immune anatomy/dealing with antigens - block c Flashcards

Question

positive selection

Answer 1

t cells don't have enough affinity don't receive 'survive signal' - death by neglect selects for t cells with tcr of moderate/high for mhc ensures mature t cells can recognise mhc and antigen in periphery

Answer 2

removes t cells that bind too strongly ensures self reactive t cells are clonally deleted

Answer 3

t cells with too low an affinity for self-MHC undergo death by neglect t cells with too high an affinity for self-MHC are deleted by signals for programmed cell death – or “apoptosis Positive selection leaves cells that interact with antigen, but not too strongly

Answer 4

high affinity for self antigens presented by mhc

Answer 5

different mechanisms exist to ensure that mature t cells dont activate inappropriately remember how t cells are activated - multiple signals needed - recognition of antigen via tcr - mhc complex and presence of cd4, co-stimulatory molecules, and eventually cytokines this is where the innate system plays a role - the early innate danger signals upregulate apc co-stimulatory molecules eg. cd40 for b cell, cd28 for a dc, lack of costim --> anergy

Answer 6

antibodies bind antigens on surface of target cells receptors recognize cell bound antigens cross linking triggers degranulation target cell dies due to apoptosis

Answer 7

antigen is taken up by phagocytes in the process of phagocytosis it is taken from extracellular space and stored in intracellular vesicles (endosomes) endosomes are inactive - until macrophage is activated - ph is decreased (acidified) activates proteases which degrade antigens into peptide fragments vesicles containing peptide fragments fuse with vesicles containing MHCII

Answer 8

antibodies and t cell receptors recognise through very diff mechanisms epitopes recognised by t cells can be any portion of the protein and can be buried within by contrast antibodies recognise things i their 3d conformations and must be on the surface t cells can because the antigen has been chewed into smaller pieces and presented to it

Answer 9

the sequences of amino acids determines shape of peptide MHCI and MHCII interact with molecules on the MHC binding cleft and form covalent bonds there are other differences between the two, but this principles is the same

Answer 10

In this case, the endogenous antigen comes from a virus – e.g. Covid The virus binds to the surface of the cell and infiltrates it, translocating to the nucleus where it can start its replication During this replication, it will produce and release proteins into the cytoplasm e.g. spike proteins These are then degraded into small peptides (8-9 amino acids long) by a proteasome which are loaded into peptide transporters (TAP-1 & TAP-2) MHC produced in the RER associates with molecular chaperones including β2M and binds peptide The complex is then transported via the golgi to the cell surface for presentation to a CD8+ T cell

Answer 11

Now lets look at exogenous antigen – e.g. allergen, or a protein from a pathogen Taken up and degraded by phagocytosis in endosomes MHCII is assembled in the ER, packaged in endosomes and trafficked via golgi When it encounters peptide containing endosomes they fuse, and antigen can be loaded onto MHCII This is then transported to the surface in a similar manner to MHCI Antigen is now being presented to CD4+ T cells in the context of MHCII

Answer 12

the majority of t cells are helper cells - aim to direct, help or orchestrate the cell mediated immune response also regulate the b cell response to antigen eg. virus infects the cell and produces proteins in the cytosol these are then shipped through the golgi, bind to MHCII and are presented on the cell surface

Answer 13

Able to process a wide array of pathogens not just viruses Receptor mediated phagocytosis – could be e.g. a TLR, or when the antigen is bound by antibodies or complement. Macropinocytosis – direct uptake of soluble antigens or virus particles in the milieu Cross presentation – where receptor mediated phagocytosis has occurred, but antigen has been released into the cytosol Transfer – where an incoming DC transfers to a resident DC

Answer 14

MHCII is often said to be expressed by “professional” antigen presenting cells Discussed later – but these “professional” APCs not only express MHC, they also express co-stimulatory molecules Antigen presentation via MHC is often not enough to stimulate CD4+ or CD8+ T cells – co-stimulation is also required Professional APCs include B cells, macrophages, DCs and epithelial cells

Answer 15

Remember, these deal with intracellular pathogen e.g. viruses Viruses can infect every cell of the body – nerve cells, liver cells, kidney cells etc can all be infected by viruses The body needs to be able to recognize which cells have been infected with a virus and then be able to respond Essentially every cell in the body (with the notable exception of red blood cells – no nucleus) can express MHCI and present antigen to T cells Some cell types are better at this process than others

Answer 16

High diversity in the MHC haplotypes (everybody's MHC has different genetics) within the population The progeny within a species have further increased diversity > Increases the range of peptides presented to the immune system within species Reduces the chance of pathogen evading the immune system If everyone had the same MHC haplotype, the species as a whole would be susceptible

Answer 17

MHC polymorphism affects how antigens can be recognised by T cells. MHC binding the antigen is not the only determinant of “fit” There are also contacts between the TCR and MHC, and between the peptide antigen and the TCR All 3 of these must match for the fit to be correct, and for recognition to occur >

Answer 18

Adaptive immune system takes time to respond Immune responses occur in different locations Requires cells to move, interact and produce cytokines to influence effector function Although it takes time, this is needed as we need different immune responses in different locations at different times

Answer 19

It starts with the entry of the pathogen near the origin It might be dealt with quickly by innate response, and so we might need to induce adaptive immune response However, if the microorganism is not dealt with quickly by the innate immune system it will start to establish an infection Once we reach the inductive phase, DAMPs are produced and PAMPs will further enhance response – the body resident APCs now know to fetch T cells The effector phase is reached once activated T cells are brought back from lymph and this begins to clear the infection Finally – memory may be induced and shorten this

Answer 20

The immune system is activated by inflammatory inducers that indicate the presence of pathogens or tissue damage Innate immunity is normally initiated within minutes, and the initial response can be seen within hours The adaptive immune response takes over later, with a variable timeline that could span days-weeks, even to years if it can’t clear the infection Finally, we have the critical induction of memory including the production and maintenance of memory T cells

Answer 21

once t cells have recognized the antigen, the apc will send signals - starting proliferation signals sent through upregulation of IL-2 receptors and production of its own IL-2 receptors the IL-2 cytokine binds to its receptors on the T cell - this is the signal for proliferation other signals - such as IFNy (interferon gamma) instruct the cell to differentiate and kill

Answer 22

one effector function of helper t cells is to assist b cells in making antibodies in addition to specialized apcs, b cells can also present antigen and activate t cells the signals induce production of IL4, IL5, and IL6 which tell b cells to proliferate these can then differentiate to resting memory cells or antibody secreting plasma cells

Answer 23

Th1 - secretes IFNy and activates macrophage functions Th2 - secretes IL4 and helps antibody production

Answer 24

Th17 cells are important in response to extracellular bacteria and production of neutrophils Tfh are found in the germinal centers and help b cells produce antibodies treg cells downregulate immune response and prevent harmful immune responses

Answer 25

activation via tcr antigen mhc co-stimulation (CD28) appropriate cytokines signal

Answer 26

bcr structure is a surface bound version of ig when b cell is activated, secretes antibody of same specificity once b cell expresses functional bcr, matures from primary bone marrow and enters periphery migrates via lymph nodes

Answer 27

recognition of antigen by bcr leads to activation once internalized, antigen is broken down to peptides peptides are loading into mhc-II within the b cell and presented to antigen-specific CD4+ T cells if t cell also recognizes antigen, provides help to b cell (costim) allows b cell to fully activate and secrete antibodies

Answer 28

b cells can only produce one antibody on recognition the bcr will undergo endocytosis and be degraded along with the antigen it will the load the epitope onto MHCII and express antigen on the cell surface at high density here it can interact with a t cell that also recognizes the antigen

Answer 29

CD4 helper cells provide help to b cells via CD40 t cells can influence antibody production through secretion of cytokines induces proliferation of b cell and differentiation

Answer 30

Linked recognition by T and B cells is important in ensuring a robust and appropriate antibody response – but DCs can also play a part Here, the DC uptakes antigen, breaks it down and presents it via MHCII to a CD4+ T cell If a B cell recognises the surface epitope of that antigen as well it can also process it, but it can also present other epitopes – linked recognition Downstream, TFH cells can provide help after recognising a linked epitope

Answer 31

Variable region binds to specific antigen Different antibodies recognise/bind to different antigens or different parts of antigens Binding site of antibody is known as the epitope - Can be linear sequence or based on antigen-folding

Answer 32

Neutralisation Opsonisation Complement All depend on antigen-specific binding of the variable region Different functions are associated with the constant region Depends on the isotype of antibody secreted by the B cell Binds to Fc receptors on effector cells

Answer 33

Involves the antibody binding bacterial (or other) toxins Prevents the interaction of the toxin with its target protein and thus prevents damage The antibody complexes can then be ingested by a macrophage and destroyed

Answer 34

A response to bacteria in the extracellular space e.g., in serum or tissue fluid Antibodies bind to the surface of bacteria, coating them The constant region of the Ab is free to interact with Fc receptors on the surface of macrophages This triggers the ingestion and destruction of the bacteria

Answer 35

A response to bacteria present in plasma Complement is a cascade of enzymes which punch holes in cell membranes by assembling an MAC (membrane attack complex) As before, Abs coat the pathogen – but this time they recruit complement proteins which puncture and kill the pathogen The remains can then be taken up by a macrophage

Answer 36

High affinity IgG and IgA antibodies can neutralize toxins and block the infectivity of viruses and bacteria Viruses can bind receptors on the cell surface, and become endocytosed Once inside the cell, the virus can release its own DNA into the cell, and attempt to take over the host cells cellular machinery for replication Antibodies can prevent all of this by binding to the receptor and preventing entry You can see where vaccines and mAb therapies exploit these mechanisms

Answer 37

In the classical complement activation pathway, antigen-antibody complexes bind to complement component C1q, which initiates the complement cascade Here, we see how tertiary Ab structure contributes to this activation. IgM is most stable (and most common) as a pentamer – it can bind many antigens at the same time and a single structure is required for C1q binding. In the case of IgG, it exists as a monomer, and multiple IgGs are required to bind C1q

Answer 38

If a T cell escapes clonal deletion in thymus and isn’t tolerised in periphery, it can become activated… To non-harmful antigens > allergy An example of this is celiac disease, where antibodies are produced against the harmless gluten in wheat following erroneous T cell “help” The resultant inflammatory response in the gut causes damage in the gut – “enteropathy” Villi (responsible for nutrient absorption) are lost, the epithelium becomes leaky, and there is an increased number of goblet cells (produce mucus) can also respond to inhalants or self antigens

Answer 39

Genetic factors are known to predispose people to both allergy and autoimmune disease However, about 40% of us carry the gene that predisposes us to allergy, and few develop these Likely that environmental factors and infection also play a role A good example is ankylosing spondylitis, an autoimmune condition against MHC If a person harbours the gene that predisposes them to ankylosing spondylitis and they are infected with the bacterium shigella, it is likely they will develop the autoimmune condition This is likely due to a degree of cross-reactivity, but also because of innate activation > danger signals > increased co-stim. expression.

Answer 40

central tolerance - selects cells based on affinity, - approx. 95% of cells deleted, failing positive selection or negative selection prevents immune responses to other antigens, E.g. food antigens, ‘good’ bacteria, autoantigen, Peripheral tolerance usually works because danger signals are lacking – no PAMPs or DAMPs, so no upregulation of costimulatory molecules, normally > anergic T cells it is only in rare situations where you might have a danger signal being encountered at the same time as these antigens that you will go on and make an immune response

Answer 41

Immunodeficiencies - Primary (genetically acquired) Secondary - Infections e.g., HIV, Metabolic dysregulation, Therapeutically-induced (e.g., chemotherapy) Immune-evasion by pathogens

Answer 42

the parasite that causes sleeping sickness These trypanosomes have an antigen coat on them, called the VSG (the variant surface glycoprotein) Much like the immune system, they are encoded by many genes which can recombine to produce lots of different forms of these VSG In this way, as the immune system begins to mount a response towards the VSG antigen, they start to recombine their VSGs Once these are selected out, a new type of VSG will have become predominant – and so on and so forth The parasite changes its antigenic markers to stay a step ahead of the immune response and evade it

immune anatomy/dealing with antigens - block c Flashcards

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