Immunopharmacology
Barbro Melgert
Introduction & chapter 1
13/04/2021
Biologics: derived from the immune system. Becomes more popular over simple molecule drugs.
Adalimumab: TNF-α blocker > binds > immunosuppressant > inflammation inhibited
B cells produce antibodies, but shows up last to an infection.
Mast cells produces histamine.
Variolation: first small pox vaccination. Minor and major variant > vaccinate with minor (lighter)
variant > protect against to the major (deadly) > picked up by Lady Montague > tested on prisoners
and abandoned children.
- Rudolf Virchow: was first to see pathological change to cells, was against the germ theory of
diseases, first to use forensic analysis of hairs and systematic autopsy. Anti-racism (all cells
the same), anti-Darwin.
- Robert Koch: isolated and cultured many germs, improved laboratory methods, discovered
mycobacterium.
- Louis Pasteur: microbial fermentation, pasteurisation, principle of vaccination, disproves
spontaneous generation.
- Emil von Behring: discovered diphtheria toxin and serum therapy
- Paul Ehrlich: first suggested existence of antibodies
- Elie Metchnikoff: discovered phagocytes, suggested the importance of the microbiome.
Theory that phagocytes protect the body, cellular immunity, later evolved into innate
immunity (starfish) > founder of probiotics and the study of aging.
1900-1942: humoralists, but antibodies could not explain everything
1997: discovery of lymphocytes, clonal selection, MHC, costimulation
1197: discovery of Toll-like receptors and their role in immunity
Immune system: homeostasis (balance)
1. Defence against invaders: bacteria, viruses, fungi, objects, parasites
2. Removal of: dead cells, tumors, damaged molecules (e.g. smoking), artificial objects
Immune alarm system > epithelial barrier > tissue-resident immune cells > help from the bone
marrow > cleaning up tissue damage > specialised help from lymphocytes > T-helper cells (direct the
cytotoxic T cells), cytotoxic T cells, B cells, antibodies.
Two types of immune system:
- Innate immunity: humoral (complement), cellular
(granulocytes, macrophages, natural killer cells)
- Adaptive immunity: humoral (antibodies produced by B-
cells), cellular (T cells)
,All leukocytes (white blood cells) develop from stem cells in bone
marrow or yolk sac/fatal liver. The stem cell develops into a
progenitor cell that can differentiate into many types of cells.
Myeloid: innate immune system
Lymphoid: adaptive immune system
Effective immunity: delicate balance
- Barriers for prevention
- Recognition: detection and identification of foreign
substances
- Communication and organization: coordination to mount
the most optimal immune response
- Effector mechanisms: to destruct or suppress the invading
pathogen
Organisation of the immune system allows to prevent, response
fast, intracellular and extracellular, adapt, specify and prevent
recurrence. The immune system can be seen as a diffuse body-
spanning organ. It contains solid tissues, fluid tissues (cells), and fluid molecules (plasma).
Solid lymphoid tissues:
Primary: development and maturation
- Bone marrow
- Thymus
- Generative lymphoid organs
Secondary: meeting place for immune cells and antigen
- Spleen and lymph nodes
- Site where immune responses are initiated
Primary lymphoid tissues: in the bone marrow, all immune cells are generated. Maturation of T cells
happens in the thymus, where also the selection of non-self-reactive T cells is.
Progenitors from the bone marrow migrate to thymus to develop into naïve T/B cells. Naïve T cells
develop into effector T cells after recognition of an antigen. Naïve B cells that recognise antigen,
develop into antibody-producing plasma cells.
Connection of innate to adaptive systems: antigen-presenting cells (APC) like dendritic cells and
macrophages. These are phagocytosing cells, strategically located to sample antigen. They are
broken down into little pieces and present these to the T cells. The dendritic cell travels from the
tissues to the lymph nodes, where B and T cells are/stay.
Secondary lymphoid tissues: lymph nodes
Part of the lymphatic circulation > drains tissues, collects microbial antigens and
delivers these to the lymph nodes. Immune cells in the lymph node sense and
intercept pathogens preventing their spread throughout the body by initiating and
immune response. (cortex)
,The spleen in highly vascularized, and monitors/filters the blood for ‘rubbish’
including pathogens but also e.g., aged red blood cells.
- Red pulp: macrophages to remove damaged cells (RBC) and
invaders/reservoir of monocytes
- White pulp: B and T cells, for adaptive response against blood-born antigens
Lymphoid structures in tissue: connected to outside world have their own lymphoid
structures for a faster response
- BALT: bronchus-associated
- GALT: gut-associated
- MALT: mucosa-associated
Clonal expansion
Autoimmunity is caused by a failure of clonal deletion.
Epitopes are found on antigens.
During an adaptive immune response, mainly T-cells are present.
Antibodies react to pathogens they have been in contact before.
During a viral infection, cytotoxic T-cells are most important.
Defensin disrupts the cell membrane.
Plasma cells are formed during the effector part.
Humoral immunity deals with B-cells and antibodies.
Immunopharmacology
Barbro Melgert
Chapter 2
14/04/2021
Alarm system: innate immunity > macrophages, dendritic cells,
mast cells, granulocytes, T cells, natural killer T cells.
Receptors of innate immunity encoded in germline > limited
diversity (pattern recognistion receptors).
Receptors of adaptive immunity encoded by genes produced by
somatic recombination of gene segments > great diversity.
Innative distribution: nonclonal > identical receptors on all cells of
the same lineage.
Adaptive distribution: clonal > clones have different receptor. But
when activated > divide > have the same receptor.
, Innate can divide between self and nonself > not very good.
Adaptive can discriminate between self and nonself > when self recognized > deleted.
Innate alarm system
MO are recognized by the innative system by pathogen associated molecular patterns = PAMPS.
Tissue damage is recognized by the innative system by damage-associated molecular patterns =
DAMPS.
Pattern recognition alarm receptors:
- Toll-like receptors (TLR) > outside for bacterial things, inside the cell for uptaken products
- C-type lectin receptors > only on the outside, sense microbial polysaccharides
- NOD-like receptors (nucleotide oligomerization domain) > only in the cytosol, senses
peptidoglycans / products of damaged cells
- RIG-like receptors (retinoic acid-inducible gene) > only in the cytosol, senses viral RNA
Toll-like receptors:
In the outside sense for bacterial products, inside the
endosome senses for viral products.
When product is recognized > activation > activation of
transcription factors > recruits adapter proteins > outside
activated NF-kB pathway, inside activated IRFs pathway.
Other important components of cellular alarm systems
are cytokines and chemokines > messengers / growth
factors.
IL-10 and TGF-β suppress inflammation. People with
increased gene activity of these compound frequently
die of inflammatory diseases.
Rheumatoid arthritis: cells sense danger > TNF-α and IL-
1β cause oedema/weak joints/ fever/etc.
Cytokine storm: during inflammation many cytokines leak into the general system and leads to
clotting/shock/lung injury/cell death/immune paralysis/intestinal injury and that can lead to death.
Signal transduction of NOD-like receptors:
NLRP-3 sensor (crystals/K+) > assembles into complex with adapter proteins and inactive caspase-1 =
inflammasome > caspase-1 activated > complex can cleave IL-1β of pro-IL1β > secretion of IL-1β.
Barbro Melgert
Introduction & chapter 1
13/04/2021
Biologics: derived from the immune system. Becomes more popular over simple molecule drugs.
Adalimumab: TNF-α blocker > binds > immunosuppressant > inflammation inhibited
B cells produce antibodies, but shows up last to an infection.
Mast cells produces histamine.
Variolation: first small pox vaccination. Minor and major variant > vaccinate with minor (lighter)
variant > protect against to the major (deadly) > picked up by Lady Montague > tested on prisoners
and abandoned children.
- Rudolf Virchow: was first to see pathological change to cells, was against the germ theory of
diseases, first to use forensic analysis of hairs and systematic autopsy. Anti-racism (all cells
the same), anti-Darwin.
- Robert Koch: isolated and cultured many germs, improved laboratory methods, discovered
mycobacterium.
- Louis Pasteur: microbial fermentation, pasteurisation, principle of vaccination, disproves
spontaneous generation.
- Emil von Behring: discovered diphtheria toxin and serum therapy
- Paul Ehrlich: first suggested existence of antibodies
- Elie Metchnikoff: discovered phagocytes, suggested the importance of the microbiome.
Theory that phagocytes protect the body, cellular immunity, later evolved into innate
immunity (starfish) > founder of probiotics and the study of aging.
1900-1942: humoralists, but antibodies could not explain everything
1997: discovery of lymphocytes, clonal selection, MHC, costimulation
1197: discovery of Toll-like receptors and their role in immunity
Immune system: homeostasis (balance)
1. Defence against invaders: bacteria, viruses, fungi, objects, parasites
2. Removal of: dead cells, tumors, damaged molecules (e.g. smoking), artificial objects
Immune alarm system > epithelial barrier > tissue-resident immune cells > help from the bone
marrow > cleaning up tissue damage > specialised help from lymphocytes > T-helper cells (direct the
cytotoxic T cells), cytotoxic T cells, B cells, antibodies.
Two types of immune system:
- Innate immunity: humoral (complement), cellular
(granulocytes, macrophages, natural killer cells)
- Adaptive immunity: humoral (antibodies produced by B-
cells), cellular (T cells)
,All leukocytes (white blood cells) develop from stem cells in bone
marrow or yolk sac/fatal liver. The stem cell develops into a
progenitor cell that can differentiate into many types of cells.
Myeloid: innate immune system
Lymphoid: adaptive immune system
Effective immunity: delicate balance
- Barriers for prevention
- Recognition: detection and identification of foreign
substances
- Communication and organization: coordination to mount
the most optimal immune response
- Effector mechanisms: to destruct or suppress the invading
pathogen
Organisation of the immune system allows to prevent, response
fast, intracellular and extracellular, adapt, specify and prevent
recurrence. The immune system can be seen as a diffuse body-
spanning organ. It contains solid tissues, fluid tissues (cells), and fluid molecules (plasma).
Solid lymphoid tissues:
Primary: development and maturation
- Bone marrow
- Thymus
- Generative lymphoid organs
Secondary: meeting place for immune cells and antigen
- Spleen and lymph nodes
- Site where immune responses are initiated
Primary lymphoid tissues: in the bone marrow, all immune cells are generated. Maturation of T cells
happens in the thymus, where also the selection of non-self-reactive T cells is.
Progenitors from the bone marrow migrate to thymus to develop into naïve T/B cells. Naïve T cells
develop into effector T cells after recognition of an antigen. Naïve B cells that recognise antigen,
develop into antibody-producing plasma cells.
Connection of innate to adaptive systems: antigen-presenting cells (APC) like dendritic cells and
macrophages. These are phagocytosing cells, strategically located to sample antigen. They are
broken down into little pieces and present these to the T cells. The dendritic cell travels from the
tissues to the lymph nodes, where B and T cells are/stay.
Secondary lymphoid tissues: lymph nodes
Part of the lymphatic circulation > drains tissues, collects microbial antigens and
delivers these to the lymph nodes. Immune cells in the lymph node sense and
intercept pathogens preventing their spread throughout the body by initiating and
immune response. (cortex)
,The spleen in highly vascularized, and monitors/filters the blood for ‘rubbish’
including pathogens but also e.g., aged red blood cells.
- Red pulp: macrophages to remove damaged cells (RBC) and
invaders/reservoir of monocytes
- White pulp: B and T cells, for adaptive response against blood-born antigens
Lymphoid structures in tissue: connected to outside world have their own lymphoid
structures for a faster response
- BALT: bronchus-associated
- GALT: gut-associated
- MALT: mucosa-associated
Clonal expansion
Autoimmunity is caused by a failure of clonal deletion.
Epitopes are found on antigens.
During an adaptive immune response, mainly T-cells are present.
Antibodies react to pathogens they have been in contact before.
During a viral infection, cytotoxic T-cells are most important.
Defensin disrupts the cell membrane.
Plasma cells are formed during the effector part.
Humoral immunity deals with B-cells and antibodies.
Immunopharmacology
Barbro Melgert
Chapter 2
14/04/2021
Alarm system: innate immunity > macrophages, dendritic cells,
mast cells, granulocytes, T cells, natural killer T cells.
Receptors of innate immunity encoded in germline > limited
diversity (pattern recognistion receptors).
Receptors of adaptive immunity encoded by genes produced by
somatic recombination of gene segments > great diversity.
Innative distribution: nonclonal > identical receptors on all cells of
the same lineage.
Adaptive distribution: clonal > clones have different receptor. But
when activated > divide > have the same receptor.
, Innate can divide between self and nonself > not very good.
Adaptive can discriminate between self and nonself > when self recognized > deleted.
Innate alarm system
MO are recognized by the innative system by pathogen associated molecular patterns = PAMPS.
Tissue damage is recognized by the innative system by damage-associated molecular patterns =
DAMPS.
Pattern recognition alarm receptors:
- Toll-like receptors (TLR) > outside for bacterial things, inside the cell for uptaken products
- C-type lectin receptors > only on the outside, sense microbial polysaccharides
- NOD-like receptors (nucleotide oligomerization domain) > only in the cytosol, senses
peptidoglycans / products of damaged cells
- RIG-like receptors (retinoic acid-inducible gene) > only in the cytosol, senses viral RNA
Toll-like receptors:
In the outside sense for bacterial products, inside the
endosome senses for viral products.
When product is recognized > activation > activation of
transcription factors > recruits adapter proteins > outside
activated NF-kB pathway, inside activated IRFs pathway.
Other important components of cellular alarm systems
are cytokines and chemokines > messengers / growth
factors.
IL-10 and TGF-β suppress inflammation. People with
increased gene activity of these compound frequently
die of inflammatory diseases.
Rheumatoid arthritis: cells sense danger > TNF-α and IL-
1β cause oedema/weak joints/ fever/etc.
Cytokine storm: during inflammation many cytokines leak into the general system and leads to
clotting/shock/lung injury/cell death/immune paralysis/intestinal injury and that can lead to death.
Signal transduction of NOD-like receptors:
NLRP-3 sensor (crystals/K+) > assembles into complex with adapter proteins and inactive caspase-1 =
inflammasome > caspase-1 activated > complex can cleave IL-1β of pro-IL1β > secretion of IL-1β.
