Case 7- immune response Flashcards
Role of Macrophages
1) Perform phagocytosis
2) Release cytokines and chemokines
Cytokines
A small protein that alters the behaviour of other cells, typically immune cells
Chemokine
A type of cytokine that stimulates the migration and activation of other cells
What do cytokines and chemokines do ?
They recruit neutrophils and monocytes from the blood stream, this is inflammation
What happens if there are a high number of pathogens?
The signalling PRR (Pattern recognition receptor) is activated, releasing cytokines to recruit immune cell reinforcements. Toll-like receptors are a family of signalling PRR’s which trigger the release of cytokines. If the number of pathogens are low only Phagocytosis will occur
What happens when the Macrophage encounters a stranger (pathogen)
If it’s a stranger the bacteria will have a PAMP which is recognised by a Toll like receptor (type of PRR), this activates transcription factors NFKB and IRF3/7. This causes the transcription of mRNA and the release of cytokines which go on to promote inflammation.
What happen when a Macrophage encounters danger?
When cells are damaged (danger) for example due to hammering your thumb, the Toll like receptor detect DAMP (Damage Associated Molecular Patterns). This is released from the damaged cell. This sets up the same signalling cascade as with a microbial injury and causes inflammation. This is because the epithelial barrier is likely to be broken so it stops an infection forming.
What do Macrophages respond to
Stranger/danger response
Roles of inflammation
- Delivery of effector cells and molecules to the site of infection to enhance and speed up killing of the invading microorganisms.
- Promotion of blood clotting at the site of infection to provide a barrier against further spread.
- Promotion of tissue repair.
Mechanism of action- inflammation
1) Binding of pathogen by tissue sentinel macrophages leads to its activation and induces the release of cytokines and chemokines.
2) Cytokines and chemokines: induce dilation of localised blood vessels and the production of adhesion molecules on the surface of blood vessels. These anchor neutrophils and monocytes which would normally flow past as the adhesion molecules make the blood vessel more sticky. They increase vascular permeability by producing gaps in the blood vessels.
3) Neutrophils and monocytes migrate into the tissue in a process known as extravasation (dipedesis and transmigration), they go through the gaps in the blood vessel. Monocytes differentiate into Macrophages during extravastion.
Major organs and tissues of the immune system
• Lymphatic system including Lymph Nodes • Bone Marrow • Thymus • Spleen The immune system is part of the lymphatic system. In the lymph system you have immunological surveilance
Bone marrow- immune system
Primary site of new white blood cell generation (haematopoiesis). It is composed of multipotent hematopoietic stem cells – which give rise to all white blood cells (+ others cell types)
Thymus- immune system
Site of T lymphocyte maturation
What is a primary lymphoid organ
Sites of white blood cell generation and maturation
What is a secondary lymphoid organ
The storage of white blood cells and where the majority of induced innate and adaptive immune reactions take place
Lymph node- immune response
Are small glands that filter lymph for harmful substances. Immune reactions, most notably induced innate and adaptive immune responses primary take place within Lymphoid nodes.
Spleen- immune response
Similar in structure to a large lymph node, it acts primarily as a blood filter for harmful substances. It is also important for white blood cell storage namely monocytes. Spleen also synthesises antibodies in its white pulp and removes antibody-coated bacteria and antibody-coated blood cells by way of blood and lymph node circulation.
What stem cell generates all blood cell
The multipotent haematopoietic stem cell in the bone marrow
What stem cell gives rise to the lymphoid’s
The multipotent haematopoietic stem cell which gives rise to the Common lymphoid progenitor which creates the lymphoid (B cell, T cell and natural killer).
What stem cell gives rise to the other blood cells?
The multipotent haematopoietic stem cell which gives rise to the common Myeloid progenitor gives rise to the rest of the blood cells like Macrophages and erythrocytes. All the Myeloid cells are a part of the innate immune response.
Mast cell generation
The myeloid progenitor gives rise to mast cell precursors in the blood, when they enter the tissues they form mast cells, they have a rounded nuclei
Types of granulocytes
Neutrophils, Eosinophils, Basophils and Mast cells. Have granules in the cytoplasm
Granulocytes (phagocytic and non-phagocytic)
Granulocytes can be split into phagocytic and non-phagocytic cells. Phagocytic granulocytes use their granules phagocyticaly to destroy the pathogen. Non- phagocytic Granulocytes undergo de-granulation.
Phagocytic granulocytes- Neutrophils
Most abundant granulocyte. Can undergo oxidative burst where the different lysosome contents are released all at once, to kill both the neutrophil and the internalised pathogens. They can eat 30 bacteria at once. They have a three lobular structure due to the nucleus. In the blood moves in tissue for inflammatory response
Phagocytic Granulocyte= Eosinophil
In the blood, enters the tissues in an immune response They eat antibody coated parasites, they are abundant in allergic disease. When stained with Eosin they are a pinky orange. They have a C-shaped nucleus.
Non-phagocytic Granulocytes- Basophils
Stained blue in a Haematoxylin dye. It instigates its response in degranulation. Has large internal granules. Live in the blood
Non-phagocytic Granulocytes- Mast cells
Sentinel cells. There is the release of granules containing histamine and active agents. Has a major role in allergic response. Found in the tissues so when imaged there wont be any red blood cells.
Formation of dendritic cell
Myeloid progenitor cell can form a monocyte which can then form an immature dendritic cell in the blood. The immature dendritic cell can then form a mature dendritic cell in the tissue. The immature dendritic cell can live in both the blood and the tissue
Agranulocytes / Professional Antigen Presenting cells
Monocytes, Macrophage and Dendritic cells
Agranulocytes- Monocytes
Phagocytic and cause Cytokine release, antigen presentation from the blood. Differentiate into Macrophages and myeloid lineage dendritic cells. Found in the blood.
Agranulocytes- Macrophages
In the tissue and lymph node. Phagocytic and cause cytokine release. They are antigen presenting. Histologically they will look different due to the absence of red blood cells in the slide.
Agranulocytes- Immature dendritic cells
Mainly Phagocytic, matures in the lymph. They examine the lymph for new antigens, if they come across a pathogen that they have seen for the first time they will migrate to the lymph node and mature into a mature dendritic cell. In the lymph node it undertakes antigen uptake and antigen presentation at the peripheral sites. Really important for bridging the gap between innate and adaptive immune response.
Agranulocyte- mature dendritic cell
Most important antigen presenting cell due to its role in continual lymph immune-surveillance
T cell maturation
In the bone marrow you have the Multipotent Haematopoietic stem cell which gives rise to the lymphoid progenitor, it then becomes a precursory T cell. They move from the bone marrow and into the Thymus to become the Thymocyte. They undergo a process called T cell maturation where they are trained to recognise self from non-self. The Thymocyte becomes either CD4 T cell’s or CD8 T cells.
CD4 T cells
Can become either Regulatory T cells, memory cell’s or Helper T cells. These cells will be found in the lymph node
CD8 T cells
Can become cytotoxic T cells in the lymph node or memory cells.
Difference between cytoxic and helper T cells
Cytoxic T cells kill the pathogen whilst Helper T cells allow for communication and activation between other immune cells.
T cells action
All T cells are antigen specific but cant secrete antibodies. They recognise antigens using their TCR (T cell receptor). They can only recognise ‘processed’ antigens which present on MHC complexes that have gone through Phagocytosis
Regulatory and helper T cell (CD4)
Actively suppress activation of the immune system and prevent pathological self-reactivity i.e. an autoimmune disease. Roles of Helper T cell (CD4)
• Very good at making cytokines.
• Help in the maturation of B cells into plasma cells and memory B cells.
• They also help activate cytotoxic T cells and Macrophages.
• CD4 T cells recognise ‘foreign’ antigens presenting on MHC 2 complexes
Memory T cells (either CD4 or CD8)
T lymphocytes that have previously encountered and responded to a specific antigen. They are long-lived and can quickly expand to large numbers upon antigen re-exposure.
Cytotoxic T cells (CD8)
They induce apoptosis in cancer cells, infected cells (particularly with viruses) or cells that are damaged- apoptosis is mediated by cytotoxins (perforins, granzymes and granulsin).
How Cytoxic T cells (CD8) respond to self cells
- MHC 1 complexes bind ‘Self antigens’- peptides generated from degradation of cystolic proteins by proteasome.
- CD8+ Cytotoxic T cells use complementary T cell receptors (TCR) on their surface to recognise these self antigens/ MHC1 complexes presented on host cells.
- In order for the Cytotoxic T cells to bind MHC I, they require the expression of CD8+ glycoproteins. The cytotoxic T cells binds to the cells when it recognises that it’s a self cell it leaves.
- Cells recognised as “SELF” are left alone by Cytotoxic T cells
How cytoxic T cells (CD8) respond to virally infected cells
1) In viral infected or tumour cells, MHC I complexes are loaded with viral proteins – the peptides are generated from degradation of cytosolic proteins within infected cells.
2) TCR receptors on host cytotoxic T cells, recognise these viral antigens as not being self
3) Cytotoxic T cells launch an immune response & degranulates.
4) Apoptosis is mediated by cytotoxins (perforin, granzymes). A perforin can be added to the virally infected cell to allow Granzymes to enter to allow for apoptosis,
Natural killer cells
Part of innate immunity. They complete development in the bone marrow and move around the tissue, lymph and bloodstream.
What do NK cells respond to
Non-antigen specific. They recognised the number of MHC1 complexes on the cell, the number of complexes are reduced in infection and tumorigenesis
Why do infected cells have low levels of MHC 1 complexes
They are trying to hide from cytotoxic T cells which bind to the complexes to determine whether the cell is foreign or not.
Action of NK cell
When the NK receptor (natural killer) recognises the low levels of MHC1 complexes in undergoes degranulation, using perforins to punch holes in the infected cell to allow for Granzymes (Proteases) to enter the cell. This drives the process of Apoptosis or osmotic cell lysis
NK cells- ADCC
The second mode of action that natural killer cells use is Antibody dependent cell-mediated cytotoxicity (ADCC). Dependent on antibodies binding to antigen on target cells (infected or tumours). The primary NK cells recognise cell bound antibodies. Crosslinking of CD16 triggers the release of perforins and other proteins. Target cell killing occurs through the process of apoptosis as Granzymes enter the cell.
What do B cells differentiate into
Plasma cells and memory B cells. Plasma cells generate and secrete antibodies, memory B cells remember how to make antibodies for a specific antigens
Action of B cells
- B cells have B cell receptors on the cell surface, they bind and recognise specific naïve antigens which are not processed.
- They don’t need antigens to be presented to them by an antigen presenting cell (Macrophages / Dendrites)
- B cells are Phagocytic and capable of antigen presentation on a MHC 2 complex.
- The helper T cell promotes maturation of the B cell. The helper T cell makes cytokines which promote B cells to turn into a plasma cell. The plasma cell can now solubilise the antibodies stuck on their surface and release them.
What do antibodies do
They bind to the surface of the pathogen, neutralising them and stopping them from replicating. The antibodies bind to the outside of the pathogen opsonising them, preparing the pathogen to undergo Phagocytosis
How does antibody opsonisation aid the immune system
1) Greatly enhances phagocytosis by tagging them for destruction.
a. Agglutination – clumping / aggregation of pathogens – easier to phagocytose.
b. Chemoattraction – attraction of phagocytes to site of infection / microbes.
2) Neutralisation - Disrupt pathogen function / replication.
3) Natural Killer cell activation - Antibody-dependent cell-mediated cytotoxicity (ADCC)
4) Classical Complement Cascade Activation
a. Increased C3b production –promoting phagocytosis
b. Increased C3a and C5a – promoting chemoattraction of phagocytes
c. Generation of membrane attack complex (MAC) - Pathogen Osmotic Shock.
BCR’s (B cell receptors)
Recognise processed and non-processed antigens. BCR’s are essentially non-solubilised antibodies
B cells- antigen presentation
B cells are also capable of antigen presentation on MHC class 2 molecules, binding with T Helper cell TCRs in order to promote T helper cell activation and cytokine production.
Processes that occur in the lymph node
In the lymph node the dendritic cell displays the antigen in antigen presentation to the helper T cell which recognises it using its TCR. This sets up a signalling cascade which releases Cytokines. These cytokines tell the B cells to convert into plasma cells. The plasma cell releases antibodies specific to the pathogen, making the pathogen easier to Phagocyte.
Differences between B and T lymphocytes- antigens
B lymphocytes- B cells can recognise native antigens
T lymphocytes- T cells only recognise processed antigens, which are displayed as peptides on antigen presenting cells
Differences between B and T lymphocytes- antibodies
B lymphocytes- B cells differentiate into plasma cells that secrete antibodies
T lymphocytes- Do not produce antibodies
Differences between B and T cells- cytotoxins
B lymphocytes- produce relatively low amounts of cytokines
T lymphocytes- produce large amounts of cytokines
Active immunity
Requires an immune response and the production of B/T memory cells. They can then rapidly multiply when introduced to a foreign invader. Provides long term memory
Passive immunity
Requires no immunological memory and is the transfer of antibodies from mother to foetus across the placenta or through the breast milk to infants. It provides immediate short-term protection. No immunological memory will be produced
Natural active
Foreign invader enters the body and initiates an immune response. Provides long term protection
Natural passive
Antibodies pass from mother to fetus across the placenta or through breast milk to infants. Provides immediate short term protection
Artificial active
Antigens enter the body through vaccination, initiates immune response and provides long term protection
Artificial passive
Antibodies from an immune individuals is injected into the body. Provides immediate short term protection
What is recruited first in an acute immune response
Neutrophils
What is recruited in a chronic immune response
Monocytes and Macrophage
Why are neutrophils first
Most abundant leukocytes, have the most peptides
What chemical mediators promote vasodilation
Prostglandins, Histamine and Bradykinin
