Samenvatting van alle colleges - Immunopharmacology (WBFA015-05)

Immunopharmacology

Lecture 1: Introduction + Chapter 1

Case study: Rheumatoid Arthritis
Autoimmune disease of the joints. Immune system attacks cartilage  degrade  inflammation.
- Symptoms: pain in joints, stiffness, muscle weakness, weight loss, fatigue, fever.
- Goal of treatment: hit hard hit fast.
- Drugs: painkillers, NSAIDs, corticosteroids, Disease Modifying Anti Rheumatic Drugs
(DMARDs)  methotrexate and biologicals.

Immune system
- Innate immunity  immunity you are born with.
- Adaptive immunity  immunity you need to develop.

History
- Robert Hooke  discovered cells.
- Rudolph Virchow  father of modern pathology. Against germ theory, describes pathological
changes to cells.
- Robert Koch  germ theory, isolated and cultured many germs, discovered mycobacterium,
improved lab methods.
- Louis Pasteur  germ theory, microbial fermentation, principle of vaccination.
- Emil von Behring  discovered serum therapy.
- Paul Erhlich  first to describe antibodies. (adaptive immunity)
- Elie Metchnikoff  discovered phagocytes./ Importance of microbiome. Theory that they
protect the body. (innate immunity).

Humoralists (1900-1942)  side chains of antibodies were interesting  adaptive immunity. But
they could not explain everything. In 1997 lymphocytes, clonal selection, MHC, co-stimulation, Toll-
like receptors were discovered. New interest in innate immunity instead of only adaptive.

The immune system tries to keep homeostasis in the body.
Defence against: bacteria, viruses, fungi, parasites and objects.
Removal of: dead cells, tumour cells, damages molecules, artificial objects.

Requirements for effective immunity
- Barriers for prevention
- Recognition
- Communication and organization
- Effector mechanisms

Layers of immune system
- Cellular alarm systems on individual cells.
- Epithelial barriers.
- Tissue-resident immune cells. If they are not enough 
- Help from bone marrow. Fights invader and cleans up and repairs tissue damage. If this is not
enough 
- Adaptive immune system.
 Lymphocytes: T-helper-cells (help other cells), Cytotoxic-T-cells (kill), B-cells (produce
antibodies).



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,Characteristics of innate vs adaptive system
Innate Adaptive
- Fast - Slow
- Not specific - Specific
- Limited recognition - Recognizes millions of antigens
- Limited memory - Memory
- Limited recognition of self - Distinguishes self/nonself
- Not flexible - Fast expansion/contraction
- Present at birth - Develops after birth

Where do immune cells com from?
- All leukocytes (white blood cells) develop from stem
cells in bone marrow OR yolk sac/fetal liver.
- Stem cell develops into a myeloid cell or lymphoid cell
 Myeloid  red blood cell, platelets, basophils,
neutrophils, eosinophils or monocytes.
 Lymphoid  B-cells, T-cells or NK cells.
- Macrophages starts from the yolk sac (first fetal cells).
Not from stem cells in bone marrow because a foetus
doesn’t have bone marrow yet.
- Roughly, lymphoid = adaptive, meyoloid = innate.

 NK cells, NK-T cells, yδ T cells and Innate
lymphoid cells belong to both.

Antigen presenting cells (APCs) connect innate and adaptive immunity. They are dendritic cells and
macrophages  phagocytosing, sample antigens if they sense danger and present the antigens to
T-cells.

Dendritic cells are messenger cells that travel from tissues to lymph nodes to look for help from T and
B cells.

Solid lymphoid tissue
- Primary lymphoid tissue  generative lymphoid organs.
 Bone marrow and thymus.
- Secondary lymphoid organs  sites for initiation of immune response.
 Spleen, lymph nodes, mucosa-associated lymphoid tissues.

Antigen: any molecule that is specifically recognised by lymphocytes or antibodies.

Primary lymphoid tissue
- Bone marrow  generation of all immune cells.
- Thymus  maturation and selection of T cells.

Development of T- cells and B-cells
- T-cells: progenitor goes from bone marrow to thymus  learn self and nonself  naïve T-
cell  circulating and recognition of antigen  becomes effector T-cell or memory T-cell.
- B-cells: progenitor stays in bone marrow  naïve B-cell  circulating and recognition of
antigen  antibody-producing plasma cell.




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,Secondary lymphoid tissue
- Lymph nodes  against antigens in tissues
 Part of the lymphatic circulation. It drains tissue cells, collects microbial antigens and
delivers these to the lymph nodes.
 Immune cells in lymph nodes sense and intercept pathogens, preventing their spread
through body.
 Cortex contains B-cells and paracortex contains T-cells.
 Lymph nodes at work increase in size.
- Spleen  against antigens in blood.
 Highly vascularized, filters blood.
 Red pulp: macrophages to remove damaged cells and invader, and reservoir of
monocytes. (red blood cells).
 White pulp: B and T cells, for adaptive response against blood-born antigens. (white
blood cells).
- Lymphoid structures in tissues
 Tissues connected to outside world have their own lymphoid system for faster
response against threats:
 BALT: bronchus-associated lymphoid tissue.
 GALT: gut-associated lymphoid tissue
 MALT: Mucosa-associated tissue (in gut and lung)

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, Lecture 2: Chapter 2, Innate immune system

Alarm Systems

Innate system  rapid
- Receptors that recognise damaged cells and microorganisms.
- Limited variabilities (only around 10)  encoded in DNA.
- Nonclonal: same receptors on the same cells.
- Discrimination of self and non self.
Adaptive system  slow
- Antigen receptors that recognize millions of antigens.
- Big variability.
- Clonal distribution: different receptors on different lymphocytes, expect after cloning.
- Discrimination of self and non self may be imperfect.

Characteristics of microorganisms (PAMPs)
Very different from own body cells so they can be recognized.
- Viruses  RNA and DNA.
- Bacterial cells  LPA, DNA, flagellin.
- Parasites  proteins produced by parasites (GPI).
- Fungi  DNA, beta-glycan.

Recognition of damaged tissue (DAMPs)
Things that are normally not present outside the cell are recognized by receptors.
- Endogenous  envelope proteins, group specific antigen (GAG) proteins.
- Dead cells  ATP, RNA, DNA, Uric acid
- Injured tissue  heparin sulphate, hyaluronan.

Pattern recognition receptors
- Toll like receptors (TLR)  extracellular and inside endosomes.
- C-type lectin receptors  extracellular.
- NOD-like receptor  cytosolic.
- RIG-like receptors  cytosolic.

Toll-like receptors
- Extracellular  sense bacterial or fungal products
- Inside endosomes  sense viruses or intracellular bacteria.
- Signal transduction (activation) of TLR: receptor recognized a product  recruits adaptor
proteins  activation of
 NF-KB pathway (outside cell)  more cytokines, adhesion molecules, costimulators
 acute inflammation, stimulation of adaptive immunity.
 IRF pathway (interferon regulatory pathway) inside cell) production of type 1
interferon  antiviral state against inhibitors.

Cytokines and chemokines
- Chemokines  attracts cells to place of inflammation.
- Cytokines  messengers and growth factors.
 TNFa and IL-1beta  mediators of acute inflammation. (used in RA)

 IL-10 and TGF-B  anti-inflammatory.



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