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Summary - Immunopharmacology (WBFA015-05)
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Summary of Immunopharmacology lectures with supporting images. Lecture notes are included here.
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IMMUNOPHARMACOLOGYLECTURE 1
Case: Rheumatoid arthritis is an autoimmune disease in the joints. The cartilage is attacked by the
immune system and will be degraded. Symptoms of rheumatoid arthritis are pain in joints, stiffness,
muscle weakness, weight loss, fatigue, and fever. Quickly and effectively treatment is necessary to
prevent damage to joints. RA is most progressive at the start of the disease and therefore hit hard and
hit fast. Drug which can be used:
- Painkillers (paracetamol)
- Non-Steroidal Anti Inflammatory Drugs (NSAIDs)
- Corticosteroids
- Disease Modifying Anti Rheumatic Drugs (DMARDs), like methotrexate, or biologicals
Immunity you are born with is called the innate immunity and the immunity you have to develop is the
adaptive immunity.
Variolation is the first type of vaccination. There are two main types of smallpox, major and minor. The
major one had a higher mortality than the minor one. Once you have had the minor variant, they were
immune for smallpox for their whole lives. This was picked up by Lady Montague and brought to
Europe.
→ Virchow was the first one to show pathological changes to cells. It was against the germ
theory of diseases and he was the first one to use forensic analysis of hairs and systematic
autopsy. His theory was anti-racism and anti-Darwin.
→ Robert Koch and Louis Pasteur supported the germ theory of disease. Koch isolated and
cultured many germs and improved laboratory methods. Pasteur discovered microbial
fermentation and pasteurisation. Moreover, he discovered the principles of vaccination.
→ Paul Ehrlich postulated a side chain theory, which tried to explain humeral immunity and this
was later evolved into adaptive immunity.
The immune system tries to restore a balance (homeostasis). When the balance is disturbed, it needs
to be restored asap. This balance can be disturbed by bacteria, viruses, fungi, parasites, and by
objects. Moreover, it takes care of removal of dead cells, tumour (cells), artificial objects, and
damaged molecules.
Epithelial barrier → tissue-resident immune cells → help from the bone marrow → cleaning up tissue
damage → specialised help from lymphocytes (adaptive immune system)
T-helper cells tell other cells what to do and cytotoxic T-cells are
able to kill cells themselves. B cells make antibodies but are not
used for other purposes.
Innate Adaptive
Fast (sec-hours) Slow (days-weeks)
Not specific Specific
Limited recognition Recognized millions of
antigens
Limited memory Memory
Limited recognition of self Distinguished self/nonself
Not flexible Fast expansion/contraction
Present at birth Develops after birth
,All leukocytes (white blood cells) develop from stem cells
in bone marrow or yolk sac/foetal liver. The stem cell
develops into a progenitor cell that can differentiate into
many types of cells.
For effective immunity you need:
- Barriers for prevention
- Recognition: detection and identification of the
foreign substance
- Communication and organization: coordination
to mount the most optimal immune response
- Effector mechanism: to destruct or suppress the invading pathogen
The immune system can be seen as a diffuse, body-spanning organ. Solid lymphoid tissues are
everywhere:
1. Primary lymphoid tissues: bone marrow, thymus, generative lymphoid organs
→ development and maturation (myeloid cells, lymphoid cells (B and T-cells))
2. Secondary lymphoid tissues: spleen, lymph nodes → site where immune responses are
initiated
→ meeting place for immune cells and antigens (selection for non-self-reactive T-cells)
Progenitors from bone marrow migrate to
thymus to develop into naïve T-cells.
Naïve T-cells develop into effector T-cells
after recognition of an antigen.
Progenitors from bone marrow stay in the
bone marrow to develop into naïve B-
cells. Naïve B-cells that recognise antigen,
develop into antibody-producing plasma
cells.
Antigen-presenting cells (APCs) connect the innate immune system with the adaptive immune system.
These APCs are most often dendritic cells or macrophages and are described as phagocytosing cells.
They are strategically located and present the antigen to T-cells. The dendritic cells is the messenger
as it travels from tissues to lymph nodes to look for help from more specialised cells, like B- and T-
cells.
APCs patrol tissues, especially the ones that connect to the outside world. Lymphocytes patrol the
body looking for antigens they recognise. They find each other in lymphoid structures and
communicate with each other there.
Lymph nodes are part of the lymphatic circulation. Lymphatic
circulation ‘drains’ tissues, collects microbial antigens and delivers
these to lymph nodes. Immune cells in the lymph node sense and
intercept pathogens preventing their spread throughout the body
by initiating an immune response.
The spleen is highly vascularized. Monitors and filters the blood for
‘rubbish’ including pathogens but also aged red blood cells. For
antigens in blood the spleen contain a red pulp for macrophages to
,remove damaged cells and invaders/reservoir of monocytes. The white pulp consists of B- and T-cells,
for adaptive response against blood-born antigens.
Tissues connected to outside world have their
own lymphoid structures:
- BALT: bronchus-associated lymphoid
tissue
- GALT: gut-associated lymphoid tissue
- MALT: mucosa-associated lymphoid
tissue
LECTURE 2
The way that cells of the innate and adaptive
immune system recognise danger is different.
Innate immune system has pattern recognition
receptors, these are specific for damaged cells and
microorganisms, but the variety is rather small. The
cells from the adaptive immune system has a
higher variety of recognition.
Microorganisms are very different from cells in the
body. The immune cells recognise pathogen-
associated molecular patterns (PAMPs), which are
present on viruses, bacteria, fungi, and protists.
Moreover, they recognise damage-associated molecular
patterns (DAMPs), which are patterns which normally do not
leak out of the cell and which are therefore recognised.
Cellular alarm systems are:
- Toll-like receptors (TLR)
There are 9 known Toll-like receptors, some of which
are on the outside of the cell and others are in present
in endosomes (for viruses and intracellular bacteria).
Once they recognise a patterns which is not known it
initiates a signal transduction.
- C-type lectin receptors
- NOD-like receptors (nucleotide oligomerization domain)
These receptors are present in the cytosol and the most important component is the NLRP-3
component, which is a sensor. When it senses bacterial products, crystals, K+ efflux, and ROS,
it form a complex, called inflamazon.
- RIG-like receptors (retinoic acid-inducible gene)
Cytokines are very important in the immune system. These are messengers of the immune system, as
they activate and tell cells about the state. Moreover, they can be growth factors. Important cytokines
, are tumour necrosis factor
(TNFα) and interleukin-1 (IL-1).
Most cytokines are pro-
inflammatory, whereas IL-10
and TGF-β are anti-
inflammatory cytokines.
If cytokines are released into
the systemic circulation this
can lead to a cytokine storm,
which will lead to clotting,
shock, lung injury, cell death,
immune paralysis, and
intestinal injury. This together
leads to inflammation, organ
failure and infection, resulting
in death.
Specific antiviral defences:
- Production of type I interferons (IFN-α and IFN-β) by
infected cells
- After activation of specific types of Toll/RIG-like
receptors
- IFN-α and IFN-β upregulate antiviral mechanisms in
healthy cells.
The first barriers are:
- Physical barrier to infection
There are three major interfaces between body and
external environment, namely skin, respiratory tract,
and GI tract. These interfaces are covered with
continuous epithelia to protect against entry of microbes. Moreover, they produce things to
make it harder for bacteria to survive, like saliva, tears, stomach acid, and “good” gut bacteria.
The epithelium is tightly packed which makes it more difficult for bacteria to enter.
- Killing of microbes by locally produced antibiotics
Defensin is a natural antibiotics, which is positively charged.
Defensin makes a pore in the bacterial cell membrane, which
will cause leakage and death of the bacteria.
- Killing of microbes and infected cells by intraepithelial
lymphocytes
The most important ones are: innate lymphoid cells (ILC),
natural killer (NK) cells, γδ T cells, NK-T cells, B-1 cells, and
marginal zone B cells.
▪ Innate lymphoid cells produce cytokines. They give
the immune response direction before helper T-cells
have developed. There are three groups of ILCs and
they do not express a T-cell receptor.
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