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Immunopharmacology Summary
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Immunopharmacology Summary
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IMMUNOPHARMACOLOGYLecture 1 –
Nowadays, a lot of our drugs are derived from the immune system.
Rheumatoid arthritis (RA) is a chronic
autoimmune disorder that affects the joints. RA
occurs when the immune system mistakenly
attacks the synovium (the lining of the
membranes that surround the joints), leading to
inflammation and damage to the joint tissue.
There is an increased presence of immune
cells within the synovium. The accumulation of
these immune cells in the synovium leads to
the production of inflammatory molecules, such as cytokines and chemokines,
which further amplify the immune response and cause damage to the joint tissue.
This chronic inflammation results in the characteristic symptoms of RA:
• Pain in the joints
• Stiffness
• Muscle weakness
• Weight loss
• Fatigue
• Fever
The pro-inflammatory cytokine TNF-α is expressed in high levels. TNF-α (tumor
necrosis factor) is an important cytokine involved in the body's immune response to
infections. TNF-α plays a crucial role in activating immune cells, such as
macrophages, to kill and eliminate invading pathogens. However, while TNF-α is
necessary for the body's defense against infections, excessive or dysregulated
production of TNF-α can lead to chronic inflammation and tissue damage, as seen in
autoimmune diseases like RA.
RA is the most progressive at the start of the disease. Quick and effective treatment
is needed to prevent damage to the joints. Therefore: Hit hard and hit fast!
Drugs used in RA:
• Painkillers (paracetamol)
• Non Steroidal Anti Inflammatory Drugs (NSAIDs)
• Corticosteroids
• Disease Modifying Anti Rheumatic Drugs (DMARDs): methotrexate,
biologicals
Paracetamol is a mild pain reliever that can help alleviate minor joint pain associated
with RA. However, it does not have significant anti-inflammatory properties and is not
effective for reducing inflammation in RA.
1
,NSAIDs are used to reduce pain and inflammation in RA. They work by blocking the
enzymes (COX-1 and COX-2) involved in the production of inflammatory
prostaglandins.
Corticosteroids are powerful anti-inflammatory medications that can quickly reduce
inflammation and alleviate pain in RA.
DMARDs work to slow down the progression of joint damage and reduce
inflammation. The most important DMARD is methotrexate. Methotrexate inhibits the
rapid proliferation of immune cells, thereby reducing the inflammation.
CASE: a women has RA symptoms, should she get paracetamol or NSAIDs?
The women has hypertension and a low renal function.
Paracetamol is not sufficient in reducing inflammation. But, NSAIDs have side effects
on your kidneys. So both paracetamol and NSAIDs are not given to the patient.
Instead, a low dose of methotrexate (DMARD) is given. Methotrexate can also have
an effect on the kidney, therefore, check the renal function when increasing the
methotrexate dose.
Adalimumab is also added to the treatment. Adalimumab is a TNF inhibitor. It is a
TNF-α antibody, which binds to TNF-α and blocking its activity.
Methotrexate + Adalimumab → amplify each other.
TNF-α is an important cytokine involved in the body's immune response to infections,
including intracellular bacteria such as Mycobacterium tuberculosis, the bacterium
that causes tuberculosis (TB). However, while TNF-α is necessary for the body's
defense against infections, excessive or dysregulated production of TNF-α can lead
to chronic inflammation and tissue damage, as seen in autoimmune diseases like
RA. Therefore, medications that block TNF-α, such as adalimumab, can effectively
reduce inflammation and alleviate symptoms in conditions like RA but may also
increase the risk of TB infection.
So people with RA using a treatment of adalimumab must take a vaccination against
TB when they go to foreign lands (e.g. Thailand) for holiday.
When the women does not feel well and feverish, can she just take paracetamol
to lower the fever?
Yes, she can take paracetamol to lower the fever. But a fever can be a symptom of
an (TB) infection, so she also needs to visit a rheumatologist. The rheumatologists
checks if she has an infection that she maybe cannot clear because she is on TNF-α
inhibitors.
There are 2 types of immunity:
• Innate immunity: immunity you are born with.
• Adaptive immunity: immunity you have to develop.
2
,Requirements for effective immunity:
• Barriers for prevention
• Recognition: detection and identification of the foreign substance
• Communication and organization: coordination for the most optimal immune
response.
• Effector mechanisms: to destruct or suppress the invading pathogen.
The body's first line of defense includes physical and chemical barriers that prevent
pathogens from entering the body. This includes the skin, which acts as a physical
barrier, as well as mucous membranes in the respiratory, gastrointestinal, and
genitourinary tracts, which produce mucus and other substances that trap and expel
pathogens.
Following antigen recognition, immune cells communicate and coordinate their
actions for an appropriate immune response. This involves the release of signaling
molecules, such as cytokines and chemokines, which help recruit and activate other
immune cells to the site of infection. Lymphoid organs serve as central hubs for
immune cell communication and organization.
Function immune system:
• Defense against invaders (bacteria, viruses, fungi, parasites, objects)
• Removal of dead cells, tumor cells, damaged molecules (smoking, ageing)
and artificial objects.
Epithelial barriers are a component of the innate immune system. Epithelial cells
form protective layers that line the surfaces of various tissues and organs. Within
these epithelial layers, there are tissue-resident immune cells. Tissue-resident
immune cells are a specialized subset of immune cells that reside in specific tissues
throughout the body. Unlike circulating immune cells, such as lymphocytes and
monocytes, which constantly travel through the bloodstream and lymphatic system,
tissue-resident immune cells remain localized within specific tissues for extended
periods.
Lymphocytes (T cells and B cells) are part of the adaptive immune system.
3
, T-helper cells (Th cells) express the CD4 surface protein and are also known as
CD4+ T cells.
They primarily function as "helpers" by coordinating and regulating immune
responses. Th cells recognize antigens presented by MHC-II molecules on antigen-
presenting cells (APCs).
Upon activation, Th cells differentiate into various subsets, including Th1, Th2, Th17,
and regulatory T (Treg) cells, each with specific functions:
• Th1 cells produce cytokines such IFN-γ and TNF-α, which activate
macrophages and enhance cellular immunity against intracellular pathogens.
• Th2 cells produce cytokines such as IL-4, IL-5, and IL-13, which stimulate
antibody production by B cells and promote immune responses against
extracellular parasites and allergens.
• Th17 cells produce IL-17 and IL-22, which contribute to the defense against
extracellular bacteria and fungi, as well as the pathogenesis of autoimmune
diseases.
• Treg cells regulate immune responses and maintain immune tolerance by
suppressing the activity of other immune cells, thereby preventing excessive
inflammation and autoimmune reactions.
T-cytotoxic cells (Tc cells) express the CD8 surface protein and are also known as
CD8+ T cells. They primarily function as "killers" by directly targeting and destroying
infected or abnormal cells. Tc cells recognize antigens presented by MHC-I
molecules on the surface of infected or abnormal cells. Upon activation, Tc cells
release cytotoxic molecules, which induce apoptosis (cell death) in target cells.
Activated B cells differentiate into plasma cells, which produce and secrete large
quantities of antibodies. Antibodies are Y-shaped proteins composed of two heavy
chains and two light chains, with variable regions that recognize and bind to specific
antigens. Each antibody molecule has antigen-binding sites at the tips of its Y-
shaped structure, allowing it to bind to antigens with high specificity.
Antibodies have several functions in the immune response:
• Neutralization: Antibodies can neutralize pathogens by binding to their surface
antigens, preventing them from infecting host cells.
• Opsonization: Antibodies can coat pathogens, marking them for phagocytosis
by immune cells such as macrophages and neutrophils.
• Complement activation: Antibodies can activate the complement system, a
group of proteins that enhance immune responses by promoting inflammation,
opsonization, and lysis of target cells.
• Antibody-dependent cellular cytotoxicity (ADCC): Antibodies can recruit
immune cells, such as natural killer (NK) cells, to kill antibody-coated target
cells.
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