Immunology- Innate immune response, B and T cells, tolerance Flashcards
(96 cards)
1
Q
Immunity to infection in the body involves two mechanisms
A
• Innate Mechanisms (Innate immunity) – First line of defence – Non-specific response and/or • Adaptive Mechanisms (Adaptive immunity) – Second line of defence – Highly specific with memory
2
Q
Two different types of immunity
A
• Active immunity – Antigens enter body and trigger • Innate and adaptive immune systems – Provides long term protection • Passive immunity – Antibodies pass from mother to: • Foetus across the placenta • Infant in breast milk – Provides short term protection
3
Q
Origins of cells in the immune system
A
• Derived from common pluripotent hematopoietic stem cell in bone marrow (generate all the immune cells)
-Myeloid lineage generates: • Polymorphonuclear leukocytes (neutrophil, eosinophil, basophil) • Monocyte/macrophages • Dendritic cells • Mast cells
– Lymphoid lineage:
• B- (produce antibodies) and T (bring about cell mediated immunity)- and natural killer (NK) lymphocytes
4
Q
Neutrophils
A
Principal phagocytic cell of innate immunity. Rapidly migrate to sites of infection, ingest microbes by phagocytosis, release oxygen free radicals, degranulate releasing proteins with microbicidal properties e.g. lysozyme.
5
Q
Eosinophils
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Defence against multicellular parasites and have a role in allergy and asthma.
6
Q
Basophils
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Involved in inflammatory allergic reactions. Releases the potent vasodilator, histamine.
7
Q
Monocytes
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- Circulate in blood, bean shaped nuclei, precursors of tissue macrophages.
- Effectors of the inflammatory response to microbes.
- Kills pathogens via phagocytosis, free radical production, myeloperoxidase and inflammatory cytokines.
8
Q
Macrophages
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- Derived from blood monocytes
- Participate in innate and adaptive immunity
- Phagocytosis, microbicidal mechanisms, antigen presentation to other cells
9
Q
Dendritic cells
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Process and present antigens (antigen presenting cell {APC}) on their cell surface to T-lymphocytes to initiate specific immune responses.
10
Q
Mast cell
A
Similarities with basophils, release histamine, close association with allergy and inflammation.
11
Q
Two types of lymphocytes what are they?
A
Small lymphocytes and large granular lymphocytes.
12
Q
Small lymphocytes
A
Small lymphocytes are involved with specific immunity:
• B-lymphocyte (B-cell) – produce antibodies, present antigens to other cells (APC), can produce long lived memory cells
• T-lymphocyte (T-cell)- plays critical role in development and regulation of cell mediated immunity. Influences the activities of other cells (e.g. B-cells), able to kill virally infected and tumour cells, generate long lived memory cells
13
Q
Large granular lymphocyte
A
- Natural Killer (NK) cell – generally considered part of the innate immune response.
- Release perforins and granzymes and trigger apoptosis in target cell.
- Kill infected cells which do not express foreign surface antigen, respond rapidly, involved in tumour immunosurveillance
14
Q
Key immunological sites in the body- Primary lymphoid tissue
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Development and maturation of lymphocytes : bone marrow (B lymphocytes) and thymus gland (T lymphocytes)
15
Q
Key immunological sites in the body- Secondary lymphoid tissue
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Mature lymphocytes encounter antigens/pathogens:
Includes: lymph nodes, spleen and lymphoid tissue at other sites e.g. tonsils, appendix, adenoids, Peyer’s patches (in ileum), bronchial associated lymphoid tissue (BALT).
16
Q
Lymph nodes form what?
A
Found at specific sites in the body.
B- and T-lymphocytes from
bone marrow and thymus to specific
sites in lymph nodes
17
Q
What is the spleen, what does it do and what is the structure?
A
• Spleen – Lymphoid organ in the abdomen – Removes damaged or old erythrocytes – Key site of activation of lymphocytes from blood borne pathogens • Architecture of Spleen – Red pulp- Erythrocytes removed – White pulp- Lymphocytes stimulated
18
Q
Key components of the innate immune system
A
1) Mechanical barriers : Provided by skin and mucous membranes, competition with normal flora, mucous entraps, and cilia propel microbes out of body.
2) Physiological : Stomach acid kills some pathogens ; fever response inhibits pathogen growth
3) Chemical mediators including circulating plasma proteins:
Lysozyme cleaves bacterial cell wall
Interferon induces antiviral defences in uninfected cells
Complement lyses microbes directly or facilitates phagocytosis
4) Phagocytic leukocytes
• Phagocytes - Cells specialized in the process of phagocytosis
• Macrophages: Reside in tissues and recruit neutrophils, become activated release cytokines (TNF, IL1)
• Neutrophils: Enter infected tissues in large numbers, become activated, release cytokines (TNF), phagocytose bacteria
5) Natural killer (NK) cells
• Summoned from the blood
• Release cytokines (IFN-γ, IL2)
• Kill infected cells (trigger apoptosis)
19
Q
Two types of adaptive immune responses- what are they?
A
Humoral immunity-mediated by antibodies produced by B lymphocytes
Cell-mediated immunity-affected by T lymphocytes
20
Q
Typical kinetics of immune response to infection
A
Innate response:
• Early on- phagocytes, interferons, cytokines
• Then- NK and T cell cytokines
Adaptive response:
• Cell mediated T cells take effect
• Antibody production
21
Q
Infected tissue
A
Dendritic cells exit the infected tissue to inform lymphocytes in the lymph nodes about the invading pathogen.
Neutrophils from the blood-stream into the infected tissue to kill the pathogen.
Neutrophils have killed the pathogen but they have destroyed themselves in the effort: ‘pus’.
Monocytes flood in from the blood-stream and become inflammatory macrophages.
Macrophages clear away the debris, while some may also migrate to lymph nodes to inform lymphocytes.
Inflammatory macrophages change properties as the infection resolves and help to repair damage to the tissue.
22
Q
What do macrophages do?
A
- Macrophages-phagocytose dying cells. The membrane plasma lipid profile changes when a cell dies and macrophages can recognise this
- They phagocytose opsonised (make (a foreign cell) more susceptible to phagocytosis) cells and pathogens. The surface is coated either with complement proteins or with antibodies
- If the cell or pathogen is coated with antibodies it can be efficiently taken up by the Fc receptor on macrophages.
- Dendritic cells have migrated to lymph nodes to recruit lymphocytes to the fight
23
Q
What specialisation do dendritic cells have?
A
The dendritic cell has specialised receptors on its surface that allow it to recognise patterns of foreign molecules, e.g. clusters of sugars, that are present on the surface of many pathogens.
This can kick start the adaptive immune response.
The naïve T-cell can now proliferate and the daughter T-cells can help B-cells.
Although macrophages can’t present to naïve T-cells they can present to the primed daughter cells of a T-cell activated by a dendritic cell.
24
Q
B cells form two type of cells- what are they?
A
Plasma cells that produce the antibody to fight the infection and memory cells that survive in the blood stream so that if the antigen is encountered in the future, there are more cells ready to respond (hence- immunity to the organism that carries that antigen).
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Types of antibodies
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IgG (4 types)
• Secondary response
• Major Ig in the blood
• Enters tissue space
• Prepares bacteria to be killed
• B cell receptor
IgD
• Found in B cell membrane
• Helps cell division
IgE
• Trace amount
• Allergic reactions
IgA (2 types)
• Protects entrance of pathogens
• Saliva, tears, GI & respiratory tract
IgM
• Primary repsonse
• Mainly bloodstream
• Kills bacteria
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26
Variable region creates diversity- how?
The building blocks for the variable regions are called the variable, diversity and joining segments.
In addition there are the so-called constant regions, but these are not part of the actual antigen binding site.
- Variable region – building blocks:
• Variable segment (V) – 46 diff types
• Diversity segment(D) – 23 diff types
• Joining segment (J) – 6 diff types
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- Constant region – 1 of 5 types in antibody:
• Alpha – IgA
• Delta – IgD
• Epsilon – IgE
• Gamma – IgG
• Mu – IgM
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Antibody diversity
* The rearrangement of immunoglobulin gene segments to create huge diversity in mature B cells
* This is followed by somatic hypermutation. If randomly hypermutation increases affinity, then the clone expressing the better antibody will receive more stimulation than other clones so it will divide more and more of the high affinity antibody will be produced.
* Class switching generates immunoglobulins with different properties- such as IgG which has no transmembrane domain and so is secreted so that it can encounter pathogens in the blood
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How do antibodies function?
1) Antibodies bind to bacteria and viruses. This is called “opsonization”. The Fab region of the antibody binds to the antigen on the surface of the microorganism, and the Fc regions are available to bind to Fc receptors on the surface of cells such as macrophages.
• This enhances phagocytosis.
2)Bound antibody also triggers complement activation and lysis of bacteria by the classical pathway
* An antibody can bind to an antigen on the surface of a bacterium and also to the Fc region receptor on the surface of a cell such as a macrophage
* The macrophage can then more easily destroy the bacterium. The binding of the Fc region of the Ab to the macrophage also helps to activate the macrophage
* Antibodies can also bind to viruses to prevent them from entering into cells, and target them for destruction
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Primary versus secondary antibody responses
• Primary Response
– Following exposure to an antigen, there is a slow rise in IgM followed by a slow rise in IgG
• Secondary Response
– Following exposure to previously encountered antigen, there is a rapid and greater rise in specific IgG (and limited rise in IgM)
• Memory or anamnestic response
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T cells and cell mediated immunity
* They display T cell receptors (TCRs) on their surface
* Like antibodies, they are also very diverse and arise from recombination of gene segments in a similar fashion
* T cell receptors are not released from the cell, but remain on the surface of the T cell and exhibit clonal expansion, in response to peptides that they recognise
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Why do T cells only recognise antigens as complexes with MHC molecules?
* Peptides are presented on the surface of antigen presenting cells (APC) in association with the MHC.
* This allows immune cells to discriminate between normal antigens on the surface of all cells, and those that are foreign and potentially dangerous.
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MHC class I- process
* MHC class I proteins are present on almost every cell in the body
* They present endogenous antigens that are synthesised in the cytoplasm
* Samples of all proteins made on ribosomes, whether normal host proteins are chopped up into short peptides by the proteasome.
* The resulting peptide fragments are transported into the endoplasmic reticulum, where peptides of ~10 amino acids can bind to MHC I proteins
* These peptide MHC complexes are transported via the Golgi apparatus to the cell surface
* Once at the cell surface, the membrane-bound MHC I protein displays the antigen for recognition to cytotoxic T cell lymphocytes (CD8+)
* If foreign (viral) protein fragments are detected, the cell is killed otherwise the cell is spared
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MHC class II- process
* MHC II proteins are only present on specialised antigen-presenting immune cells - macrophages, dendritic cells and B cells
* MHC II proteins present exogenous antigens that originate extracellularly from foreign bodies such as bacteria
* Following phagocytosis, foreign peptide fragments are bound to MHC II proteins in the endosome, before being transported to the cell surface.
* Once at the cell surface, the membrane-bound MHC II protein displays the antigen.
* It is recognised by a different type of T cell, namely the helper T cell lymphocyte (CD4+)
* The binding of helper T cells to B cell MHC II-antigen stimulates the development of antibody-producing B-cells against that antigen (T-cell help)
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Disorders of the immune system- autoimmunity
Autoimmunity
– Misdirected adaptive immune response
– Results from a loss of self-tolerance (e.g. type I diabetes, rheumatoid arthritis, Crohn’s disease, vitiligo, thyroiditis, multiple sclerosis)
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Disorders of the immune system- hypersensitivity reactions
Over-reaction of adaptive immune response (types I-IV) (examples: peanut allergy, asthma)
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Disorders of the immune system- Immunodeficiencies
– Components of immune system either absent or defective
| – Genetic or acquired etiology (e.g. AIDS, congenital complement deficiencies)
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How the innate immune system works
• Responds to invading pathogens immediately upon contact
• Involves humoral (fluid phase) and cellular responses
1) Complement activation (blood plasma)
2) Phagocytosis by macrophages and neutrophils
3) Natural Killer Cells (NK)
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Complement activation- 3 pathways what are they?
1) Classical pathway
2) Lectin or mannose-binding pathway
3) Alternative pathway
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Complement activation- classical pathway?
5 steps:
The classical complement pathway is activated when complement factor C1 binds to antibody/antigen complexes (generated by the adaptive immune response).
Step 1) C1 cleaves complement factor C2 into C2a and C2b
Step 2) C1 also cleaves factor C4 into C4a and C4b.
Step 3) C2a and C4b form a complex which cleaves factor C3 into C3a and C3b.
Step 4) C3b joins the C2a/C4b complex forming a C2a/C4b/C3b complex which cleaves C5 into C5a and C5b.
Step 5) C5b finally forms a complex with C6, C7, C8 and C9 producing the Membrane-attack complex (MAC) which perforates the cell membrane of pathogens or virus-infected host cells.
Some of the byproducts of the complement activation pathway play a role in other processes:
C3a, C4a and C5a are anaphylatoxins.
C3b plays a role in opsonisation: it binds to pathogens to prime phagocytosis by macrophages.
40
Complement activation- Lectin or mannose-binding pathway
* Involves MBL (Mannose-Binding Lectin), which binds sugars (mannose) found on the surface of pathogens but not mammalian cells
* MBL binds MASP 1 & 2 (MBL Associated Serine Protease) which activate C2 and C4
* Rest of pathway (C3-9) identical to the Classical pathway
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Complement activation- alternative pathway
* Involves auto-activation of C3 into C3a and C3b which occurs constantly at very low rate
* Upon contact with bacteria, auto-activated C3b binds factor B and properdin which rapidly activates more C3 then activates C5
* Rest of pathway the same again (C6-9)
42
Anaphylatoxins- what are they and what do they do?
* C3a, C4a and C5a-By-products
* Trigger degranulation of endothelial cells, mast cells (releasing histamine) and phagocytes (releasing cytokines)
* Cause smooth muscle contraction and enhance vascular permeability-easier for neutrophils and natural killer cells
* C3a and C5a also act as chemoattractants: they attract and activate neutrophils
* Involved in allergic reactions but in large concentrations they may cause anaphylactic shock
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Opsonisation by C3b- how?
* C3b renders bacteria more susceptible to phagocytosis
* C3b is cleaved to iC3b on the bacterial surface
* The macrophage membrane has iC3b receptors, facilitating phagocytosis of the bacteria by the macrophage
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Professional Phagocytes- what cells are they?
```
• “Professional” since they make their living mainly by eating
• Professional phagocytes:
– Macrophages
– Dendritic cells
– Neutrophils
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How does phagocytosis work?
Pathway for phagocytosis:
• Pathogens are engulfed by the (macrophage, dendritic cell or neutrophil) cell membrane forming phagosomes
• The phagosome fuses with a lysosome that contains digestive enzymes, and forms a phagolysosome
• The digestive enzymes in the phagolyosome digest the pathogen
• Indigested material is then secreted by fusion of the residual body with the cell membrane
• Some secreted material- small peptides- held on surface of cell by MHC class II and act as antigen presenting cells
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3 stages of macrophages- the resting macrophage
* Collects debris from tissues by phagocytosis
* Eliminates apoptotic cells
* Expresses very little Major Histocompatibility Complex (MHC) class II molecules on their membrane
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3 stages of macrophages- the primed macrophage
* Macrophages are primed by the cytokine interferon gamma (IFN-g) produced by NK cells and helper T cells
* Primed macrophages express increased levels of MHC II (antigen presentation) on membrane
* And take up larger objects by phagocytosis
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3 stages of macrophages- the hyperactive macrophage
* Macrophages become hyperactive when stimulated with both IFN-g and lipopolysaccharide (LPS) produced by Gram-negative bacteria
* Hyperactive macrophages stop proliferating, become larger and increase their rate of phagocytosis
* Hyperactive macrophages produce cytokines: tumour necrosis factor (TNF), which can kill tumour cells and virus-infected cells, and interleukin-1 (IL-1)
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The Neutrophil- The “on call” killer from the blood
* Reside in the blood
* Activated and attracted to the site of infection
* Short-lived (5 days) (macrophages are long lived)
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How do neutrophils ‘sense’ where to go?- Step 1 just before rolling
Step 1
• Under normal conditions, the neutrophil expresses Selectin ligand (SLIG) on its cell membrane and the endothelial cell expresses Intercellular Adhesion Molecule (ICAM), which are incompatible and the neutrophil circulates freely
• When the tissue is infected and inflamed, the cytokines interleukin-1 (IL-1) and tumour necrosis factor (TNF) are secreted by the activated macrophages
• IL-1 and TNF stimulate the expression of Selectin on the endothelial cell membrane to which SLIG on the neutrophil binds
• The Selectin-SLIG interaction is not enough to stop the neutrophil completely, but the cells bind and start “rolling” on the endothelium
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How do neutrophils ‘sense’ where to go?- Step 2 - just before cells stop rolling
* Next, when C5a accumulates in the inflamed tissue due to increased complement activation, and the bacteria secrete significant amounts of lipopolysaccharide (LPS), LPS and C5a induce integrin (INT) expression on the neutrophil cell membrane
* INT binds to ICAM, which is constitutively expressed on the endothelium, and now the neutrophil – endothelium interaction is so strong, that the cells stop rolling and stick to the vascular wall close to the site of infection
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How do neutrophils ‘sense’ where to go?- Step 3- Met as the N-terminus amino acid
* Human proteins have methionine (Met) as the N-terminal amino acid
* Bacterial proteins on the other hand start with the amino acid formyl methionine (f-Met)
* Neutrophils “track” F-Met peptides (secreted by macrophages after phagocytosis of bacteria…)
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The Natural Killer (NK) cell- assisted suicide cell- where it is produced, what it produces and what its function is
* Lymphoid lineage (as opposed to myeloid lineage for the macrophage and neutrophil)
* Produced in bone marrow and found mainly in blood, liver and spleen
• Produce cytokines (IFN-g, IL-2)
• Destroy infected cells (“assisted suicide”)
– Uses Fas ligand (also used by killer T cells) to bind Fas on target cell inducing apoptosis (programmed cell-death)
– Saves healthy host cells by recognising “normal” MHC-I molecules on the membrane of these cell
– If no MHC-1 molecules on membrane- Perforin protein to inject granzyme B (“suicide” enzyme) into the cell
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Innate immune system and virus infections
• Complement opsonises viruses with C3b for phagocytosis by macrophages and neutrophils
• Complement produces Membrane-attack complexes on enveloped viruses
• Host cells infected by viruses:
– TNF (tumour necrosis factor) and IFN reduce virus production by infected cells
– NK cells induce apoptosis of infected cells
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Components of specific immunity- cellular and soluble
```
• Cellular
– B cells (bone marrow derived)
– T cells (thymus derived)
• Soluble
– Immunoglobulins (produced by B cells)- immunoglobulin and antibody are the same thing
– Cytokines (many produced by T cells)
```
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B cell maturation
i) Clonal expansion
ii) Production of large amounts of the antibody
The plasma cell is the mature version of the B cell, after it has been activated. Each specific B cell proliferates to produce a clone of identical cells (ie producing the same specific antibody).
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Memory B cells
Memory
* B cells remember an antigen
* If B cells are confronted by an antigen on a second occasion, the Ab response is much quicker (memory)
* This forms the basis for vaccination
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Primary versus secondary antibody responses
• Primary Response
– Following exposure to an antigen, there is a slow rise in IgM followed by a slow rise in IgG
• Secondary Response
– Following exposure to previously encountered antigen, there is a rapid and greater rise in specific IgG (and limited rise in IgM)
• Memory or anamnestic response
• Basis for vaccination
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Are B cells APC?
* B cells can act as antigen presenting cells, thereby stimulating the T cell arm of the immune system
* Interaction between B and T cells is crucial for a healthy immune response
So, B cells are also Antigen Presenting Cells (APC). This means that they present the antigen to other cell types, triggering those cells to respond to the pathogen as well.
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Common pathological conditions involving B cell “over-activation”
* Graves’ disease (autoimmune hyperthyroidism) is production of antibodies that mimic the action of TSH
* This leads to uncontrolled hyperthyroidism
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3 main types of specific T cells
```
• T helper (Th) cells (CD4 +ve on the surface)
– Help one another
– Activate B cells
– Activate phagocytes
• T killer cells
– Cytotoxic T lymphocytes (Tc) (CD8 +ve)
– Effective at attacking viruses
• T regulatory cells (Tregs)
– regulate or suppress other cells in the immune system
– protect against autoimmune disease
```
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Cells which can present the antigen
* Monocytes and macrophages
* B cells
* Dendritic cells
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T cell receptor (TCR)
• TCR is associated with CD3 molecule (CD3/TCR complex)
• Lymphocytes can be subdivided according to cluster of differentiation. Most important:
– CD4 (helper cells)
– CD8 (cytotoxic cells)
• TCR only recognises the antigen when it is presented together with an MHC molecule
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Major histocompatibility complex (MHC) what are they?
• Glycoproteins present on cell surfaces that help differentiate self from non-self
• Play a crucial role in T cell activation
- MHC I (cytotoxic/killer cells)
- MHC II (helper cells)
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T cell activation
* Antigen is processed and presented in conjunction with MHC class I or II to T cells
* A second signal is needed, otherwise T cell fails to be activated and becomes “anergic”
* Need CD4/ CD8 co-stimulation in this example need CD80 and CD28 to activate/respond to the antigen. Second signals add further checks so don’t get inappropriately stimulated.
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What happens when T cells are activated?
Activation of T helper (Th) cells result in cytokine production
• Chemoattraction
• Autoactivation
• Augmentation of inflammation
• Stimulation of Ab production by B cells
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Cytokines
* Cytokines produced by lymphocytes (mainly T cells)
* Draw more cells to site of injury
* Activate T cells
* Activate B cells and cause Ab production
* Activate macrophages- monokines (e.g. interleukin 1)
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Th1 and Th2 cytokines- what do they do?
• Th1 activate cell mediated immunity
– IL-2, IL-15, IFN-g
• Th2 are responsible for antibody production
– IL-4, IL-10, IL-13
• Balance between Th1 and Th2 can decide disease presentation or clinical course
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Disease from Th1 response
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Tuberculoid leprosy (Th1 response)
Relatively contained, not many bacteria present- patients can recover
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Disease from Th2 response
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Lepromatous leprosy (Th2 response)
Much more severe form of disease and worse for patients.
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Treatment of cytokines
Immune treatment of multiple sclerosis (autoimmune condition) (Th1 disease) can result in the development of Graves’ disease (Th2 condition).
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HIV structure and how it works?
* HIV virus has an antigen on the surface called gp120
* Gp120 binds to CD4 molecule
* Now come into close contact to cell
* CD4 forms the receptor for this antigen (virus is attached to CD4 cells)
* Virus injects its RNA and reverse transcriptase into the cell (transforms RNA to DNA) and forces the cell to make viral genes and forget about its own function, with the net result of HIV replication
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Central tolerance- B cells and T cells
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Bone marrow (B cells)
• Clonal deletion when cells encountering self are recognised
• Receptor tolerance (daily encounter with the antigen)
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Thymus (T cells)
• Positive selection: only cells recognising MHC survive
• Negative selection: cells recognising self-antigen die (clonal deletion)
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What is peripheral tolerance?
• Regulatory T cells that eliminate immune cells directed against self-antigens
• Absence of second signal when lymphocytes are activated (immune cell anergy)
• Anatomical barriers and immune privileged areas:
– Inside the eyes (injury to one eye can cause immune destruction to the other eye – complete tragedy)- respond to antigens in one- disease can cause immune response in healthy eye and lead to blindness- when tolerance in immune privilege areas breakdown
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What are autoimmune diseases (AD)?
• AD occur when self-tolerance against a body antigen is broken.
• These include organ specific autoimmune conditions
– Thyroid disease
– Type 1 diabetes
– Pernicious anaemia
– Some skin conditions
• Non-organ specific autoimmune conditions
– Systemic lupus erythematosus (SLE)
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Interaction between T and B cells
1. B cell encounters antigen then antibodies triggered
2. B cell (APC) takes antigen then digests
3. Displays antigen fragments with MHC – attracts help Th cell
4. T cell secretes lymphokines then B cells multiply plasma cells
5. Increase in antibodies – antigen-antibody complexes then eliminated by liver, spleen or complement cascade
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Interaction between B and T cells is a two way process
The B cell that has recognised its specific antigen will only proliferate and mature after it has interacted with a Th cell (by presenting the antigen with the MHC class II molecule to the Th cell).
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Haematopoiesis
* Bone marrow where haematopoiesis takes place
* A haematopoietic stem gives rise to pluripotent stem cells, meaning that these cells can still differentiate into many different cell types
• In the bone marrow pluripotent stem cells give rise to unipotent precursors of red blood cells, platelets, granulocytes and monocytes which can than go into the tissue and develop into macrophages. In addition, the pluripotent stem cell gives rise to precursor of immature lymphocytes. The immature, or naïve, B cells migrate to the lymph node for maturation, while the T cells mature in the thymus.
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B cells
* Recognise extracellular, foreign material
* Make and secrete antibodies
* Activate macrophages to phagocytose (engulf) and digest (chop into pieces) extracellular pathogens which are then presented via MHC class II
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T cells
CD8+ or CD4+
• Recognise intracellular and extracellular foreign material
• Presented either by MHC class I or II
• Activate B cells
(extracellular pathogen)
• Or kill the infected cells (intracellular pathogen)
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Antigen presentation via major histocompatibility (MHC) class I
* Your cells are continuously producing and recycling proteins. The breaking down of these proteins occurs inside the proteasome. Both your own proteins as well as intracellular-virus-derived proteins are cut into pieces, thereby forming specific peptide sequences
* The cell also continuously produces new major histocompatibility class I proteins. From the endoplasmic reticulum the peptides on their way to the membrane the MHC class I pick up the unique peptide sequences that are produced by the proteasomes and move them to the cell membrane where they present them to the cells of the immune system.
* MHC class I are found on all cells. MHC class I present antigens derived from intracellular material so material that can be found in the cytosol. This will be parts of your own proteins but also parts of viruses. And since every cell may get infected, every cell has MHC class I. Via MHC class I you can activate cytotoxic T cells, these are the CD8 positive T cells that will subsequently kill the infected cell they got activated by.
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Antigen presentation via major histocompatibility (MHC) class II
Material that has been phagocytosed (engulfed) from outside of the cell gets digested or cut to pieces in the endosomes, these are small vesicle like structures.
The cell also continuously produces new major histocompatibility class II proteins, which then take different routes to the cell membrane. From the endoplasmic reticulum the peptides on their way to the membrane the MHC class II pick up the unique peptide sequences that are produced either by the endosomes and move them to the cell membrane where they present them to the cells of the immune system.
• MHC class II picks up exogenous material, so the material that has been taken up by cells via phagocytosis. MHC class II are therefore mainly found on cells whose main job is phagocytosis and antigen presentation, thus antigen presenting cells like macrophages or dendritic cells. MHC class II will activate T helper cell, thus the CD4 positive T cells. These cells will subsequently activate more macrophages and B cells to help clean up the infected surrounding of the cell.
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Need co-stimulators CD4 and CD8 why? What happens if there is missing co-stimulation?
Need CD4, additional co stimulators and MHC class II to activate the T cell. CD8 need co stimulation so no accidental cytotoxic toxicity.
Missing (or incorrect) co-stimulation- Don’t have extra ligand binding interaction, won’t get cytotoxic T cell activation and get anergy response- cells become unresponsive to all signals.
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Lymphocyte selection- positive and negative
Positive- Need to recognise pathogenic antigens (non-self) e.g. bacteria, toxins, viruses
Negative- Need to ignore autologous (self) antigens to prevent auto-immune disease e.g. destruction of insulin-producing B-cells in type I diabetes
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T cell maturation / selection
| - how does lymphocyte selection work?
* The lymphoid precursor cell in the bone marrow forms immature T and B cells. The naïve B lymphocytes migrate to the lymph nodes
* The immature T cells migrate from the bone marrow into the thymus, where they arrive in the cortex. In the cortex they divide or proliferate and start expressing both the CD4 and CD8 co-receptors. This means that at this point the T cell can bind with both MHC class I and II.
* These cells now migrate to the medulla, where they encounter antigens presented by both MHC class I and II. If they recognise any antigen, they become positively selected, so they survive
* The surviving cells stop expressing either CD4 or CD8: If the cell recognised a peptide presented via MHC class I it keeps the CD8 co-stimulator and if the peptide recognised was presented by MHC class II the cell keeps CD4 for future cell activation. Thus here it is decided whether they become cytotoxic T cells or T helper cells.
* While migrating through the middle of the medulla, the surviving cells are again presented with antigens. But this time, the cells can be activated by only one of the MHC classes. In addition, in the middle of the medulla, the antigens presented to the maturing cells are all self-antigens, and if the new T cells bind to any of these they get negatively selected, meaning that they die, because we do not want to start an immune response against our own materials
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Non-self presentation
Non-self-antigens by APCs
- Macrophages
- Dendritic cells
- Cortical epithelial cells
• Present non-self-antigens to the immature lymphocytes for the positive selection. But these are only a few cell types and they only make a very limited amount of self-antigens.
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Self-antigen presentation
Self-antigens produced by Medullar thymic epithelial cells-in the centre of medulla
Controlled by Aire gene: Auto-immune regulatory
Expression, breakdown & MHC I/II presentation of organ -specific proteins not expressed in thymus. Prevents self-recognition of mature T cells outside thymus.
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Acquired tolerance- example with reproductive system
Reproductive system
• Eutherian fetoembryonic defence system (Eu-FEDS)
• Foetal material (sperm, eggs, gametes) lack MHC molecules so to lymphocytes these cells are invisible
• Overproduction of glycoproteins (suppresses immune response)
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1 B cell receptor has 5 variations of antibody types
5 types of antibodies called IgD, IgM, IgG, IgE and IgA. These are 5 variations of the same original B cell receptor.
The bottom part of the antibody is called the Fc region and this is the part of the antibody that is swappable. The part of the antibody that allows for the immunoglobulin-switching.
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Ig class switching- what do immature and activated B cells produce
• Immature B cells produce some IgD, but mainly IgM (relatively low affinity)
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• Activated mature B cells switch
Ig class depending mainly on location and function (high affinity)
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Forming the antigen recognition site
The building blocks for the variable regions are called the variable, diversity and joining segments.
• In the human heavy chain genome there are 46 different variable-segments, 23 diversity segments and 6 different joining segments. These are the segments that will form the antigen binding region. The additional C-segment lets you only choose from alpha, delta, epsilon, gamma and mu and are therefore called the constant genes.
Light chain genome there are less options to choose from for the diversity-segments are lacking completely and on top of that the C-gene is a lot shorter for it only gives the option between lambda or kappa
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Monoclonal versus polyclonal
* Monoclonal- Identical antibodies from 1 type B cell clones against same pathogen
* Polyclonal – Different antibodies with different antigen sites from different B cell clones same pathogen
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Somatic hypermutation
* Normally mutation frequency is very low
* In the V, D and J gene segments mutation frequencies are very high (1 in 1000) → somatic hypermutations
* Occurs after first B cell activation in lymph node
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What is the benefit of hypermutations in the variable region?
A mutation can cause a worse, equal or better binding
to the antigen.
Mature B cells continuously need to be activated in order to proliferate so there is an ongoing positive selection of B cells, leading to higher antigen affinity.
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B cell maturation in lymph node
* B cells mature in the germinal centre of the lymph node. Here they proliferate and form clones. In these clones lots of somatic hypermutations occur which increases or decreases the affinity to the pathogen
* The cells with the higher affinity will get further positively selected while the non-binding or badly binding cells will not get the co-activation signal from the antigen presenting cells and thus die via apoptosis
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What if negative T cell selection fails?
1. Chance that co-stimulation fails Anergy
2. Self-recognising CD8+ T cells start attacking cells
3. Self-recognising CD4+ T cell could cause positive selection of a maturing B cell in the lymph node
