SUMMARY Integrated biomedical sciences (AM_1281); VU Amsterdam; Biomedical Sciences Year 1
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Course
Integrated Biomedical Sciences (AM_1281)
Institution
Vrije Universiteit Amsterdam (VU)
This document contains an elaborate summary of all the lectures given during the course Integrated Biomedical Sciences at the Vrije Universiteit Amsterdam. It was made in 2024. Good luck studying!
Contents
Lecture Introduction (very short) ........................................................................................................2
Lecture Core concepts and processes in immunology ...............................................................2
Lecture Core concepts and processes in neurobiology........................................................... 10
Lecture Infectious diseases ................................................................................................................ 20
Lecture Determining adaptive immune responses ................................................................... 27
Lecture Research techniques in neurobiology ............................................................................ 32
Lecture Outbreaks IBMS...................................................................................................................... 35
Lecture Research techniques infectious diseases ...................................................................... 39
Lecture Measles ...................................................................................................................................... 43
Lecture Epidemiology Applied Biostatistics I .............................................................................. 46
Lecture Epidemiology Applie Biostatistics part II....................................................................... 50
Lecture Innovations in biomedical sciences / valorization in life sciences ....................... 52
Lecture Ethics .......................................................................................................................................... 57
Lecture BMS in dialogue ..................................................................................................................... 59
,Lecture Introduction (very short)
Reductionism
- An ontological claim that a whole organism is ‘nothing more’ than the sum of its
parts;
- Epistemological claim that the organism is best explained by reference to its parts
- A methodological claim that the organism is best investigated by its parts.
Lecture Core concepts and processes in immunology
You can have an immune response against pathogens, but also molecules that shouldn’t be
harmful, like pollen or gluten.
A tolerance against f.e. pindas, are not an absence of an immune response, but just a wrong
one/too much activated?
Different types of pathogens require different defence mechanisms
Extracellular:
- Opsonization
- antibodies
Intracellular:
- kill the whole cell
o NK/CD8 T cells
Inflammation is caused by recognition by the innate
immune system. Requirement for different types of effector
cells and molecules to defend against many different
pathogens.
There is a diversity in immune cell that belong to the innate
or adaptive immune system.
The innate immune system consists of three important compartments:
- Soluble components: complement
2
, - Pattern recognition receptors: TLRs, RIG-I receptors, NOD like receptors, C-type lectins
- Cells: macrophages, neutrophilic granulocytes, DC and NK cells
Complement
System of 30 soluble proteins that are present in your fluids
Proteolytic system: enzymes that can cut proteins, that get
activated during this cutting.
1. Alternative route
a. Most common and important
b. Spontaneous activation
c. Suppressed by ‘self’ but pathogens cannot
d. Proteins on surface of cells
2. Lectin route
a. Receptors that bind to sugars
(carbohydrates)
b. Mannose binding
c. Lectin (MBL (mannose binding lectin) binds
to carbohydrates on pathogens
3. Classical route
a. First to be discovered and least important
b. Activation by IgM antibodies and
c. C reactive protein (CRP) via C1q
All complement activation routes converge on C3 activation.
C3 is cut into C3b and C3a.
C3b sticks to the bacteria, and C3a is an anaphylatoxin. An anaphylatoxin activates the
endothelial cells
Downstream effects of complement activation
- Recruitment of inflammatory cells.
- C3b fixation results in opsonization, facilitating uptake and killing by phagocytes
- Perforation of pathogen cell membranes
People who lack C3 are very susceptible to bacterial infections.
PRRs
The cellular innate immune response is mediated by PRRs
Cells recognize a family of pathogens/molecules. We have receptors that recognize these
pathogen associated molecular patterns (PAMPs). The receptors bind the PAMPs, and then it
can activate the cell, that can lead to cytokine production.
- PAMPs are conserved molecular signatures of invading pathogens
o DNA/RNA
o Cell wall components, such as lipids, sugars, proteins
- Discrimination between self and non-self
- Extracellular and intracellular receptors
3
, - Results in activation of cells and the production of cytokines and/or induction of
phagocytosis
- Expressed by many cell types including macrophages, monocytes, granulocytes, DC
and NK cells
Different classes of PRRs
- TLR
o Membrane-bound receptors
o Results in inflammatory cytokines and type
I IFN
o Can recognize lipids/nucleotides
o TLR4 binds to LPS
o In endosomes, TLRs recognize RNA/DNA
strands
- C-type lectin receptors
o Ca2+- dependent recognition of
carbohydrates (sugars)
o Pathogen recognition
o Antigen uptake/Phagocytosis
o Signalling
- NOD-like receptors
o Cytosolic recognition various ligands
o Results in inflammatory cytokines and IL-1
- RIG-I-like receptors
o Cytosolic recognition of RNA
o Results in type I IFN
▪ IFN I associate with VIRAL infections!
Cells
Macrophages
- Are big (macro) eaters (phagocytosis)
- Present in tissue and stay there
- Expression of many PRRS
- One of the first to respond
- They signal neutrophils via CXCO8
Neutrophils
- Signature multi-lobular nucleus
- Recruited to infection site
- Efficient killers with a short-life span because they are only necessary to kill
- Important in bacterial and fungal (not virus!)
Expression of
- Multiple receptors for pathogen recognition
- Toxic granules for killing
Dendritic cells (DC)
- Present in all tissues
4
, - Phagocytose pathogens and dead cells
- Express PRRs and become activated when stimulated
- Migrate to secondary lymphoid organs
- Activate adaptive immune responses via antigen presentation to T cells.
NK cells
- Important for viral infection (contrary to neutrophils)
- It notices a cell and starts producing IFNs. The neighbouring cells are warned and
then they start to induce mechanisms to prevent viral reproduction in these cells.
- Later the cells kills the virus infected cells.
Summary of first part
First phase of the immune response after a pathogen has entered the body
Role of the innate immune system:
- Eradication of the pathogen
- Alerting the adaptive immune system
Fast response with limited specificities
Complement system
PRRs: TLRs, CLRs, RLRs, NLRs
Cells of the immune system
- Macrophages → clearance of pathogens, induction of inflammation
- Granulocytes → pathogen clearance
- NK cells → Detection and elimination of virally infected cells
- Dendritic cells → Bridging innate and adaptive immunity
Adaptive immune response
Adaptive immune system is characterized by a diverse repertoire and clonal selection. Every
individual cell has a different receptor.
Antibody = secreted immunoglobulin
B cell receptor = membrane-bound immunoglobulin
Negative selection in the bone marrow and thymus prevents that self reacting adaptive cells
can circulate.
An antigen can have multiple epitopes.
B and T cells recognize antigens in different forms
- T cells recognize processed peptide antigens presented in context of MHC molecules
on the surface of cells (epitope).
- B cells and antibodies recognize intact Ag
5
,The protein structures of MHC I and II are similar, they fit a peptide in their a-helixes.
Human MHC genes are highly polymorphic. Presence of multiple variants of each gene within
the population.
Polymorphisms: lots of different forms of the MHC molecules. In humans MHC is called HLA.
3 MHC I: HLA-A,B,C
3 MHC II: HLA -DR,DQ.DP
Everybody expresses different molecules, ensuring that there is a variety that beats the
pathogen better.
Generation of B cell and T-cell receptors via somatic recombination in bone marrow
and thymus
RAG enzymes
- help cut out a piece of DNA and join them together.
- They mediate DNA recombination of gene segments of the variable regions of the
BCR and TCR in developing B and T cells in bone marrow and thymus.
- They are unique to the immune system. You don’t have adaptive immune cells if you
don’t have RAG enzymes.
In every B cell and T cell a different (random) recombination occurs.
Positive selection
Only T cells have to undergo this!!
The MHC molecules are made random, so positive selection is necessary to select the self
MHC molecules that do bind to the APC (binding should not be too strong).
Negative selection
This is to remove B/T cells that are reactive to self: removal of ‘self’ specificities: TCR or BCR
that bind autoantigens. It is performed in the thymus and bone marrow.
T cell activation is induced in secondary lymphoid organs by DC.
Pattern recognition receptors
PRR stimulation leads to DC maturation and upregulation of costimulatory molecules. Only
pathogens can be recognized by the DC by PRRs. The pathogens activate the DCs via the
TLR/RLR/CLRs. When this happens, they upregulate co-stimulatory molecules. Enables
dendritic cells to activate naïve T cells.
6
,Two antigen presentation pathways
Extracellular Ag-MHC class II only on antigen-presenting cells B cells, macrophages, DCs
Intracellular Ag- MHC class I on all cells.
APCs have specific receptors to pick up pathogens from the outside (exogenous).
Cross-presentation
- Cross-presentation: Presentation of extracellular antigens on MHC
class I
o Take up antigens from the outside, but are still presented via
MHC class I.
- Cross-priming: activation of naïve CD8+ T cells via cross-
presentation
- Only in DC!!!!
Activation of naïve T cells by DC
Done by 3 signals
Signal 1: antigen presentation in MHC to TCR → specificity
Signal 2: costimulation → proliferation and survival
- is only by the DC when they are activated and that is necessary for the first activation
(of naïve cells). Then the naïve cells become effector cells. Effector cells don’t need co-
stimulation anymore.
Signal 3: skewing cytokines/ligands → differentiation in specific effector subsets
- are the cytokines that drive the differentiation of the CD4 T cells.
Clonal selection
➔ expansion of T/B cell clones that recognize Ag. Differentiation in effector cells.
Regulatory T cells that suppress (auto)-immune responses are generated in the thymus and in
the secondary lymphoid organs
- natural regulatory T cells are formed in the thymus and are specific for self-antigens
7
, - induced regulatory T cells are formed in the periphery and specific for self or
microbiota antigens
- they both express IL-10 and TGFβ which are suppressive cytokines
naïve/resting B cells generated in the bone marrow express IgM/IgD
BCR on their cell membrane.
Naïve B and T cells enter via the high endothelial venules (HEV) and
then migrate to B and T cell areas. Intact Ag is presented to B cells in
the B cell follicles and T cells recognize processed Ag in MHC on DCs
in the T cell area. Next, B and T cells interact: CD4+ T cells provide help
to B cells.
The CD4 T cell help for B cell responses is Ag and CD40L dependent! B cells
get help from TFH antigen dependently.
In the germinal center two processes occur that are dependent on CD4+ T
cell help: somatic hypermutation and isotype switch. This leads to BCR
with a higher affinity and different isotype.
- Somatic hypermutation and isotype switch improves the quality of
antibody.
o The primary antibody response starts with low affinity IgM
o Due to isotype switching and affinity maturation high affinity
IgG develops
o The secondary immune response is characterized by high
affinity IgG
Summary
Adaptive immune system
- Slow to develop
- Very specific for the pathogen: depends on clonal selection
- Different in everyone, because of MHC polymorphism and unique TCR and BCRs
- Generates memory
- Memory immune repsonses are faster, stronger, better
- Mediated by soluble factors (humoral response), which are antibodies produced by
B cells, and T cells that constitute the cellular response
- T and B cells are generated in primary lymphoid organs, and activated in secondary
lymphoid organs
- Depends on expansion of clonal T and B cells
- T and B cells express rearranged receptors
- MHC molecules are polymorphic
- TCRs recognize peptides in MHC (MHC restriction)
- MHC class I present endogenous peptides
- MHC class II present exogenous peptides
- Dendritic cells activate naïve T cells with 3 signals
- Effector T cells migrate into peripheral tissues
- Subsets of CD4+ effector T cells have different function
- Activation of B cell responses is dependent on CCD4 T cell help
- Germinal centers leads to isotype switch and affinity maturation
- Ab neutralize and opsonize pathogens
- Different isotypes have different functions
9
, Lecture Core concepts and processes in neurobiology
There is a central nervous system (CNS) and a peripheral
nervous system (PNS).
Nervous system
- Central system
o Brain
o Spinal cord
- Somatic system
o Cranial nerves
o Spinal nerves
- Autonomic system
o Sympathetic division
o Parasympathetic division
Somatic nervous system (SNS) (part of the PNS)
- All spinal and cranial nerves to and from
o Sensory organs
o Skeletal muscles
o Joints
o Skin
- SNS produces movement
- SNS transmits incoming sensory information (vision, hearing, pain, temperature,
touch, position + movement of body parts) to CNS
Autonomic nervous system (ANS)
- ANS innervates body’s internal organs (heart, blood vessels, lungs, airways,
intestines..)
- It balances the internal organs and is ‘out of control’
- Rest and digest through parasympathetic nerves
- Fight or flight through sympathetic nerves
Origin and development of CNS
- CNS originates from a tube
- Basic plan brain fish/amphibian/reptile = three-part structure
o Encephalon= Greek word for ‘brain’
- Forebrain = prosencephalon
- Midbrain = mesencephalon
- Hindbrain = rhombencephalon (diamond-shaped)
The forebrain will grow the most, and will be the most different
from that of fish. Telencephalon means end (telomere). The
hindbrain will also develop the most.
10
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