Advanced molecular immunology and cell biology
Lecture 1: Introduction into Immunology Monday 06 sept 2021
Immunology is the study of the body’s defense against infection.
Two immune systems:
• Adaptive (acquired) immune system: composed of specialized, systemic cells and processes
that eliminate pathogens or prevent their growth.
• Innate immune system: the body's first line of defense against germs entering the body.
Hematopoiesis
All the cellular elements of blood ultimately derive from the hematopoietic stem cell of the bone
marrow. The hematopoietic stem cell give rise to common lymphoid precursor and common
myeloid precursor.
Lymphoid cells become:
• B cell (plasma cell)
• T cell (effector T cell)
• NK cell
Myeloid cells become:
• Granulocyte
o Macrophage and dendritic
o Neutrophil
o Eosinophil
o Basophil
o Mast cell
• Megakaryocyte
o Megakaryocyte → Platelets
o Erythroblast → Erythrocyte
Recognition mechanisms of innate immunity
• Fast (hours)
• Fixed
• Limited number of specificities
• Constant during response, doesn’t change
Common effector mechanisms for the
destruction of pathogenesis
Recognition mechanisms of adaptive immunity
• Slow (days to weeks)
• Variable
• Numerous highly selective specificities
• Improve during response, getting better
Innate cells can distinguish ‘self’ and ‘non-self’.
Macrophage receptors recognize the cell-surface
carbohydrates of bacterial cells but not those of human
cells. Natural killer cell receptors recognize changes at the
surface of human cells that are caused by viral infection.
1
,Phagocytosis:
Macrophage receptors that recognize components of the microbial surfaces:
• Dectin-1
• Complement receptors
• SR-A, MARCO
• SR-B
Microorganisms are bound by phagocytic receptors on the macrophage surface.
Binding of bacteria to phagocytic receptors on macrophages induces their
engulfment and degradation.
Signaling:
The cell is maturing and starts to become different, acquiring different functions
like Toll-like receptors. Once the pathogen is taken up, and a signal has been gone
through Toll-like receptors, the cell will start digesting it better and will start
presenting it to T cells. Binding of bacterial components to signaling receptors on
macrophages induces the synthesis of inflammatory cytokines.
Adaptive immunity starts in secondary lymphoid organs. Via the blood, naïve B
cells and T cells travel through the arteries.
The bacteria entered the skin via a wound. Macrophages start digesting and take
up. Dendritic cells get activated via the Toll-like receptors and also take up the bacteria.
Macrophages engulf the bacterium, and show it to blood cells. Dendritic cells transfer to a
lymphoid organ, and activate T cells. T cells recognize and starts fighting (3-4 days), and B
cells take longer to become plasma cells and produce antibodies.
Dendritic cells (DC) in peripheral tissues:
Immature DCs: take up antigen (good at phagocytosis)→ activation → antigen processing
→ Mature DCs: present antigen through MHCII (good at presenting antigens).
Adaptive response starts when DCs meet T lymphocyte (within the Lymph node).
Complement
There are specific antibodies against bacteria. The antibody helps macrophages to take up,
opsonization, phagocytosis and destruction. Phagocytosis occurs readily when bacteria are
covered in antibodies. Antibodies consist of:
• Fc tail (constant)
• Antigen-binding sites (variable)
Fc tail binds to Fc receptors on the macrophage.
Covered with complement = Antibody + complement (C3b). Macrophage has not only the
Fc receptor but also the complement receptor (CR1). Complement further stimulates
phagocytosis. Complement works before seen bacteria
Complement factors:
• Factors present in serum, lymph, and extracellular fluids.
• Synthesized by the liver
• Bind pathogens, causing them to undergo phagocytosis
• Without these factors, many bacteria would not be phagocytosed.
2
,Activating the complement system (three pathways)
C5 will make the mac (membrane
attack complex) which will punch
holes in the membranes of pathogens
→ pathogens die.
Also breaks down in C5a and C5b
The specific adaptive immune system Teffector cells (cytokines)
T cells and B cells → antigen recognition → effector cells
Plasma cells (antibodies)
B lymphocytes (bone marrow) and T lymphocytes (thymus). Both have specificity antigen receptors
(different for each lymphocyte). The receptors on individual lymphocytes are identical.
T cell activation → CD8 MHCI → CD4 MHCII.
Antigen receptors B cell
• Transmembrane part (only B cells)
• Antigen recognition on the tip
• Need to pair with IgB and IgA (immunoglobulins)
• Antigen receptor and effector molecules
Antigen receptors T cell
• Antigen recognition part
• Has to pair with CD3
• Other effector molecules → cytokines, enzymes
Required for rearrangement of immunoglobulin genes
RAG-enzyme expression (recombination-activating genes). Only lymphocytes express RAG enzymes.
B cell receptor diversity
• Gene rearrangement gives diversity
• More diversity during immune response by somatic hypermutation (random process):
o High affinity antibodies are selected
o During maturation in germinal centers (affinity maturation)
B cell lymphocyte / B cell can bind directly to pathogen → becomes a plasma cell or memory B cell.
T cell receptor diversity by gene rearrangement in the thymus (expression of RAG enzymes).
T cells recognize antigenic peptides and HLA (MHC).
3
, Major Histocompatibility Complex (MHC) (human Leukocyte Antigens HLA)
• MHC I (HLA I)
• MHC II (HLA II)
Antigenic peptides are situated in antigens binding sites non-covalently. Peptides in
antigens binding sites: 9 amino acids on average.
MCHI and II molecules present peptides from different cellular compartments
MHC I: cytosol → ER → Golgi → lysosomes (green)
MHC II: phagosomes → lysosomes → Class II compartment (red)
Variations in MHC allotypes at sites that bind peptide and T cell receptor
MHC class I variability→ a2, a3, a1
MHC class II variability → B1, B2, a1, a2
Peptide binding motifs and sequences of bound peptides
Green =
determines
peptide binding
in MHC molecule
White = can vary
and is used for
TCR recognition
9 amino acids long. Different MHC I on every cell → provides possibility to have many different
peptides on MHC I on the surface. Green (2/3 amino acids) are necessary for holding it there.
Dendritic cells take up bacterial antigens in the skin and then move to enter draining lymphatic vessel
(only because of Toll-like receptor). Dendritic cells bearing antigen enter the draining lymph node,
where they settle in the T cell areas. DCs present antigens to the T cell.
Naïve T cells recirculate through secondary lymphoid organs. The naïve T cells need L-selectin,
recognize the chemokines on the surface, recognizes that chemokine and leads to activation of the
integrin (LFA-1), stop rolling and go into the lymph node. Two molecules that are needed for this:
CD602L (L-selectin) and CCR7 and only naïve T cells and naïve B cells have these.
Two signals are needed to activate naïve T cells
• T cell receptor recognition peptide in MHC (CD4 helps binding by recognizing MHC II)
• Co-stimulation (B7 = CD80, CD86)
T cells that recognize self-antigens in absence of co-stimulation → become anergic.
4
Lecture 1: Introduction into Immunology Monday 06 sept 2021
Immunology is the study of the body’s defense against infection.
Two immune systems:
• Adaptive (acquired) immune system: composed of specialized, systemic cells and processes
that eliminate pathogens or prevent their growth.
• Innate immune system: the body's first line of defense against germs entering the body.
Hematopoiesis
All the cellular elements of blood ultimately derive from the hematopoietic stem cell of the bone
marrow. The hematopoietic stem cell give rise to common lymphoid precursor and common
myeloid precursor.
Lymphoid cells become:
• B cell (plasma cell)
• T cell (effector T cell)
• NK cell
Myeloid cells become:
• Granulocyte
o Macrophage and dendritic
o Neutrophil
o Eosinophil
o Basophil
o Mast cell
• Megakaryocyte
o Megakaryocyte → Platelets
o Erythroblast → Erythrocyte
Recognition mechanisms of innate immunity
• Fast (hours)
• Fixed
• Limited number of specificities
• Constant during response, doesn’t change
Common effector mechanisms for the
destruction of pathogenesis
Recognition mechanisms of adaptive immunity
• Slow (days to weeks)
• Variable
• Numerous highly selective specificities
• Improve during response, getting better
Innate cells can distinguish ‘self’ and ‘non-self’.
Macrophage receptors recognize the cell-surface
carbohydrates of bacterial cells but not those of human
cells. Natural killer cell receptors recognize changes at the
surface of human cells that are caused by viral infection.
1
,Phagocytosis:
Macrophage receptors that recognize components of the microbial surfaces:
• Dectin-1
• Complement receptors
• SR-A, MARCO
• SR-B
Microorganisms are bound by phagocytic receptors on the macrophage surface.
Binding of bacteria to phagocytic receptors on macrophages induces their
engulfment and degradation.
Signaling:
The cell is maturing and starts to become different, acquiring different functions
like Toll-like receptors. Once the pathogen is taken up, and a signal has been gone
through Toll-like receptors, the cell will start digesting it better and will start
presenting it to T cells. Binding of bacterial components to signaling receptors on
macrophages induces the synthesis of inflammatory cytokines.
Adaptive immunity starts in secondary lymphoid organs. Via the blood, naïve B
cells and T cells travel through the arteries.
The bacteria entered the skin via a wound. Macrophages start digesting and take
up. Dendritic cells get activated via the Toll-like receptors and also take up the bacteria.
Macrophages engulf the bacterium, and show it to blood cells. Dendritic cells transfer to a
lymphoid organ, and activate T cells. T cells recognize and starts fighting (3-4 days), and B
cells take longer to become plasma cells and produce antibodies.
Dendritic cells (DC) in peripheral tissues:
Immature DCs: take up antigen (good at phagocytosis)→ activation → antigen processing
→ Mature DCs: present antigen through MHCII (good at presenting antigens).
Adaptive response starts when DCs meet T lymphocyte (within the Lymph node).
Complement
There are specific antibodies against bacteria. The antibody helps macrophages to take up,
opsonization, phagocytosis and destruction. Phagocytosis occurs readily when bacteria are
covered in antibodies. Antibodies consist of:
• Fc tail (constant)
• Antigen-binding sites (variable)
Fc tail binds to Fc receptors on the macrophage.
Covered with complement = Antibody + complement (C3b). Macrophage has not only the
Fc receptor but also the complement receptor (CR1). Complement further stimulates
phagocytosis. Complement works before seen bacteria
Complement factors:
• Factors present in serum, lymph, and extracellular fluids.
• Synthesized by the liver
• Bind pathogens, causing them to undergo phagocytosis
• Without these factors, many bacteria would not be phagocytosed.
2
,Activating the complement system (three pathways)
C5 will make the mac (membrane
attack complex) which will punch
holes in the membranes of pathogens
→ pathogens die.
Also breaks down in C5a and C5b
The specific adaptive immune system Teffector cells (cytokines)
T cells and B cells → antigen recognition → effector cells
Plasma cells (antibodies)
B lymphocytes (bone marrow) and T lymphocytes (thymus). Both have specificity antigen receptors
(different for each lymphocyte). The receptors on individual lymphocytes are identical.
T cell activation → CD8 MHCI → CD4 MHCII.
Antigen receptors B cell
• Transmembrane part (only B cells)
• Antigen recognition on the tip
• Need to pair with IgB and IgA (immunoglobulins)
• Antigen receptor and effector molecules
Antigen receptors T cell
• Antigen recognition part
• Has to pair with CD3
• Other effector molecules → cytokines, enzymes
Required for rearrangement of immunoglobulin genes
RAG-enzyme expression (recombination-activating genes). Only lymphocytes express RAG enzymes.
B cell receptor diversity
• Gene rearrangement gives diversity
• More diversity during immune response by somatic hypermutation (random process):
o High affinity antibodies are selected
o During maturation in germinal centers (affinity maturation)
B cell lymphocyte / B cell can bind directly to pathogen → becomes a plasma cell or memory B cell.
T cell receptor diversity by gene rearrangement in the thymus (expression of RAG enzymes).
T cells recognize antigenic peptides and HLA (MHC).
3
, Major Histocompatibility Complex (MHC) (human Leukocyte Antigens HLA)
• MHC I (HLA I)
• MHC II (HLA II)
Antigenic peptides are situated in antigens binding sites non-covalently. Peptides in
antigens binding sites: 9 amino acids on average.
MCHI and II molecules present peptides from different cellular compartments
MHC I: cytosol → ER → Golgi → lysosomes (green)
MHC II: phagosomes → lysosomes → Class II compartment (red)
Variations in MHC allotypes at sites that bind peptide and T cell receptor
MHC class I variability→ a2, a3, a1
MHC class II variability → B1, B2, a1, a2
Peptide binding motifs and sequences of bound peptides
Green =
determines
peptide binding
in MHC molecule
White = can vary
and is used for
TCR recognition
9 amino acids long. Different MHC I on every cell → provides possibility to have many different
peptides on MHC I on the surface. Green (2/3 amino acids) are necessary for holding it there.
Dendritic cells take up bacterial antigens in the skin and then move to enter draining lymphatic vessel
(only because of Toll-like receptor). Dendritic cells bearing antigen enter the draining lymph node,
where they settle in the T cell areas. DCs present antigens to the T cell.
Naïve T cells recirculate through secondary lymphoid organs. The naïve T cells need L-selectin,
recognize the chemokines on the surface, recognizes that chemokine and leads to activation of the
integrin (LFA-1), stop rolling and go into the lymph node. Two molecules that are needed for this:
CD602L (L-selectin) and CCR7 and only naïve T cells and naïve B cells have these.
Two signals are needed to activate naïve T cells
• T cell receptor recognition peptide in MHC (CD4 helps binding by recognizing MHC II)
• Co-stimulation (B7 = CD80, CD86)
T cells that recognize self-antigens in absence of co-stimulation → become anergic.
4
