Microbes and Immune System Flashcards

Question

What is Quorum sensing? And how is it useful to the Hawaiian Bobtail Squid and the A. fischeri?

Answer 1

Quorum – specific/minimum number _Quorum sensing_ * Bacteria sensing their population size and coordinating their behaviour (biofilms formation, virulence, antibiotics) * Behaviour changes depending on low or high cell density In the A. fischeri emitting light is an energy expensive process and only emit it when the bacteria use qurorum sensing to decide whether there's enough of them for the light to impact the host (Hawaiian Bobtail Squid). The Individual behaviour is different from group of organisms - multicellular

Answer 2

Quorum sensing relies on autoinducers (AI) to sense the environment population. Once a threshold has been reached, AI’s activate cellular process to respond to the environment – luminescence within the A. fischeri

Answer 3

The lux operon controls the production of light in A. fischeri. 1. LuxI – synthesises AHL. At low A. fischeri densities, the AHL diffuses out of the cell and no light is produced. 2. However, at high A.fischeri concentrations, there are also higher concentrations of AHL which can then re-enter the bacterial cell and bind to luxR. 3. The binding of AHL to LuxR activated transcription of luxC, luxD, luxA, luxB and luxE. 4. LuxA and luxB genes produce proteins which form luciferase. Luciferase then catalyses a redox reaction which produces light.

Answer 4

LuxR is the regulatory gene which produces transcription activator

Answer 5

A biofilm is a growth of organisms within a mucous bound film either in a substrate or on a surface. Majority of microbes to be in a sessile state. 1. They usually begin by colonising a surface. Here they can be easily detached. 2. At this point an Extracellular matrix has been produced (like sugars and peptides). 1. When the biofilm is fully formed. Quorum sensing detects growth slowing and aids biofilm dispersal and the cycle starts again,

Answer 6

Biofouling – fouling of underwater structures with micro/macroorganisms Can cause loss pf functionality in pipes, chains and bottoms of ships etc. The biofilming of microbes onto these surfaces allow for other higher lifeforms to latch on like barnacles etc.

Answer 7

They are usually more toxic to their environment.

Answer 8

_Restricts growth_ * Does not cater for organisms found in all environments * Laboratory environment is far removed from reality _Time consuming_ * Some organisms can take weeks to grow (Mycobacterium spp.) Therefore, it is approximated that we only know of 1% of all microbes that exist.

Answer 9

1. Extract all DNA from the population and digested into smaller fragments. 2. Cloned in to plasmid vectors before sequencing. 3. Data analysis to identify organisms.

Answer 10

Large and mixed population of microorganisms coexisting together under many circumstances.

Answer 11

Although we tend to consider study these organisms in pure culture, in nature they are infrequently found in isolation, but rather as dynamic communities, which compete for resources but frequently depend on each other for survival.

Answer 12

Commensal: on or in host without injuring or benefiting the host

Answer 13

* Commensalism: when a product produced by one organism can be used beneficially by another

Answer 14

* Definition: an organism that causes damage and disease to the host * Much smaller group of organisms

Answer 15

1. He said that to be a pathogen, the microbe must be absent in all healthy individuals but present in all diseased hosts. 2. It should be possible to isolate and grow the microbe in pure culture from all diseased patients and that if this microbe was then used to inoculate a healthy host, it should cause the same disease in that host. 3. And that finally it should be possible to reisolate the pathogen from the inoculated host. * These postulates are still valid today although recovery of the genetic material rather than the organism is now sufficient and resulted in renaming these as Kochs molecular postulates

Answer 16

The capacity of a microbe to cause damage in a host

Answer 17

* Virulence refers to the degree of damage caused by the microbe

Answer 18

* A product made by the organism that contributes to overall virulence (eg toxin)

Answer 19

_Tetanus toxin_ Released by C. tetani, following its growth within the anaerobic environment of a deep puncture wound. On release from the organism, the toxin binds to the peripheral neuronal axons and undergoes retrograde transport to the inhibitory interneuron, where it prevents the release of inhibitory neurotransmittors such as glycine and g-aminobuytric acid (GABA).

Answer 20

This prevents the deactivation of the neurone resulting in contraction in both agonist and antagonist muscles. This causes tetanic muscle spasm, an extreme example of which is shown here. The vaccine that is given to prevent disease results in antibody production that binds to the toxin, preventing its interaction with nerve endings. However, in the absence of such antibodies, mortality is high.

Answer 21

The capacity of these organisms to cause disease depends upon the opportunity they are given to cause disease hence the term ‘opportunistic pathogens. This may include the age the patient (with the very young and very old often being immunocompromised, antibiotic treatment that may reduce the presence of protective organisms, the prevalence of exposure, how much and in what form you are exposed to that pathogen, your host genetics and factors that influence your immune system including nutrition and stress

Answer 22

Many of the opportunistic infections on man are also zoonotic organisms in that these are diseases transmitted to man from animals Interestingly many of these microbes are commensals in the animals – only causing disease when they cross the species barrier. These include Campylobacter jejuni which is a common cause of diarrhoea in man, enterohemmorhagic E.coli or EHEC which causes kidney failure in children and rabies in bats, which is always lethal in man but can be carried without symptoms in bats.

Answer 23

Evolution in microbes is much more rapid than humans due to their high rate of multiplication. Under optimal growth conditions in a lab, there growth is rapid, with doubling times as short as 25 min under optimal conditions. This means that 1 organism can replicate to 100 million within 8h

Answer 24

* Alter sensitivity to particular drugs * Alter receptor recognition (of tissue) * Alter recognition by the host (immunity) However, this type of mutation does not explain how much larger pieces of DNA that encode specific virulence traits such as toxins are acquired.

Answer 25

1. In natural transformation, bacteria take up DNA from the environment, which depending on regions of homology between the DNA and the bacterial DNA may recombine and replace exitsing regions of the chromosome. 2. In conjugation, DNA is exchanged between bacteria through the formation of a conjugative pilus 3. And in transduction, genetic exchange is the result of predation by bacteriophage, small viruses of bacteria, which inject DNA into the cells as part of the infection process.

Answer 26

Occurs in bacteria that are naturally ‘Competent'. Occurs when ssDNA is released when bacteria die and lyse. The uptake of DNA and incorporation into genome of ‘competent’ bacteria is done through homologous recombination. ## Footnote Some become competent in response to quorum sensing compounds – released by bacteria – competency factors But if gene associated with antibiotic resistance – transformed bacteria will now be resistant

Answer 27

These competency factors modify the membrane to enhance uptake of single strand pieces of DNA, which due to the homology found in closely related species, allows rapid recombination into the bacterial chromosome. If the piece of acquired DNA encodes something like an antibiotic resistance gene, the clone with the acquired DNA will outgrow those bacteria that are not naturally competent.

Answer 28

* Conjugation in contrast to transformation is an active process that requires the generation of a conjugative link between two bacteria that allows the direct transfer of Dna from one bacteria to another. Conjugative plasmids found in bacteria, are self replicating pieces of DNA that encode tra genes, which are essential for the transfer of DNA. * Once of the best described systems of conjugation if the transfer of the F pilus in E.coli. * Exchange of DNA occurs when an F +ve organism carrying the plasmid meets an F- organism that does not have this plasmid. The F pilus encoded on the plasmid and expressed on the surface of the F+ bacteria, is used to initiate contact with the F- cell. On contact, a structure is formed between the two cells, through which the plasmid DNA is able to pass.

Answer 29

The tra genes found on the conjugative plasmid encode all the proteins necessary to make the the relaxasome, which is the structure through which the DNA passes.

Answer 30

DNA is transferred in a process known as rolling circle, with the DNA cut at a site close to the original of replication of the plasmid. The DNA is then drawn through the relaxasome, with DNA polymerase activity required in both cells to generate a second strand of plasmid DNA. Both cells now contain the plasmid and are capable of producing an F pilus and transferring their plasmids to other strains.

Answer 31

In some cases the plasmid may have regions that are homologous with the bacterial chromosome allowing direct integration of the plasmid through recombination. In this situation the integrated DNA can remain in the chromosome or can excise. Sometimes when they do excise, they do so imprecisely taking some adjacent bacterial chromosome DNA with them. The presence of this DNA means they are more likely to integrate at Higher frequency than normal conjugation. This is known as High frequency or Hfr transfer.

Answer 32

Transduction, a process of genetic recombination in bacteria in which genes from a host cell (a bacterium) are incorporated into the genome of a bacterial virus (bacteriophage) and then carried to another host cell when the bacteriophage initiates another cycle of infection.

Answer 33

They have 2 life cycles 1. The lytic cycle in which the virus binds to a receptor on the surface of the bacteria and injects in its genome. Like mammalian viruses, It then hijacks the cellular machinery of the bacteria to produce multiple copies of its genome that are packaging inside structural proteins also made by the bacteria. It then escapes from its host by lysis of its bacteria membrane 2. Bacteriophage are also also to undergo lysogeny, which occurs when the injected phage genome integrates into the host chromosome. In this form, it is replicated as part of the natural lifeccyle of the bacteria and is transferred from mother to daughter. However, if the bacteria becomes stressed or under threat, the intact phage can excise from the chromosome and reinitiate the lytic cycle that results in the production of intact and infectious phage.

Answer 34

Although the infection process, including the packing of the viral DNA into the structural heads of the phage is largely efficient, occasionally a piece of bacterial chromosomal is packaged into a phage head by mistake. These defective phage will be released from the bacteria during lysis. However, as the structure of the virus is unchanged, the defective phages are able to bind to any susceptible bacteria and the DNA inside the head injected into the bacteria by this molecular syringe. Once inside the cell, the DNA may or may not integrate into the bacterial chromosome. This type of transduction is known as generalised transduction

Answer 35

In contrast specialised transduction is linked to the lysogenic lifestyle that follows the integration of phage DNA into the bacterial chromosome and follows imprecise excision form the bacterial chromosome, that means that some of the DNA adjucaent to the site of integration is also excised and packaged, These chimeric phage that carry both viral and host DNA can transfer these genes to a new host. As a phage head can package up to 40kb of DNA, this offers a significant opportunity for DNA exchange

Answer 36

The best example of how acquiring DNA using these mechanisms can enhance virulence can be demonstrated using E.coli. E.Coli is considered as a commensal organism that lives in the gut. However, some strans of E.coli have acquired a plasmid that encodes 2 toxins, that cause toxin mediated diarrhoeal disease in humans Other strains have acquired a plasmid that encodes an adhesin that allows successful adhesion and mediates invasion into the epithelial tissues Enterohemmorahgic E.coli has acquired both the capacity to intimately adhere to the gut surface through gene found on an integrative plasmid and produce a toxin that was acquired through phage transduction. Similarly enteropathogenic strains cause damage and diarrhoeal disease through acquisition on mechanisms that allow increased adhesion by this organism

Answer 37

When large pieces if DNA are integrated they are known as pathogenicity islands and frequently encode structures such as the very elegant type 3 secretion injector that is important in the attachment of several medically important gut bacteria including Salmonella and Shidella.

Answer 38

* DNA introduced may not persist * Restriction systems, such as phage encoded CrispR/Cas recognise foreign DNA * Endonuclease activity * If persist may integrate and multiply within the chromosome * Many toxins – cholera toxin, diphtheria toxin (phage encoded)

Answer 39

1. Inhibition of bacterial cell wall synthesis or activation of enzymes that disrupt bacterial cell walls 2. Inhibition of protein synthesis by bacteria or production of abnormal bacterial proteins. These drugs bind irreversibly to bacterial ribosomes, intracellular structures that synthesize proteins. When antimicrobial drugs are bound to the ribosomes, bacteria cannot synthesize the proteins necessary for cell walls and other structures. 3. Disruption of microbial cell membranes 4. Inhibition of organism reproduction by interfering with nucleic acid synthesis 5. Inhibition of cell metabolism and growth

Answer 40

_Clinical usage:_ * Treatment of infections: wounds, burns, abcesses * Vital for recovery post surgery * Required for chemotherapy patients * Chronic diseases, diabetes, end stage renal disease * Changed life expectancy

Answer 41

Selman Waksman discovered streptomycin - effective against M. tuberculosis. They won a Noble prize in 1952.

Answer 42

_Intrinsic Resistance_ Intrinsic resistance is when a bacterial species is naturally resistant to a certain antibiotic or family of antibiotics, without the need for mutation or gain of further genes. This means that these antibiotics can never be used to treat infections caused by that species of bacteria. _Acquired Resistance_ Acquired resistance is said to occur when a particular microorganism obtains the ability to resist the activity of a particular antimicrobial agent to which it was previously susceptible.

Answer 43

Pseudomonas infections are diseases caused by a bacterium from the genus Pseudomonas. The bacteria are found widely in the environment, such as in soil, water, and plants. They usually do not cause infections in healthy people. If an infection does occur in a healthy person, it is generally mild.

Answer 44

Triclosan is a chlorinated organic compound with antibacterial and antifungal properties, widely used in household and medical products. Triclosan is broadly effective against Gram +ve and many Gram –ves but does not inhibit Pseudomonas.

Answer 45

Gram positive bacteria have a thick peptidoglycan layer and no outer lipid membrane whilst Gram negative bacteria have a thin peptidoglycan layer and have an outer lipid membrane.

Answer 46

Pseudomonas carry a gene that makes a protein which is insensitive to the antibiotic.

Answer 47

More generally many Gram negatives are resistant to antibiotics because the antibiotics cannot cross the bacterial membrane.

Answer 48

Microbes can also acquire resistance by using one of several mechanisms: * Minimise entry of the antibiotic * Modify the target of the antibiotic (mutate) * Inactivate the antibiotic itself by hydrolysis.

Answer 49

* Pharma companies are profit making organisations * Antibiotics have always been very cheap, effective (single course) and therefore not good at generating revenues * Contrast to chronic conditions: arthritis, blood pressure or long terms conditions like HIV

Answer 50

* Bacteria susceptible to an antibiotic * Mutation of the target gives a target with reduced affinity * Modification of the target by addition of a chemical group can prevent the antibiotic binding Natural selection occurs when an antibiotic is introduced onto a large population. The bacterial genomes are subject to variation (mutation) for example when they acquire additional genes from other species via plasmids, phages, recombination.

Answer 51

_Sites of b-lactam antibiotics_ 1. b-lactamase 2. Acylase 3. Esterase

Answer 52

_According to the O'Neill report:_ 1. Reduce demand- several steps to this. 2. Increase the number of effective antimicrobial drugs to defeat infections that have become resistant to existing medicines. 3. A global coalition for action on antimicrobial resistance (AMR)

Answer 53

1. A massive global public awareness campaign 2. Improve hygiene and prevent the spread of infection 3. Reduce unnecessary use of antimicrobials in agriculture 4. Improve global surveillance of drug resistance 5. Promote new, rapid diagnostics to cut unnecessary use of antibiotics 6. Promote development and use of vaccines and alternatives 7. Improve the numbers, pay and recognition of people working in infectious disease

Answer 54

The microbiota is a collective term for the micro-organisms that live in or on the human body. Specific clusters of microbiota are found on the skin or in the gastrointestinal tract, mouth, vagina and eyes. * There are tens of trillions of microbes 10¹⁴ * They mostly live in the colon. * However there are some in the lungs, skin, teeth and everywhere else 80% of the bacteria are unculturable. We know there are a huge number, however we cannot grow them in the lab environment.

Answer 55

many bacteria are sgtill not culturable, so we analyse them using new tech such as: * 16S sequencing * Whole Genome Sequencing + Metagenetics * And computation

Answer 56

16S rRNA Gene Sequencing. The 16S ribosomal RNA gene codes for the RNA component of the 30S subunit of the bacterial ribosome. It is widely present in all bacterial species. Different bacterial species have one to multiple copies of the 16S rRNA gene. Whole-genome sequencing (WGS) is a comprehensive method for analyzing entire genomes. Genomic information has been instrumental in identifying inherited disorders, characterizing the mutations that drive cancer progression, and tracking disease outbreaks. Diagram shows further differences

Answer 57

Bacterial communities differ at different sites

Answer 58

Bacteriodes is the most common genus in the colon.

Answer 59

* Include butyrate (most abundant), acetate and propinate * Produced by bacterial fermentation of dietary fibre, mostly in the colon. * The main energy source for epithelial cells * Butyrate has anti-inflammatory effect on intestinal epithelial cells * Involved in differentiation of colonic Tregs and ameliorates colitis in mice.

Answer 60

They are produced by micribiota in the colon however they do not just act locally, they can also be found in the blood and influence immune cells in the bone marrow and prevent them from being so activatory. They also prevent allergic reactions in the lungs.

Answer 61

_There are two types:_ 1. Ulcerative Colitis 2. Crohn's disease _Essentially they inflame the bowels and is caused by three things:_ 1. Host genetic factors has a weak causal explanatory factor as some people have genes which do not dictate the development of this disease but end up getting it. 2. Innate and adaptive immune response - The immue system responds to the intestinal microbiota and ends up damaging our own tissues as a result. 3.

Answer 62

The infiltration of bacteria out of the intestinal wall creates the immune response of inflammation Lesions of white blood cells are generated by immune system against the microbes. Abnormal microbial colonisation might contribute to disease.

Answer 63

* Activation of local innate immune cells * Increased permeability of local blood vessel * Migration into tissues of more immune cells and plasma proteins

Answer 64

PAMPs: Pathogen Associated Molecular Patterns Key point is that the forms of these molecules expressed by pathogens are distinct from those expressed by mammalian host cells.

Answer 65

The immune responses triggered by damage or danger rather than "non-self" antigens. The danger model is a theory of how the immune system works. It is based on the idea that the immune system does not distinguish between self and non-self, but rather between things that might cause damage and things that will not.

Answer 66

* The molecules in the diagram are normally tightly sequestered in intracellular compartments of the cell. * When they are released from cells as a consequence of death or trauma, they act as signals of tissue damage.

Answer 67

Leukocytes and tissue cells detect and control pathogens at infection sites.

Answer 68

Numerous host soluble and cell surface molecules help sense pathogens. Pathogens that can evade these molecules are better at causing damage.

Answer 69

Complement: series of plasma proteins that act in an enzymatic cascade

Answer 70

Key for acronyms in diagram: * Smallpox inhibitor of complement enzymes (SPICE) * CRIT: Complement C2 receptor inhibitor trispanning

Answer 71

Pattern Recognition Receptors

Answer 72

There are so many due to the rapid evolution of pathogens which would give redundancy in detection. The various PRRs make it harder for the pathogens to escape througj mutation.

Answer 73

The location of different PRR reflects their role in responding to different types of infection/threat.

Answer 74

PRR can be found on leukocytes and tissue cells.

Answer 75

1. TLR activation drives an intracellular pathway that activates NF-κB 2. NF-κB translocates into the nucleus and drives altered gene transcription 3. This allows the cell to warn the immune system about the infection

Answer 76

Bacteria can reduce NF-κB activation and inhibit the immune response. ## Footnote E.coli virulence factors degrade NF-κB Shigella enzyme cause degradation of an activator of NF-κB Thus the warning signal to the immune system is reduced.

Answer 77

* Innate immunity: always present; ready to attack * Adaptive immunity: stimulated by exposure to microbe; more potent

Answer 78

_Humoral_ * Antibody mediated 'extracellular attack' * Antibody from B cells * B cells mature in the bone marrow * In chickens the B cells mature in the Bursa of Fabricius _Cell Mediated_ * Intracellular attack * Due to T cells * T cells mature in the thymus

Answer 79

Different types of immune responses are mediated by different classes of lymphocytes and defend against different types of microbes

Answer 80

1. Generation of clonal diversity in primary lymphoid organ - bone marrow. 2. ‘Education’ to remove self reactivity in primary lymphoid organs - bone marrow and thymus 3. Recirculation to peripheral secondary lymphoid organs – spleen and lymph nodes 4. Clonal selection by antigen in secondary lymphoid organs

Answer 81

* Need for proliferation and differentiation results in delay * (typically 4-7 days) in effective adaptive immunity

Answer 82

* Mediated by T cells * Several components * Helper T cells – the managers of the immunological football team * Help B cells * Help cytotoxic T cells * Direct innate responses * Cytotoxic T cells

Answer 83

* T lymphocytes mature in the thymus * T cell receptor complex on surface, part of which (CD3) identifies these cells * Further subdivided by expression of one of two surface molecules, CD4 or CD8

Answer 84

* CD4 - Th –T helper * Recognise antigen presented in MHC II on the surface of antigen presenting cells and ‘help’ them * CD8 - Tc – Cytotoxic T cells CTL * Recognise antigen presented in MHC I on many cell types and can be induced to kill

Answer 85

* The link between innate and adaptive immunity is antigen-presenting cells (APCs) such as macrophages and dendritic cells * The link between humoral and cell mediated immunity is antigen presentation by B cells * Antigen is presented in the context of MHC (major histocompatibility complex)

Answer 86

T cell activation requires both T cell receptor (TCR) and CD3 binding to major histocompatibility complex (MHC) and co-stimulatory molecules, as with CD28 binding to CD80 (B7-1) or CD86 (B7-2). * Antigen presented in the context of MHC * Surface molecule ‘costimulation’ * Soluble molecules - cytokines

Answer 87

* “Help” the antigen-driven maturation of B and T cells * Facilitate and magnify the interaction between APCs and immunocompetent lymphocytes _Steps_ 1. Th interacts through antigen-specific and antigen-independent mechanisms 2. Undergoes differentiation 3. Mature Th interacts with plasma or T-effector cells * There are different types of Th cell * Th cell subsets!

Answer 88

_Coeliac Disease_ * Immune response to gluten proteins; T cells activate macrophages in the gut leading to inflammation. _Rheumatoid Arthritis_ * T cells in joints activate macrophages sustaining inflammation. _Inflammatory Bowel Disease_ * Immune system attacks components of the gut; T cell activation of macrophages plays central role in tissue damage. _Multiple Sclerosis/Experimental Autoimmune Encephalomyelitis (EAE)_ * Immune response against central nervous system

Answer 89

Th2 cells are essential to control helminth infections * Collagen Production for wound repair and encapsulation of parasite egg * Note: Failure to wall of egg and its toxins leads to excess Th1 inflammation that causes death. * IL-5 induced eosinophilia: release of cytotoxic cationic proteins that damage parasite * IL-4 and IL-13 act on macrophages: involved in tissue repair and angiogenesis * IL-13 promotes mucus production – response to injury and promotes egg/worm expulsion * Mast cell degranulation: release of many mediators to enhance parasite expulsion * Parasite specific IgE

Answer 90

* Collagen/Fibrosis driven by IL-13 e.g. in airways in asthma * IL-5 induced eosinophilia: release of cytotoxic cationic proteins that cause tissue damage * IL-4 and IL-13 act on macrophages: These cells are found in asthma/allergy models but role is unclear * Mast cell degranulation: release many mediators that cause smooth muscle constriction, vascular permeability e.g. in asthma and allergic dermatitis * Mast cell mediators: of cytokines, chemokines, histamine, heparin, serotonin, proteases *

Answer 91

IgM is usually seen first in the immune response. It has a pentameric shape because it has a low affinity so putting 5 chains together would increase the affinity and also makes it better at glutanating pathogen. With help from t cells, the b cells are able to make the other isotypes.

Answer 92

B cells are helped by helper T cells. B cell presents antigen in context of MHC II B cell presents peptide of antigen and is put in groove of MHC II Now the T cell can recognise the peptide from the antigen and can respond in the appropriate way.

Answer 93

* Activated T cells migrate towards follicles where the B cells are found. * Activated B cells migrate to the paracortex where the T cells are generally found. * These two sites are largely where these two immunoglobins interact. * They meet at the edge of the follicle. Their interaction gives rise to B cells returning to the follicle and undergo rapid proliferation and form a germinal centre. * Here, the affinity maturation of memory B cells is developed. Assisted by T cells. * Leads to long lived high affinity memory cells. *

Answer 94

Lymphoid follicles are small masses of tissues that contain aggregations of inflammatory cells, mainly B cells with some T cells and dendritic cells. It is also a marker of germinal center origin of T cells.

Answer 95

Follicular helper T (Tfh) cells are specialized providers of T cell help to B cells, and are essential for germinal center formation, affinity maturation, and the development of most high affinity antibodies and memory B cells. On their surface they have a unique collection of effector molecules. Some are costimulatory molecules: ICOS, CD40L and some are associated with stabalising the interaction between the t cell and the b cell like the SLAM family (signalling lymphocyte activation) e.g. CD84 These T cells are very good at moving towards B cells in the follicle and the germinal centre.

Answer 96

_Soluble cytokines mediate a range of effects including:_ * Preventing death * IL-4 * Promoting proliferation * IL-2, IL-4 * Aiding maturation and differentiation * IL-5, IL-6, IL-21, TGFβ * Enhancing processing and presentation * IL-4 can increase MHC class II expression * Promoting isotype switching * IL-4 - IgG1, IgE, IFNγ - IgG2a, TGFβ - IgA

Answer 97

* First described in 1884 (Walther Flemming). * Saw sites of large lymphocytes undergoing division in follicles of secondary lymphoid tissue. * Now known that this site (GC) is associated with T-dependent antibody responses. * Main site where high-affinity antibody-secreting plasma and memory B cells are generated.

Answer 98

* Allows fot the average affintiy of serum antibody to increase over time. * This is termed affinity maturation * This is due to somatic hypermaturation (SHM) of the antibody variable region * SHM occurs in Germinal Centre B cells * Mutations cluster in regions of antibody that bind to antigen. * B cells in an individual GC are usually clonally related. * GC are specialised site supporting events required for affinity maturation

Answer 99

Follicular dendritic cells (FDCs) are non-haematopoietic cells that are present in the B cell follicles of secondary lymphoid tissues. They carry intact antigens that are held on their surface for long periods in antigen–antibody complexes and are crucial for the selection of B cells that produce high-affinity antibodies.

Answer 100

* Clonal proliferation * Somatic hypermutation (SHM) * Affinity maturation * Newly mutated receptors are... * Selected (‘checked for best fit’) against antigen held on follicular dendritic cells (FDC) * Require continued T cell help to survive the selection process

Answer 101

* proliferating GC B cells accumulate in the dark zone (centroblasts) * SHM preferentially occurs here * now migrate to light zone (centrocytes) * moves among FDC network * higher affinity BCRs able to bind Ag on FDC * now process and present Ag on MHCII * presentation of pMHCII to cognate GC Tfh elicits help * higher affinity BCR - better Ag capture - more Ag presentation - better able to compete for limiting T cell help - Darwinian selection! * Tfh signals also important for memory

Answer 102

* T-B cell interaction critical for generation of effective, long-lived Ab response. * Dysregulation of this interaction manifests as various immune diseases and disorders. * HIGM - hyper IgM syndrome - CD40/L * Over abundance of Tfh in murine models (e.g. sanroque mice) and patients with autoimmune disorders, SLE, rheumatoid arthritis, Sjogren’s syndrome etc * CD40L, ICOS mutations producing reduced Tfh in humans and mice result in severe defects in protective humoral immunity. * Take advantage of the interaction for rational vaccine design * conjugate vaccine (poor antigen conjugated to carrier protein) e.g. Haemophilus influenzae type b (Hib): polysaccharide

Answer 103

A means of producing immunity agaisnt pathogens, such as viruses and bacteria, by the introduction of live, killed or altered antigens that stimulate the body to produce antibodies against more dangerous forms.

Answer 104

* Long Lived * Increased frequency * Rapid proliferation * Produce more Ab * Produce higher affinity Ab * IgG & IgA have better effector function

Answer 105

The secondary Ab response is faster they have a different isotype (IGM to IGG) The secondarry Ab response have a higher affinity.

Answer 106

* The Germinal Centre reaction drives affinity maturation and class switching of Memory B cells and Long Lived Plasma Class

Answer 107

Most vaccines work by inducing long lived plasma cells and plasma antibody responses.

Answer 108

_Killed vaccines_ * Usually use chemicals or heat * These kill the organism and render it completely uninfective * Killed organism can still induce immunity * e.g. whole cell pertussis vaccine _Subunit vaccines_ * Toxins are the pathogenic fragments of bacteria * Antibodies to toxins can protect from infection * Chemically inactivated toxins are called toxoids * e.g. acellular pertussis vaccine

Answer 109

Certain viruses/bacteria/parasites are very hard to grow * e.g. they grow in host cells that are not readily cultivated.

Answer 110

* Effective in children over 2 years * Well-tolerated in children and adults * Ease of administration * Known limitations: * ineffective in over 50s * issues with safety in children with asthma/wheezing * not for immunocompromised

Answer 111

1. Attenuated - find or make an attenuated pathogen using culture methods 2. Killed - Kill the pathogen 3. Subunit - kill the pathogen and isolate its protective antigens (toxoids) 4. Recombinant Subunit - clone genes for protective antigen, express in (e.g. yeast). Isolate the antigen 5. Live Recombinant - clone genes for protective antigen, express in vaccine vector

Answer 112

1. Genetically attenuated - knock out virulence genes with recombinant tech. 2. DNA vaccine - clone genes into expression vector. Inject construct.

Answer 113

Non-steroidal anti-inflammatory drugs (NSAIDs) are medicines that are widely used to relieve pain, reduce inflammation, and bring down a high temperature. They're often used to relieve symptoms of headaches, painful periods, sprains and strains, colds and flu, arthritis, and other causes of long-term pain.

Answer 114

1. Increased blood flow to the site fo inflammation 2. Increased temperature 3. Redness 4. Swelling 5. Pain

Answer 115

They are: * Analgesic * Antipyretic * Anti-inflammatory at high doses.

Answer 116

The release of endogenous pyrogens such as interleukin-1, released from leucocytes which act directly on the thermoregulatory centers in the hypothalamus thus increasing body temperature. This is associated with an increase in brain prostaglandin (PG)-induced gonadotropin release. Aspirin prevents the temperature rising effects of interleukin-1 by preventing the increase in brain PGs.

Answer 117

* platelet dysfunction * Gastritis and peptic ulceration with bleeding * Acute renal failure in susceptible * sodium + water retention and edema * prolongation of gestation and inhibition of labour * hypersensitivity

Microbes and Immune System Flashcards

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