesions typical for MS but without symptoms.
Disease Subtypes
Relapsing–Remitting MS (RRMS) – ~85% at onset
New lesions cause symptoms. Distinct relapses with full/partial recovery.
Inflammation-driven. Most common in young people.
Secondary Progressive MS (SPMS)
Gradual worsening with fewer relapses.
Often develops after (about 15) years of RRMS
Axon degeneration and brain atrophy
Primary Progressive MS (PPMS) – 10–15%
Steady decline from onset, no relapses.
More common in older people; motor symptoms dominate.
Disease Progression
Possible trajectory: RIS → CIS → RRMS → SPMS
Progression involves both inflammatory activity and neurodegeneration.
clinical immunology · study summary
, lecture 02
MS and Ther apy
Clinical immunology
General Principles of MS Treatment
DMTs primarily work by preventing new inflammatory lesions, not by stopping neurodegeneration. Treatment
strategies fall into three major categories:
Acute symptom management – e.g., corticosteroids during relapses
Disease-modifying therapies (DMTs) – aim to reduce inflammatory activity
Symptomatic treatment – medication, physical therapy, cognitive rehabilitation
Role of DMTs
Reduce relapse rate
Reduce formation of new MRI lesions
Prevent enlargement of existing lesions
Delay disability progression (partially)
First line therapies
Interferons & Glatiramer Acetate (injectable therapies)
Examples: IFN-β (Avonex, Rebif, Betaferon), glatiramer acetate
Interfere with inflammatory cytokine signaling
Reduce immune activation and prevent immune cells from crossing the BBB. Clinical effect:
modest reduction in relapses and new MRI lesions
Common side effects: flu-like symptoms, injection-site reactions
Teriflunomide (exact mechanism not understood)
Inhibits proliferation of activated T and B cells (pyrimidine synthesis inhibitor)
Broad but mild immunosuppressive effect
Teratogenic -> relevant for patients planning pregnancy.
Dimethyl fumarate (and related fumarates)
Activates the Nrf2 pathway → reduces oxidative stress
Has broad immune-modulating effects (precise mechanism not fully understood)
Common side effects: flushing, GI complaints. Can cause lymphopenia (need monitoring).
Second line therapies (higher efficacy)
Natalizumab
Monoclonal antibody blocking VLA-4 receptors on lymphocytes. Prevents immune cells from crossing the
BBB.
Very effective at preventing new lesions, but increased risk of PML (progressive multifocal
leukoencephalopathy).
S1P Receptor Modulators (fingolimod, siponimod, ozanimod, ponesimod)
Reduce the number of circulating immune cells by trapping them in the lymph nodes → less trafficking
into CNS.
Strong anti-inflammatory activity, but can lead to bradycardia/arrhytmias and increased infection
risk.
clinical immunology · study summary
