Immunology Flashcards
What are the 3 parts of the innate immune system?
1) Complement - humoral phase
2) Phagocytosis (macrophages and neutrophils) - cellular phase
3) Natural killer cells - cellular phase
What are the 4 functions of the complement cascade?
1) Produce membrane attack complexes (MAC) to form a pore in the cell membrane of invading pathogens
2) Produce anaphylatoxins - by products from activated complement proteins that help immune response
3) Opsonisation of pathogens - binding of C3 to pathogen primes them for phagocytosis
4) Attract neutrophils to the sight of infection
What are the 3 complement activation pathways?
1) Classical pathway - activated by Ab/Ag complexes
2) Lectin or Mannose-binding pathway - activated directly by pathogens with mannose sugar on membranes
3) Alternative pathway - Activated by direct contact with pathogens
At which point do all 3 complement activation pathways converge?
Activation of C3 to C3b and C5 to C5b (often in therapeutics have a C5 blocker which effectively blocks complement no matter which pathway it is activated by)
How is the classical pathway activated?
1) C1q, C1r, C1s come together in response to Ag/Ab complexes to form C1
2) C1 cleaves C2 and C4 to C2a and C4b
3) C2a/C4b complex cleaves C3 to C3b
4) C3b/C2a/C4b complex cleaves C5 to C5b
5) C5b joins C6, C7, C8, C9 to produce the MAC
What is the course of the lectin or mannose-binding pathway?
1) Mannose sugar on pathogen membranes binds mannose binding lectin (MBL) which then binds 2 proteases, MASP 1 and MASP 2
2) This Mannose/MBL/MASP1/MASP2 complex then cleaves C2 and C4 to C2a and C4b
3) The rest of the pathway follows the classical pathway - just bypasses factor 1
Name 4 types of pathogens which have mannose in their membranes and can activate the mannose binding complement pathway?
1) Yeast such as candida albicans
2) Viruses such as HIV and Influenza
3) Bacteria such as salmonella and streptococci
4) Parasites such as Leishmania
What is the course of the alternative pathway?
1) Complement C3 undergoes auto activation which occurs at a slow rate, low levels of C3 b produced bind to bacterial membrane
2) Upon contact with the cell membrane C3b binds Factor B and Properdin (2 proteins) which rapdily activates more C3 and C5 to C3b and C5b
3) The rest of the pathway is identical to the classical pathway
What may large concentrations of anaphylatoxins cause?
Anaphylactic shock
Which anaphylatoxins also attract and activate neutrophils?
C3a and C5a
Which by products produced in complement activation act as anaphylatoxins?
C3a, C4a and C5a (a=anaphylatoxins!!)
What do anaphylatoxins do?
Induce degranulation of mast cells (histamine) and phagocytes releasing cytokines
Cause vasoconstricton through smooth muscle contraction and increase vascular permeability making it easier for neutrophils and NK cells to infiltrate infected tissue
Macrophages and neutrophils are members of which cell line?
Myeloid line
NK cells are members of which cell line?
Lymphoid line
What cell provides the first line of defence against pathogens that come through the skin?
Macrophages
What are the 3 activation states of macrophages and what do they do in each?
1) Resting - collects debris from phagocytosis and eliminates apoptotic cells, express little MHC II
2) Primed - Primed by IFN-gamma produced by NK cells and T helper cells, increase level MHC II and take up larger objects by phagocytosis
3) Hyperactive - Stimulated by IFN-gamma and LPS produced by gram -ve bacteria, stop proliferating, get larger, increase phagocytosis rate, produce cytokines IL-1 and TNF (tumour necrosis factor which can kill tumour cells and virus infected cells)
What is the process of phagocytosis?
1) Pathogens engulphed - phagosome
2) Lysosome fuses - phagolysosome
3) Ingested material secreted
4) MHC II line phagolysosome, pick up bits of protein, so cells gets covered in MHC II presenting Ags
How long due neutrophils live?
short lived - 5 dyas
What is the double key mechanism that neutrophils use to bind to blood vessel wall in inflamed tissue?
1) Selectin ligand (neutrophil) - selectin (endothelium)
2) ICAM (endothelium) - integrin (neutrophil)
- Selectin ligand and ICAM continuously expressed
- TNF and IL-1 (from activated macrophages) cause expression of selectin on endothelium
- C5a (from complement activation) and LPS (gram -ve bacteria) cause expression of integrin on neutrophil
Once neutrophil has bound to the blood vessel wall in inflamed tissue what signal is needed to induce infiltration?
- f-Met peptides are N-terminal amino acid on bacterial proteins
- Under stimulation of C5a and f-Met peptides (released from macrophages after phagocytosis of bacteria) neutrophils infiltrate the endothelium and inflamed tissue surrounding the blood vessel
What cytokine do neutrophils produce to attract other immune cells?
TNF
Where is the natural killer cell found mainly?
Blood, liver, spleen
What cytokines are produced by NK cells?
IFN-gamma and IL-2
How do NK cells destroy infected cells and recognise healthy body cells?
Recognise healthy body cells by recognising normal MHC I molecules
Use Fas ligand to bind Fas on target host cell, inducing apoptosis
Use perforin protein to inject granzyme B (suicide enzyme) into the cell
What complement fragment is involved in opsonisation of viruses for phagocytosis by macrophages and neutrophils?
C3b
Which cytokines reduce virus production by virus infected cells?
TNF and IFN-gamma
What are the cellular and soluble components of specific immunity?
1) Cellular = B cells (bone marrow derived) and T cells (thymus gland derived)
2) Soluble = Immunoglobulins (Ab produced by B cells), Cytokines (produced by T cells)
What are B cell receptors?
Antibodies attached to the surface of the B cell
What 3 things are needed for B cell activation?
1) Ag-Ab complex
2) T cells
3) Non T cells (inflammatory mediators)
What is a plasma cell?
Mature version of a B cell after it has been activated, produces large amounts of specific Ab
What are memory cells?
Proliferating cells (after B cell activation) which remain in the blood, means the next time the body encounters the same pathogen there are more specific B cells ready to respond, response is therefore quicker and larger so the pathogen is quickly dealt with
Other than plasma cells and memory cells what else can B cells act as?
APCs to stimulate the T arm of specific immunity
How do Abs work?
1) 2 recognition sites for an Ag
2) Can cross link pathogens to stop then invading cells (viruses) or multiplying (bacteria)
3) Ab ambush Ag in the interstitial tissue or blood stream, they are unable to enter cells
What are the 5 types of Immunoglobulins and what is there main role?
1) IgG - major type in blood, gets bacteria (and viruses)
2) IgD - B cell membranes, important initially, produced all the time, helps cell division
3) IgM - mainly in blood stream, bacteria, acute phase (IgM then IgG is made)
4) IgE - trace amount, allergic reactions and parasites
5) IgA - protects entrance of pathogens, saliva, tears, GI and respiratory tract - main Ig in respiratory and GI secretions
What is the initial Ig response to an antigen in terms of the type made?
Early response is low affinity IgM - mainly in blood stream
Later immune response is high affinity IgG - in blood and interstitial tissues
What is class switching?
When B cells change the type of Ab made, not the specificity
What are the 3 things that can be used for vaccination?
1) Live attenuated virus - MMR
2) Killed virus - Flu
3) Part of a virus - Menigococcal, Hep B
What is the 3 roles of B cells?
1) Ab production
2) Activation T cells
3) Activation complement
What are the 3 types of APCs?
1) Monocytes and macrophages
2) B cells
3) Dendritic cells
What are the 2 responses of T cells to being presented with an Ag?
1) Production of cytokines to boost immune response (T helper cells CD4)
2) Kill pathogen (cytotoxic T cells CD8)
What are the 3 types of T cells and what is their role?
1) T helper cells (CD4) - produce cytokines, activate B cells and phagocytes
2) T killer cells (CD8) - effective at attacking viruses
3) T regulatory cells - regulate against self destruction, dampening down the immune response
What molecules is the T cell receptor associated with which is necessary to signal it has been activated?
CD3 molecule
What is necessary in for a T cell to recognise an antigen?
It must be presented with MHC molecule
On which cells are CD4 and CD8 molecules found and which MHC do they interact with?
CD4 - MHC II - T helper cells
CD8 - MHC I - T killer cells (thus kills virus infected body cells)
Which cells are MHC I and MHC II found on?
MHC I - on all body cells
MHC II - on APCs
Where are viral peptides loaded onto MHC I in body cells?
In the ER
What is the second signal needed for T cell (either helper or killer) activation and why?
CD28 on the T cell (either helper or killer)
CD80 on the APC (either infected body cell or pro APC)
Prevents the T cell being activated by bodies host Ag
What happens to a T cell if it recognises an Ag presented with MHC as foreign but doesnt get to second CD28-CD80 signal?
Becomes anergic, meaning it does not respond to the Ag
What are the 4 functions of cytokines produced by CD4 cells (T helper cells)?
1) Chemoattraction (attract more immune cells over)
2) Autoactivation (activate themselves)
3) Augmention of inflammation (make phagocytes work better)
4) Stimulation of Ab production by B cells
What is the difference between Th1 and Th2 cytokines?
Th1 activate cell mediated immunity (IL2 and IL15)
Th2 are responsible for Ab production (IL4, IL10 and IL13)
What is the significance of Th1 and Th2 ratio in disease presentation, give an example?
Balance between Th1 and Th2 can decide a disease presentation or clinical course
Tuberculoid leprosy (small skin rashes) - Th1 response
Lepromatous leprosy (large disfiguring lesions) - Th2 response
Immune treatment of MS (Th1 disease) with Th2 cytokines can results in development of Graves’ disease (Th2 disease)
What is the Ag of HIV and what forms the receptor for this Ag?
Ag is gp120 (glycoprotein 120)
CD4 forms the receptor for this Ag, HIV virus invades the CD4 cells by using the CD4 molecule as an anchor to attach it to the cell
What kind of virus is HIV and how does it work?
Retrovirus
Has an RNA core, injects its RNA and reverse transcriptase in to the cell and forces the cell to make RNA into DNA and make viral proteins and forget about its own function with the net result of HIV replication
Massive increase in virus and death of CD4 cells
What is the course of B cell activation by T cells?
1) Ab triggered when B cell encounters it’s matching Ag
2) B cell takes in an Ag and digests it
3) B cell displays Ag with MHC II
4) T cell binds to this complex and secretes lymphokines which allow the B cell to multiply and mature into a plasma cell
What kind of organisms do humoral immunity and cell mediated immunity target?
Humoral = extracellular organisms
Cell mediated = intracellular organisms
How are such a wide variety of variable regions of Ab made?
Constant region of Ab made from same genes
Variable region is made my mixing and matching from a set of V,D and J gene segments
What is the structure of an IgG Ab?
2 heavy chains and 2 light chains, bound by disulphide bonds
2 identical variable binding regions (Fab)
Tail constant region (Fc) which can bind to Fc receptors on surface of immune system cells such as macrophages
What is the structure of IgM?
Pentamer structure, 5 Abs attached together, good at activating complement cascade
What region of an Ab changes during class switching?
Constant region of the Ab heavy chains (light chains have constant regions but these arent part of Fc region)
What signals cause B cell to alter type of Ab made?
Helper T cells release different kinds of cytokines - in this way CD4 cells direct the Ab against the specific type of pathogen that has been encountered
Where does class switching take place?
Germinal center of lymphoid organs (in secondary follicles in cortex of lymph nodes or in germinal centers that form around follicles in spleen)
Where do B cells develop and then travel from there?
Develop in the bone marrow
Circulate through the blood to reside in B cell areas in lymphoid tissue
What are naive B cell?
B cells that have never encountered their Ag before
Where are naive B cells first exposed to their Ag?
In lymph nodes by APC
In illness why do swollen lymph nodes occur?
B cells proliferate in the lymph nodes where they have been exposed to their Ag
Where in lymph nodes are B cells found?
In the cortex
In primary and secondary follicles
Secondary follicles contain a germinal center within which B cells proliferation takes place
What is filtered by the lymph nodes and by the spleen?
Lymph is filtered by the lymph nodes
Blood is filtered by the spleen
Where in the spleen are B cells found?
Located in follicles, germinal centers (where B cell proliferation takes place) form around the follicles when B cells are activated by their Ag
What is somatic hypermutation?
In restricted regions of V,D and J segments polymerase and repair mechanisms are prevented from keeping rate of mutation low and mutation frequency can be as high as 1 in 1000
Where are T cells made and matured?
Made in the bone marrow but mature in the thymus gland
How is T cell tolerance achieved?
POSITIVE SELECTION IN THE CORTEX
1) T cells enter the thymus where they proliferate in the cortex
2) At this stage they start expressing either CD4 or CD8 co receptors
3) They undergo positive selection where they must recognise MHC molecules presented with peptides
4) If they survive they stop expressing either CD4 or CD8 and undergo negative selection
NEGATIVE SELECTION IN THE MEDULLA
1) To survive they must not recognise self antigens
2) Any that do recognise self antigens are triggered to die by apoptosis
How is B cell tolerance achieved?
1) B cells become tolerent in the bone marrow
CLONAL DELETION
1) When cells encountering self antigens are recognised, the parent clone is deleted
RECEPTOR TOLERENCE
1) Persistent exposure to self Ags means you become tolerant of them and dont attack them
What are the 2 components of central tolerence?
1) Positive and negative selection of T cells in thymus
2) Clonal deletion and receptor tolerance of B cells in bone marrow
What is peripheral tolerence?
1) B cells can undergo anergy if they recognise an Ag but dont recieve a second signal from CD4 cell
2) T cells can undergo anergy if they dont receive the second CD28-CD80 signal
What happens when central and peripheral tolerance fails?
Autoimmune disease
Organ specific - Thyroid disease, Type 1 DM, Pernicious anaemia (Ab against chief cells in stomach)
Non-organ specific - SLE (systemic lupus erythematosus)
What is the role of dendritic cells in infection?
1) Encounter invading pathogen in peripheral tissue, become activated by cytokines released by other cells
2) Activated DC’s phagocytose bacteria and process the Ag presenting them with MHC II
3) Activated DC’s travel to nearest lymph nodes where they present Ag to virgin T cells which become activated and proliferate and migrate into tissues
What is the difference in the work of macrophages and dendritic cells?
Macrophages remain in the tissues to fight invading pathogen while dendritic cells travel to lymph nodes
Macrophages present the Ag-MHC II complex to T cells when they reach the peripheries whereas dendritic cells do so in the lymph nodes
What kind of B cells can act as APC (simply to activate T cells)?
Experienced B cells (those that have encountered their Ag before) - responsible for rapidly activating T cells when Ag is encountered a second time
How is the affinity of Ab binding increased?
Somatic hypermutation
