IMMUNOLOGY
Lecture 1&2. Immune system & innate immunity (where you are born with)
History: the people that survived the plague were less likely to contract it again, in Asia they discovered the
inoculation in 1500 (due to smallpox), in the Western world it came up in 1700 (in 1718 a lady vaccinated her
son and it worked), relatively young field of science
1996-1998: identification of Toll-like receptors
2000: characterisation of M1 and M2 macrophage subsets
2010: Nobel prize for the immune checkpoint inhibitor, which activate the immune system to clean up
cancer cells
Main functions immune system
Protection against infectious microbes ‘non-self’, the immune system needs to be educated
o Intracellular: viruses, some bacteria and parasites
o Extracellular: most bacteria and parasites, fungi
Protection against modified ‘self’, difficult to recognise and to treat
o Cancer/tumour cells or transformed cells
Organisation of the immune system: every surface that is in contact with the outside world needs to be drained
by lymph nodes (very high amount of immune cells), skin has carcinocytes to protect the whole body, GI tract
is in contact by food components with microbes on it but we have to extract food from the outside
Primary lymphoid organs: sites where the immune cells are born and develop, e.g. bone marrow (with
stem cells) and thymus
Secondary lymphoid organs: drain specific areas of the body, cells of the immune system are ready to
mount an immune response (immune cells come from bone marrow and thymus and are stored here),
e.g. tonsils and adenoids, lymph nodes and lymphatic vessels, appendix, spleen, Peyer’s patches
o Lymph nodes: collect antigen from the epithelium and connective tissue
o Spleen: cleaning up red blood cells and generating new ones
o Peyer’s patches: in the intestines, makes sure that every part is screened
Throat infection
Symptoms: most are caused by the immune response against the invader and not directly by the
invaders themselves, e.g. fever (reaction on cytokines), swelling (site of infection is filling up with
immune cells and fluid), pain (swelling tissue is putting pressure on pain sensing neurons), headache,
ulcerations (damage caused by bacteria and innate immune toxic soup)
o Immune cells are responding to the cytokines of the invader and the invader is not well suited
to high temperatures but the immune system is capable of working still
o Fish are cold blooded so they cannot rise their temperature but they swim towards warmer
water
In the throat there are a lot of lymph nodes (Waldever’s ring) which consist of adenoids, tubal tonsil,
palatine tonsil and lingual tonsil and help the screening
Mucosal surface is a combat zone, prevents cytokines from coming in or they ensure that they are
getting out and killed
Skin: epithelium layer is one cell thick, but Goblet cells make mucus (protects damaged cells) and other cells
make antimicrobial peptides (AMPs, peptides released by epithelial cells and innate cells that act as
antibiotics)
Once a virus or bacterium enters our nose or throat it will first encounter the epithelial surface,
epithelial cells can recognize pathogens by so-called Toll-like receptors
Toll-receptors: pathogen associated molecular pattern (PAMP), small surface peptides of the microbes
that can be seen by the Toll-like receptors to give a signal (‘bad issue over here’)
o They are in different places (in and outside the cell) and there are a lot of different
(combinations of) receptors (in fish more than 20)
, o Recognition of a PAMP (TLR): intracellular cascade of activation, translocation to the
nucleus, activation of NF-;B (transcription factor that turns on immune genes), transcription
of alarm molecules, alert the immune cells underneath the epithelial cells
LPS: lipopolysaccharide, on the outside of gram-negative bacteria, recognised by
TLR4, TLR9 = DNA, TLR2 = lipoproteins
Endosomal TLR: recognises viruses, RNA and DNA viruses
o Damage to the epithelial layer: acute phase molecules are activated which are circulating in
the body as pro-molecules (inactivated molecules stored in the liver) and become activated
Cell types of the immune system
Innate immunity cells: ready when you are born, not needed to be educated, fast and no memory for
the specific pathogen, activated within hours after infection
o E.g. phagocytes (eat bacteria), dendritic cells, NK cells, epithelial cells, complement
o Phagocytes: also called granulocytes (see below)
Recruitment of cells to the site of infection (extravasation)
Recognition of and activation by microbes (pattern recognition
receptors (PRRs), scavenger receptors, PAMPs, e.g. TLRs,
NODs)
PRRs: Toll-receptor, on the immune cell (left, blue one)
PAMPs: on the outside, on the bad guys (right, green
one)
Ingestion of the microbe (phagocytosis): form phagolysosome
out of the lysosome and the phagosome
Destruction and communication to the adaptive immune system (antigen presentation
on MHC, secretion of cytokines, etc)
o Granulocytes: can be recognised by the shape of the nucleus (multi-lobbed/polymorph) and
the granules in the cell, are build to destroy (destruction by releasing toxic compounds or by
phagocytosing), short-lived, fast
Neutrophils: most abundant cells, have a segmented nucleus (polymorpho-nuclear
cells), produced in the bone marrow and more than 1011 per day are made, migrate
very quickly to sites of infection, terminally differentiated, can explode (necrosis) in
which their DNA is spilled to the outside (very sticky with receptors)
Neutro = have a neutral colour with staining
Streptococcal infection
Basophils: plays a role in the clearance of parasites, short-living, produced in bone
marrow, directs T cell differentiation, defensive role against allergens (e.g. pollen
with histamine), release histamine and leukotrienes and prostaglandins, express
receptors for IgE (allergy), terminally differentiated
Baso = basophilic with staining
More involved in allergic reactions or parasite defence
Eosinophils: detect and kill parasites, short-living, produced in bone marrow,
secretory vesicles which contain destructive proteins, express receptors for IgG and
IgE (inflammation and allergy), terminally differentiated
Eosino = stay bright pink with staining (eosin)
More involved in allergic reactions or parasite defence
o Monocytes: in the blood, become macrophages in tissues (out of the blood stream)
Macrophages: professional antigen presenting cell (APCs) which is needed to educate
the adaptive immune system by presenting parts of the bacteria on the outside to
instruct the other cells how to react and to develop
Produces ROS, cytokines (TNF, IL-1, IL-12), make growth factors to induce
healing of the system
o Dendritic cells: ACPs, develop from a myeloid precursor (same cells as macrophages, so like
monocytes), have very long dendrites to stick to parts or in between cells
, Adaptive immunity cells: slower but specific, works with the vaccination, not all organisms have this
system (e.g. plants, fish)
o E.g. B-lymphocytes, T-lymphocytes, effector T cells, antibodies
Lecture 3&4. Adaptive immune processes
Infection: one a virus or bacterium enters the nose or throat it will first encounter the epithelial surface, these
can recognise pathogens by Toll-like receptors
When it damages or infects the epithelial cells, these will respond by secreting factors that will recruit
immune cells by rolling, integrin activation by chemokines, stable adhesion, migration through
endothelium
First hours: innate immune processes at work
After 12-24 hours: the adaptive immune phase kicks in via antigen presentation (APCs, e.g. macrophages,
dendritic cells)
Pathogen recognition: innate response is the same after repeated exposure to the same pathogen,
adaptive response matures over time (repeated exposure leads to faster response)
Pathogen removal: early response via innate immunity, later response via lymphocyte generate
adaptive immune system and specific memory
Endogenous (from inside) pathogens or self: cytotoxic T cells have antigen recognition and immune synapse
formation, granule exocytosis, detachment of CTL → target cell death
1. Dendritic cells take up antigen
2. Dendritic cells travel to the draining lymph nodes
3. Dendritic cells present the antigen via MHC-I which present to naïve CD8 + T cells (specific for the
antigen, will expand and differentiate) which is called cross-presentation (also via MHC I as well via
MHC II)
4. The T cells migrate to the place the antigen was encountered (homing molecules)
5. The specific CD8+ T cells will kill and destroy all virus infected cells that will have peptides on their
MHC-I
MHC-I antigen presentation: all nucleated cells have MHC-I, proteins produced in the cell will be degraded,
peptides on the outside of the cell give a danger signal (general system), the immune system scans and kills
CD8+ T cells react on MHC-I by killing the virus-infected cell
Source of protein antigens: cytosolic proteins (small peptides synthesized in the cell or enter via
phagosomes)
Enzyme that generates the peptides: cytosolic proteasome
Site of peptide loading of MHC: endoplasmic reticulum
Exogenous (from outside) pathogens
1. Dendritic cells take up antigen
2. Dendritic cells travel to the draining lymph nodes
3. Dendritic cells present the antigen via MHC-II which present to naïve CD4 + T cells (specific for the
antigen, will expand and differentiate and activate B cells)
a. B cells: will become plasma cells (with mitochondrion, Golgi, ER and nucleus) that produce
antibodies
4. The T cells migrate to the place the antigen was encountered (homing molecules), they are instructed
in the lymph node to which place they have to go
5. CD4+ activated T cells will secrete cytokines combatting the bacterium
MHC-II antigen presentation: phagocytose by immune cells (APCs), phagocytosed material ends up in MHC-
II, present peptides on the Th cells → Th1, Th2, Th17, Treg
CD4+ reacts on MHC-II by activation of macrophages via Th cells that bind to the APC
Present on dendritic cells, macrophages, B cells
Source of protein antigens: endosomal/lysosomal proteins (internalised from outside the cell)
Enzyme that generates the peptides: endosomal and lysosomal proteases
Site of peptide loading of MHC: specialised vesicular compartment
T-cell clones: have all identical T cell receptors (TCRs) to identify which peptide is presented to the
Th cell via the APC
