:L:L Flashcards
structure of antibody?
- antigen binding site is combination of light chain and heavy chain
- Fragment antigen binding is at the top
- Fc is at the bottom: determines role of antibody (if IgE / IgM etc)
- how does immune system recognise pathogens?
- whats an antigen? different types? [2]
- immune system recognises pathogens by responding to non-self (self v non self)
- antigens: anything that elicits immune response
- self antigen: immune system responds to self :(
- foreign antigen: antigen from outside body
what are the receptors found on lymphocytes? - explain basic overview of adaptive immune system
what receptors found in innate immune system? on which cells/
- *adaptive immunity:**
- lymphocytes are covered in receptors:
- *- antigen specific T cell receptor (TcR):** two types - αβ and γδ (gamma delta)
-
antigen specific B cell receptor (BcR): immunglobin on B cell surface
1. once B or T cells is activated by recognising antigen: resting cell -> activated cell. massive cell division. makes cytokines, come killer cells and make antibodies - *innate immunity:**
- phagocytes, macrophages & neutrophils receptors:
- *- pattern recognition receptors (PRR)
- Fc receptors**
- response immediately
explain mechanism of skin macrophages producing cytokines -
cytokines -
skin macrophages:
- covered in molecules (Toll like receptors) that recognise pathogen associated molecular patterns (PAMPs) (things only found in bacteria / viruses like flagella)
- signalling through Toll like receptors causes them to be activated and make pro-inflammatory cytokines
- produce cytokines (TNF-a & IL-1B). cytokines work on endothelial cells - make luminal surface sticky: causes neutrophils to stick (how they know where to go)
what is inflammation?
when white cells leave the blood and move into the tissues - in process of gettting rid of pathogens, kill normal tissue too
what happens when a B cell become activated?
when B cell activated:
- divide lots (aka clonal expansion)
- B cells can become:
- plasma cells (make antibodies)
- memory cells
when T cell activated:
- clonal expansion (due to IL-2)
what controls T cell clonal expansion?
IL-2
what is an immunogen?
what is an epitope?
immunogen: anything that elicits an immune response - most (but not all) antigens are immunogens
epitope: portion of antigen that is recognised and bound by a receptor on an immune cell
how do innate immune cells recognise antigens?
how do u describe innate immune cells’ response to self?
have Pattern Recognition Receptors (PRRs) recognise Pathogen Associated Molecular patterns (PAMPs) (structures found in microbes but not people - limited no. of structures)
- can be on surface, in lysosomes or cytoplasm
inherent lack of response to self (tolerance) - antigens arent present
what are Toll like receptors?
which TLR recognise flagella and LPS?
what happens as a response to TLR engagement?
- *Toll-like receptors: examples of PRRs:**
- TLR-5: recognises flagella
- TLR-4: recognises LPS (on gram-negavtive bacteria)
get both them on plasma membranes and in lysosomes.
TLR engagement:
- dimerization of receptor
- activation of kinases
- activation of TF
- causes production of cytokines
how do B cells recognise antigens?
- B-cells have recognition molecules called immunoglobins (Ig): often the eptiope is conformational
- B-cells recognise antigens directly (without help of other cells)
- activated B cells differentiate into plasma cells: secrete immunglogulin (‘antibody’)
how is the great number of receptor diversity generated on antibodies?
- each developing B cells expresses a distinct receptor
- not different genes for millions of different receptors
- INSTEAD: diversity is generated by mixing and matching gene segements within the heavy and light chain loci:
- Immunglobin heavy chain has:
a) V segments (40); b) D segments (25); c) J segments (6)
- get splicing of each of ^ to make lots of different genes: combinatorial diversity
- also: additional nucleotides can be added at the joints of ^^ to make more variation: junctional diversity
THEN:
any of immunoheavy chain stuff can associate with any of the light chains: more diversity: combinatorial diversity
how do t cells recognise antigens? what are the distinguishable features?
- use TCR - T cell receptor
- T cells are presented antigens by antigen presenting cells (APCs): recognise linear antigens
- The APC presents the antigen to the T cell using the major histocompatability complex (MHC)
how does antigen recognition differ between T cells and B cells?
- T cells: use APCs, B cells do not
- T cells recognise short, linear peptide antigens, B cells recognise conformational epitopes
what is the structure of T cell receptor like?
- two chains: alpha and beta chains
- both chains have a constant (same between all TCR) and a variable region (different: recognises different antigens)
- antigen recognition with the peptide and MHC happens at the top
what are the two types of MHC cells? which cells express each type?
- *MHC Class 1**: expresed by all cells. made from:
- alpha chain with 3 domains
- peptide-binding cleft between a1 and 2 (see slide)
- alpha chain is encoded by MHC.
- alpha chain associates with B2 microglobulin
- *MHC Class 2:** expressed by APC cells only
- alpha and beta chains (both formed by cell)
- peptide-binding cleft: formed from B1 and alpha1
Both have peptide-binding cleft: but the fit between the amino acid side chains inthe peptide and the grove of MHC molecule determine binding
what are the properties of MHC that ensure the maximum number of peptides can be presented?
- *1. MHC genes are polygenic**: more than one type of MHC class I and MHC class II molecule - can present slightly different range of peptides
- *2. MHS genes are highly polymorphic**: multple alleles in the population mean that most people are heterozygous for MHC genes. (as a result - mother and father MHC genes are likely to be different - its this what is a barrier to organ transplant)
polygenic and polymorphic of MHC genes ensures mutlple different MHC molecules expressed, increasing the reportoire of peptides that can be presented
what is immunlogical tolerance?
immunlogical tolerance: the immune system attempting to eliminate self reactive cells that recognise self as antigens
removal during development: central tolerance
control when out in the body: peripheral tolerance
* overview of how general immune response works, e.g. for cut in the arm? *
make cells in: bone marrow (B-cells) and thymus (T-cells, CD4 & CD8) - primary lymphoid tissue. sit there until immune response required
cut happens:
- inflammation - acute localised inflammation iniates immune response
- blood vessels becomes leaky at site of injury - swelling from also makes lymph node swell
- lymph node acts as a net (draining lymph node) - catching anything thats come in from site of injury
- dendritic cells go from cut site to the draining lymph node - hold out pathogen in MHC molecules - recognised by T cells
- *- T cell clonal expansion**
what is general difference between response for extracelluar vs intracellular pathogens?
extracellular: humoral immune response. secretion of:
- antibodies
- complement proteins
- antimicrobrial peptides
intracellular: can’t secrete cuz pathogen is inside cell
- cytotoxic t cells
- NK cells
- T cell-dependent macrophage activation
which is the Fc end of an antibody - what does it do?
- Fc - bottom of Y bit
- dictates the function of antibody once bound to antigen
- has different isotypes: IgM, IgD, IgG, IgA, IgE
where are the variable regions of antobody?
what is the miracleof the immune system?
fragment antigen-binding (Fab fragment)
miracle of immune system:
- have billions of different B cells
- each one secretes a different antibody molecule
- so we have all antibodies which recognise nearly ALL possible pathogens - mixing and matching of genes
role of dendritic cells?
- dendritic cells go around tissue, continually monitoring and assessing environment by processing proteins into peptides.
- in prescence of pathogen - PAMPS are activated by dendritic cell.
- dendritic cells go down afferent lympahtics to lymph nodes
- hold proteins out on MHC Class 1/2 molecules.
- if recognised by CD4/8 - clonal expansion and cytoxic fun happens
what are 5 roles of antibodies once activated?
- neutralization
- agglunation (the clumping of particles)
- Opsonization: coat pathogens that allow other immune cells to come and kill
- antibody dependent cell killing
- activation of compliment cascade
what is affinity maturation? where occur?
making better antibodies:
when a B cell makes an antibody a ‘better-fit’ to an antigen. Occurs at the germinal in lymph node and spleen
what is the complement cascade?
another system of secreted proteins that is good at getting rid of extracellular pathogens, like bacteria.
- surface of bacteria can bind to complement proteins
- forms a pore on bacteria
- pops them !
The complement system, also known as complement cascade, is a part of the immune system that enhances (complements) the ability of antibodies and phagocytic cells to clear microbes and damaged cells from an organism, promote inflammation, and attack the pathogen’s cell membrane.
which cells work agaisnt:
- cytoplasm? (2)
- vesicular?
- cytoplasm: cytotoxic T cells (AKA CD8 T cells), NK cells
- vesicular: T cell dependent macrophage activation
what do we call the immune response that targets intracellular pathogens?
cell mediated immune response
how do CD8 / cytotoxic T cells recognise pathogensi on a cell? what happens after
- CD8 T cells have a T cell receptor (TCR) and the CD8 co-receptor
- they kill pathogen infected cells and tumour cells by:
- recognises peptide-MHC-I combination that has been presented on the cell (its the same peptide that the dendritic cell initiailly caused clonal expansion to occur by)
- cell death by apoptosis.
i) nuclear blebbing
ii) alteration in cell morophology
iii) shedding of small membrane vesciles
iv) apoptotic bodies removed by phagocytosis
what are the three types of lytic granules that CD8 cells have? [3]
have lytic granules (modified lysosomes), containing:
- perforin: forms pores in cell membrane
- granzymes: bind to proteins in cell membrane to get into cell and then: proteases start chopping up proteins in cell.
= apoptosis
what is the mechanism for cytotoxic / CD8 cells knowing which exact target cells to bind to?
- CD8 cell comes close to potential target cell
- creates a non-specific adhesion with the target cell
- then, the TCR binds with MHC-I (which holds pathogen peptide)
- once activated by TCR, get reorganisation of the microtubule organising centre, and GA, lytic granules in the CD8 cell, to line up close to TCR-MHC-I
- lytic granule release occurs
- apoptosis
what are NK cells? - what type of cells are they?
how do they kill cells/
which part of immune system are they part of?
Natural Killer cells: innate immune system
- lymphocytes
- DO NOT have antigen-specific receptors :o
- have lytic granules in them.
kill cells in same method as CD8 cells (using perforin and granzymes and inducing apoptosis)
hat is difference between resting NK and activated NK cells?
what activated by?
- Resting NK cells: can kill cells
ACTIVATED BY CYOTKINES:
- ‘activated’ NK cell: kill 20-100 x more efficiently. produce more lytic granules and IFN-y
how do activated NK cells know that a cell is infected? concept of missing self H:?
what happens when NK cell recognises cell as self or not self?
when does an NK cell cause apoptosis?
use: missing-self hypothesis:
- recognition of ‘self’ = inhbition of killing by NK cells
- recongiition of ‘missing-self’ = killing by NK cells (if not from self - could be from transplant, OR if pregnant - also ‘not from self’ from embryo cells)
SO:
- NK cell recognises that the MHC-I molecules is from own body -> inhib. receptor on NK cell switches off the NK cell
or
- NK cell recognises that the MHC-I molecules is from pathogen (not self) -> inhib. receptor on NK cell still switches off the NK cell
therefore - cytotoxic cells come along instead and kill
BUT: some viruses cause MHC-I cells to be trapped inside the pathogen infected - so cant recognise it.
- but because the MHC-I cells arent present on infected cell, the inhibitory receptors on the NK cells dont recognise the cell as self - cause apoptosis.
which T cells are the conventional cells, which are unconventional?
- *conventional: T helper cells** (CD4+), Cytotoxic T cells (CD8+)
- *unconventional T cells:** NKT cells, intraepithelial lymphocytes, yg
how do CD4+ cells recognise antigens?
what happens afterwards (differentation?)
- T cell has T cell receptor (TCR)
- Antigen presenting cell (APC) presents antigen to TCR via MHC-Class II molecule
- cell division: all have same TCR that can recognise same pathogen = activated CD4+ clonal expansion: turn into CD4+ Th0 cells:
- cytokines turn CD4+ Th0 cells into either:
- *1. CD4+ Th1 Cell
2. CD4+ Th2 Cell**
as a result, make different products:
- CD4+ Th1 Cell: IFN-y & TNFa: - triggers cell mediated immunity (to target intracellular pathogens, using CD8+, NK & macrophages)
- CD4+ Th2 Cell: IL-4, IL5, IL-13: triggers humoral immunity (extracellular pathogens - B cells & lots of proteins)
Th-1 response is neccesary to keep what type of infection under control?
TB !
CD4+ cells help the immune system to wall off the infected macrophages and bacteia - creates caseating granulomas
how do CD4+ Th2 Cells help immunity/
- produce IL-4, IL-5, IL-13
- help B cells to make antibodies
- this drives humoral immunity
how does CD4+ Th2 cell know which B cell to help? explain the mechansim xox
T-cell helper link recognition:
- dendritic cell takes up antigen, chops in smaller peptide and places onto MHC-II
- CD4+ cell recognises MHC-II, undergoes clonal expansion and differentiates into CD4+ Th2 cell.
- CD4+ Th2 cell helps B cell to help make more specific antibodies
- B cell, when not activated has antibody on cell surface (B-cell receptor), binds the antigen directly, chops into smaller peptide and places onto MHC-II
- CD4-Th2 cell binds to (peptide-MHC-II & TCR) on BOTH the dendritic cell and B cell that have same antigen on MHC-II
- B cell makes then IgM, IgG etc
how do Th0 cells know whether to turn into Th1 / 2?
CD4+ Th0 cells turn into CD4+ Th1 Cells due to the prescence of IL-12 & IL-23 (secreted by dendritic cells, if seen bacteria and viruses due to pamps)
CD4+ Th0 cells turn into CD4+ Th2 Cells due to the prescence of IL-4 (itself is secreted by mast cells)
what is Th1 vs Th2 response to allergies?
- Th2 responses lead to IL-4, which leads to IgE, which causes allergies
what do the subfamily of cytokines, chemokines, involved specifically in/
- *involved in cell movement:**
- migration along a chemokine concetration gradients provide a directional movement (can be agaisnt or with gradient)
- signal using GPCR: can bind to multiple different chemokines
- small polypeptides
- control adhesion, chemotaxis and activation
how can cytokines promote or limit immune responses?
- can be inflammatory (IL-1, TNFa) or anti-inflam (IL-10, TGFb)
- good immune response will have an appopriate balance of these
explain the role of cytokines in acute inflammation
- damage and infection stimulates inflammation
- resident macrophages and injured tissues initiate inflam. response
- *- inflam cytokines and chemokines drive leukocyte recruitment**
- neutrophils and moncytes come in and fight infection
- T and B cells come in later
how do cytokines drive the recruitment of immune cells (when endothelium is damaged)? (3)
what do TNFa and chemokines do specifically?
- *1. tethering:** cytokines make the lining the BV more sticky
- *2. rolling and activation:** chemokines activated adhesion molecules and allow rolling arrest
- *3 diapedesis & migraton:** cause cells to flow in to cells within tissues
- *TNFa**: increaes stickiness of endothelium by increasing expression of adhesion molecules:
- rapid release from Weibal-Palade bodies (WP) (adhesion molecules)
- new synthesis of TNF molecules
- *Chemokines**: activate adhesion molecules to increase binding
- causes rearangement of adhesion molecules on surface of cell, to bind more strongly to vessel wall.
how do cytokines work in T cells clonal expansion
- cytokine activation causes both production of IL-2 and expression of a high-affinity IL-2 receptor
- example of autocrine cytokine signalling
- IL-2 on T-cell receptor drives cell proliferation / clonal expansion
how do cytokines from T cells help B cells make antibodies?
- cytokines from T cells help B cells make antibodies:
- provide signals from helper T cell, to make the differentation of B-cell -> Plasma cell
- cytokines from helper T cell also influence class switching (change on antibody production) (e.g IL-4 increases IgE).
describe difference between local bacterial and widespread bacterial infection with regards to no. of cytokines produced
local bacterial infection:
- local, controlled: production of TNF-a, IL-1 and IL-6 is GOOD
- causes fever, bone marrrow production of immune cells
- limited stimulation
widespread bacterial infection (sepsis)
- *- ‘overstiumulation’ and septic shock of TNFa, IL-1 and IL-6 is BAD**
- also can occur from superantigens: toxic shock syndrome
what is a cytokine storm?
which diseases does it occur in?
cytokine production becomes uncontrolled to a potentially fatal positive feedback loop:
- *- cytokine stimulates immune cell
- immune cell produces cytokine**
what is difference between immune reponse in normal v asthma / allergy ?
normal:
- niave CD4+ T cell in presence of IL-4 = Th2 cell
- Th2 cell produces more IL-4, which induces B cell to class swich to make IgE
- IgE binds to mast cells, which, if comes into contact with antigen that induced B cells, causes degranulation
asthma:
- overproduction of IL-4 -> drives allergies and asthma
- its the release of the degranulation by mast cells that causes response
- if have an allergy: subsequent exposure are rapidly released (why get really quick response)
what are major challenges of administering cytokines in the clinic?
- short half life - hard to attain an effective dose
Examples:
- Interferon a: (aka Roferon); used for Hep B infection
- GM-CSF: (aka Leukine): used to stimulate production of myeloid cells after bone marrow transplantation
how can u subclassify leukocytes?
- *agranular:** lymphocyte & monocyte
- *granular:** neutrophil, basophil and eosinophil
role of basophil?
appearance?
Large dark purple cytoplasmic granules that often obscure the bilobed nucleus
The granules contain:
Histamine (vasoactive substance which promotes vasodilation during inflammation)
Heparin (an anticoagulant which prevents clotting
Eosinophil: appearance & function?
Bilobed nuclei with red/orange granules in cytoplasm
Involved in the defence of parasites e.g. helminths (worms) and protozoa.
Raised in allergic responses therefore eosinophilia is usually seen in allergic diseases such as asthma, hayfever and eczema (atopic triad)
lymphocyte - appearance & function?
types?
Large purple nucleus and a small rim of surrounding cytoplasm (high nuclear to cytoplasm ratio) and are mainly raised in viral infections.
Two types:
B lymphocytes (mature in bone marrow and involved in antibody production)
T lymphocytes (mature in the thymus and include CD4 T helper Cells and CD8 cytotoxic T cells).
Have the longest life span of any leucocyte since some cells can become memory cells and therefore live for many years.
Neutrophil- role and appearance?
Nucleus has 2-5 lobes
Accounts for the majority of leucocytes in the blood (60-70%) and hence are the first cell type to be raised in any type of acute inflammation.
Important in dealing with bacterial infections, therefore there is neutrophilia whenever bacteria infection the body.
monocyte - appearance & function?
Kidney Bean shaped nucleus
Turns into a macrophage when it moves from the blood into the tissues.
Involved in phagocytosis and antigen presentation to T lymphocytes in the lymph nodes via MHC molecules
whats a reticulocyte?
Reticulocytes are immature red blood cells produced in instances of increased red blood cell break down e.g. haemolytic anaemias and contain ribosomal RNA which is why they appear blue on the blood film.
Megakaryocyte - function & location?
Location: Bone Marrow Function: Makes Platelets
