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Summary of all lectures Immunopharmacology
Summary of all lectures notes of Immunopharmacology
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ImmunopharmacologyChapter 1 – Introduction
Virtual lab → questions come back in the exam
Case study - rheumatoid arthritis
Rheumatoid arthritis is an auto-immune disease of the joint. In people with RA the immune system
recognizes something in the joint as foreign and starts an immune response. This is usually the
cartilage which is being attacked by the immune system and is therefore degraded. When the
cartilage is gone the two bones won’t be cushioned anymore and will grind together. The
inflammation will start degrading the bones.
Symptoms:
• Pain in joints
• Stiffness
• Muscle weakness
• Weight loss
• Fatigue
• Fever
The disease starts unnoticeably. First pain in joints, stiffness, muscle weakness, weight loss, fatigue,
and fever. If you start treating right away very aggressively, then you might prevent the bone loss.
The goal of the treatment is therefore to hit hard and hit fast. Especially because the disease is most
progressive in the beginning.
There are several drugs which can be used.
• Painkillers (paracetamol)
• NSAIDs → non-steroidal antiinflammatory drugs
• Corticosteroids
• Disease modifying anti rheumatic drugs (DMARDs): methotrexate, biologicals
Mrs K: 62 years old with history of hypertension and low renal function.
She uses hydrochlorothiazide for hypertension. This is a diuretic.
New symptoms are painful and swollen fingers and stiffness in the morning.
To stop the pain Mrs K should use paracetamol, because NSAIDs have a side-effect which
causes kidney problems. This woman already had renal problems, so this is probably not the
best choice.
→ The physician prescribes paracetamol, but paracetamol is not sufficient for her pain (and not anti-
inflammatory). The rheumatologist suggests low dose methotrexate and checking renal function
while increasing the dose. This also helps not enough, so Adalimumab (Humira®) is added.
• Adalimumab is a monoclonal antibody and a TNFα-blocker (pro-inflammatory cytokine,
stimulating inflammation). The inflammation is now inhibited. This works fine.
→ A little later Mrs K comes to the pharmacist for advice. She is going on a holiday to Thailand for 2
weeks, is there anything she needs to prepare for/think of/take with her?
• She needs to take vaccinations, because she is in a tropical country with a lot of unknown
diseases. The biologicals screw up your immune reaction against infections. So, you are more
sensitive to infections. TNFα is important for the reaction against tuberculosis and this is an
epidemic in Thailand.
,→ She does not feel well and feverish. Can she just take paracetamol to lower the fever?
• Yes, because she was already taking it. It might be an innocent flu virus, but it might also be
something dramatic, because her immune system is depressed. In this case it is necessary to
go back to the rheumatologist to get some extra tests.
Immune system
The immune systems consists of 2 parts:
• Innate immunity: the immunity you are born with. This protects you from before you were
born.
• Adaptive immunity: the immunity you have to develop.
In the 19th century there where not a lot of drugs and people died very easily. 15% of the children
died before the age of 5 mainly due to infection diseases. The number of people dying decreased
enormous when vaccinations were introduced. Good hygeine also plays a role.
The first type of vaccination started already in the beginning of the 18th century in Western Europe,
this was called variolation. This was a vaccination against small pocks. In China it had been practiced
for a lot of years.
They had discovered that there are 2 kinds of small pocks:
• Minor (nor very lethal) → mortality 1 – 2%
• Major (is lethal) → mortality 30%
If you were infected with the minor variant you were protected for life. The Chinees took scaps of
the skin of those with minor small pocks and blow them into the noses of people who hadn’t been
infected yet. Those people would develop a minor infection and would be protected for life. This was
picked up by Lady Montague and brought it to Europe. This was first tested on abandoned children
and prisoners.
There were some theories about how this worked:
• Excess moisture driven from the blood through the pox.
• Contaminants of menstrual blood. Menstrual blood feeds the pox.
• Pocks distened pores of the skin.
• Everybody is born with all seeds of disease and you can only get them once.
19th century science
Robert Hooke (England): discovered cells
Rudolph Virchow (Germany): father of modern pathology, he discovered that cells could be
different. He looked through microscopes and saw that cells were different in healthy and diseased
people (pahtological changes to cells). This was against the germ theory of diseases. He was the first
to use forensic analysis of hairs and systematic autopsy. He thought that everybody was the same
(anti-racism). He was also anti-Darwin, because he didn’t believe that cells could change in time just
through diseases.
Germ theory of disease:
Robert Koch (Germany): isolated and cultured many germs, improved laboratory methods,
discovered mycobacterium. Several people were working in his lab:
• Emil von Behring (Germany): discovered diphtheria toxin and serum therapy.
• Paul Ehrlich (Germany): first suggested existence of antibodies. He postulated a theory
about antibodies (side chains). This was the start of humoral immunity, which later envolved
into adaptive immunity.
Louis Pasteur (France): microbial fermentation, Pasteurisation, principle of vaccination, disproves
spontaneous generation (infection doesn’t just develop, but develops from a germ).
, • Elie Metchnikoff (France): discovered phagocytes, suggested the importance of microbiome.
He studies starfish, which can have very big cells. He had a theory that phagocytes protects
the body. This was first cellular immunity, later envolved into innate immunity. He was also
looking for a cure against ageing.
The Nobel Prize committee (1908) tried to recognile the two sides. They gave a shared Nobel Prize
for Ehrlich and Metchnikoff for their contributions to immunity.
1900-1942: humoralists
The side chains lead to far more results (more attention), because they could lead to vaccinations.
But antibodies could not explain everything.
• Until 1977 a lot of effort went to explaining why sometimes antibodies work and sometimes
they don’t. Lymphocytes, clonal selection, MHC, costimulation, etc. were discovered.
• In 1997 there was the discovery of toll-like receptors and their role in immunity by
Medzhitov/Janeway/Hoffmann and a renewed interest in innate immunity.
Therefore, there is far less information about innate immunity than about adaptive immunity.
The immune system
The immune system tries to restore a balance (homeostasis). When the balance is disturbed it
needs to be restored as soon as possible. The balance can be disturbed by:
• Defence against invaders: bacteria, virusses, fungi, parasites and objects.
• Removal of: dead cells, tumors and tumor cells, artificial objects and damaged molecules
(smoking, ageing).
The immune systems is the protection of yourself. A cell need food, so things need to get in. But this
means that also pathogens can get in. Therefore, a cell has cellular alarm systems. There are
epithelial barriers, but those are not enough. There are also tissue-resident immune cells. If those
cannot handle the bacteria, they call in the help from the bone marrow. There are also cells from the
bone marrow and tissues that clean up tissue damage. If those cannot handle it, the adaptive
immune systems is called in. This gives specialised help from lymphocytes.
There are two types of T-cells:
• T-helper cells: they investigate and tell other cells what to do. They also help other cells.
• Cytotoxic T cells: they kill cells themselves.
B cells also help in protecting, but they do it in a different way. They make antibodies and spread
them around. The B cell itself does not much, the antibodies do the work.
There is first a barrier (skin mucosa) to protect the tissue and
immune systems. If the barrier is broken there is first the innate
immune system, which reacts very fast. It is non-specific and
natural. It has two components:
• Humoral: consists of complement.
• Cellular: consists of granulocytes, macrophages, natural
killer cells.
The adaptive immune system is specific and acquired. This also
consist of two components:
• Humoral: consists of antibodies produced by B cells.
• Cellular: T cells.
Humoral = in solution (not a cell).
, → What characterizes the innate immune system?
• It has to be able to react fast
→ What characterizes the adaptive immune system?
• It is specific
Characteristics immune systems
Innate
• Fast (sec-hours)
• Not specific
• Limited recognition
• Limited memory
• Limited recognition of self
• Not flexible
• Present at birth
Adaptive
• Slow (days-weeks)
• Specific
• Recognizes millions of antigens
• Memory
• Distinguishes self/nonself
• Fast expansion/contraction
• Develops after birth
All leukocytes (= white blood cells) develop from stem cells in bone marrow.
But only macrophages can also develop from fetal cells or yolk sac/fetal liver!!!
The stem cell develops into a progenitor cell that can differentiate into many types of cells.
A stem cell from bone marrow can become a myeloid progenitor
(innate immune system) or a lymphoid progenitor (adaptive immune
system).
• A lymphoid progenitor can become a B or T cell or a natural
killer cell.
• The myeloid progenitor can become a lot of different cells: red
blood cells (erythrocytes), platelets, basophils, eosinophils,
neutrophils, monocytes and macrophages.
But macrophages can also develop from yolk sac cells
and fetal liver cells.
→ What cell type belongs to the adaptive immune systems?
• B cells. Natural killer T cells are innate immune cells.
All myeloid cells are innate immune cells, but not all lympoid cells are adaptive
immune cells. Because natural killer T cell and γδ-T cells are part of the innate
immune system.
So, in the innate immunity:
• Dendritic cells
• Macrophages
• Granulocytes: neutrophils, eosinophils, basophils
• Mest cells
• Natural killer (NK) cells
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