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).
1
,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.
2
,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)
-
3
, 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.
4
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).
1
,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.
2
,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)
-
3
, 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.
4
