Immunity to Infection

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32 Terms

1
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Leukocyte extravasation (diapedesis)

E, P-selectin expressed on the endothelial surface mediated sialyl lewisx on leukocytes, adhesion to leukocyte and allow leukocytes to roll along the vascular endothelial surface - weak adhesion

Start to adhere tightly via expression of LFA1 on leukocyte binding to ICAM 1 on the endothelial surface. The migration is regulated via the chemokine concentration of IL-8

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What are found on all Gram (-ve) bacteria or Gram (+ve) bacteria?

LPS or

LTA lipoteichoic acid

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Toxic shock syndrome toxins produced by S.aureus

Due to the release of superantigen leading matching between non-compatible MHCII and TcR leading to huge storm of IL-1, TNF-a, IL-2 leading to toxic shock 

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Changes to tissue - tissue damage when protect against bacteria

Neutrophil → platelet aggregating factor 

Platelet aggregation (amplifier of permeablity) and fibrin deposition 

PDGF from platelets stimulate phenotype modulation of smooth muscle→ remodelling and contraction 

Microthrombi forms in small vessels which impair perfusion

Chemotaxis

ROI production - damage endothelium, exposing subendothelial collagen and tissue factor 

Plasma leak into tissue → Edema, hypovolemia

Significant change in vascular permeability, loss of fluid into tissue, fall of blood pressure

Symptoms = fever, circulatory collapse, diffuse intravascular coagulation, haemorrhagic necrosis, blood leak out from vasculature

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How is acute phase response generated?

Activated macrophage recognise bacteria via TLR

NF-kb transcription

IL-1, IL-6, TNF-a release

Signalling to liver hepatocytes to make acute phase proteins - mannan binding lectins, surfactans, C-reactive proteins (inflammation marker) opsonin effect, complement activation

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What are the 3 main activities by neutrophils

Phagocytosis

ROS

NETS

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Inhibitors of complement from bacteria (modulation or inhibition) 

SCIN

SIC

CHIPs

SpA

SCIN: Staphylococcal complement inhibitor , binds to C3 convertases and inhibit C3 activation

SIC: Streptococcal inhibitor of complement binds C5b-7/8, prevent MAC formation

CHIPs: of Staph, aureus, binds to C5a receptor to inhibit C5a chemotactic signalling (release out, soluble)

SpA: of Staphylococcal, deposited on bacterial surface , binds Fc region of IgG which prevents opsonisation and classical pathway

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Inhibition of complement via enzymatic degradation by bacteria

Pseudomonas protease

C5a peptidase

Pseudomonas elastase

Pseudomonas protease: cleaves C3, prevent C3b deposition 

C5a peptidase: cleaves C5a and prevent neutrophil chemotaxis (bind directly to C5a NOT to the receptor)

Pseudomonas elastase: cleaves IgG and C1q, which prevents initiation of classical pathway 

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Role of LPS in immune evasion

Modification of LPS with sialic acid

Long side chains - O antigens

Modification of LPS with sialic acid - binds to Factor H, which is a complement regulator that breaks down C3b (in Neisseria)

Long side chains - O antigens - long side chain (in Pseudomonas) that makes a physical barrier so phagocytes cannot get to deposited C3b

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Microbicidal mechanism of phagocytes: Oxygen dependent activity

Embeded on the phagosome - NADPH oxidase which pump oxygen through and makes superoxide inside the phagosome

ROS - O2-, H2O2 (from catalase)

Myeloperoxidase turns H2O2 into HClO

Catalase from lysosome

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Microbicidal mechanism of phagocytes: nitric oxide pathway

IFNy - that is released as cytokines, binds to the receptor on the cell membrane of phagocytes - actvate JAK/STAT1 pathway

At the same time, TNF signalling on the membrane surface also enhances 

Crosslinking of CD23 - FcrRII - crosslinking by immune complexes provides an additional activation signal

Boost NF-kB and AP-1 activity signalling

this induces nitric oxide synthase

NOS with tetrahydrobiopterin (cofactor)

L-arginine +O2+ NADPH → L-citrulline+ NO

NO reacts with O2- forms peroxynitrite ONOO- which is highly reactive

NO is toxic 

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Escape mechanisms from phaglysis by bacteria

Inhibits chemotaxis by Streptococcus o Staphylococcus

Capsule or outer coat prevents attachment and upatake

M. Tuberculosis - release of factors that blocks triggering and killing mechanism - block lysosome function and inhibit proton pump

M.tuberculosis, M.leprae - escape from phagosome

M,leprae - has phenolic glycolipid that scavenge free radicals

and lipoarabinomannan that blocks IFN-y signal

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Counteraction of microbes to antibodies

Rapid cellular division

Intracellular location (TB)

Host-like coast

Antibdy specific protease

Antigenic variation → creates new epitope that antibody cannot bind

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Which cytokines drift CD4+ differentiation into Th1 cells? 

What are Th1 cell roles in response infection?

In an IFNy environment, Th1 differentation is induced

Th1 response s proinflammatory and stimulates macrophages activation and NK cells

Macrophages release IL-12 which supports Th1 activity

Leading to cytotoxic effector ADCC functions 

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Which cytokines drift CD4+ differentiation into Th2 cells? 

What are Th2 cell roles in response infection?

In an IL-4,IL-5, and IL-10 environment, Th2 differentiation is induced

Stimulate B cells, mast cells and eosinophils

which generate a humoral response, ant-inflammatory

Skewing towards antibody production, allergic response

Limit macrophage activation

Low doses and oral route favours Th2 response

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Example of a response that can be Th1 or Th2 - mycobacterium leprae

How is the Th1 response different to Th2 response?

Leprosy is caused by Mycobacterium leprae

  1. Th1 response:

  • Vigorous host cellular response

  • Many immune cells in lesions

  • Tissue damage - Type IV hypersensitivity

  • Only few bacteria visibl microscopically

  • Disease progresses slowly and patient usually survive

  1. Th2 response: Lepromatous form

  • Humoral response

  • Adequate antibody response but the antibody cannot reach the intracellular bacteria

  • MANY bacteria are found in lesions

  • Gross tissue destruction, fatal

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Example of a disease that is both Th1 and Th2 - malaria at different stages

Caused by Plasmodium sp.

As sporozoites in blood: Th2 response - antibody production

As tissue schizonts in live: intracellular so now antibody response is useless: Th1 cytotoxic T cells, TNF, IL-1

As merozoites in blood: Th2 antibody production. But now the antigen is different so needs to mak new antibody

Asexual erythrocyte stage: both Th1/Th2 antibdy production, ROI, RNI, TNF

Note: specific antibody production always lag behind

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Route of infection with Schistosoma (blood flukes) -parasitic flatworms

Symptoms

Schistosoma - larvae are released from water snail and penetrate skin

Migrate through blood and lung to hepatic portal vein (adult worm) 

Egg movement to gut and urine bladder-released

Blockage of the lymphatic system, organ damage - can lead to schistosomiasis, abdominal ascites

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Immune regulation and defence in schistosome infection

Firstly, the parasitic antigen cause mast cells to release histamine and heparin that are toxic to the larvae

Increases IL-4 release, which drives B IgE classwitch and also skewing towards Th2 response that release IL-5

Drives eosinophil -IgE binding activation which release MBP that damages the parasite

Released antibody IgG from B cell humoral production also recruits macrophages and neutrophils (that are part of the Th1 response to come in, which skews about to Th1 as TNFa and INFy are relased. They try to phagocytose the larvae but it’s too big so they become confused?

Still, neutrophil and macrophages release ROI and NO that causes damage to the larve

Neutrophil, macrophages and eosinophil release of toxicants = Antibody dependent mediated cytotoxicity

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<p>Immune response to viruses </p><p>What are the characteristics of virus</p><p>What is the early innate immune response</p><p>Adaptive immune response? </p>

Immune response to viruses

What are the characteristics of virus

What is the early innate immune response

Adaptive immune response?

Viruses are obligate intracellular parasites that has high diversity due to high mutation rate

They are host specific - infection depends on specific host cell receptor

Innate immune response (early response)

  • IFN stimulates inhibition of viral replication (IFNa and IFNb from infected cells signal to non-infected cell to regulate certain translation - TAP, MHC I, LMP - resistance to viral replication PKR, ribonuclease)

→ ribonuclease cleaves RNA, PKR upregulate eIF2

  • NK cells patrol and kill virally infected cells with low MHC I - ADCC

  • Complement can damag viral envelope

Adaptive immune response:

  • antibodies limit viral spread and reinfection; Ab mediated complement activation

  • CD8 T cells destroy virally infected cells → release IFN-y

<p>Viruses are obligate intracellular parasites that has high diversity due to high mutation rate</p><p>They are host specific - infection depends on <strong>specific host cell receptor</strong></p><p>Innate immune response (early response)</p><ul><li><p>IFN stimulates inhibition of viral replication<strong> (IFNa and IFNb from infected cells signal to non-infected cell to regulate certain translation - TAP, MHC I, LMP - resistance to viral replication PKR, ribonuclease) </strong></p></li></ul><p>→ ribonuclease cleaves RNA, PKR upregulate eIF2</p><ul><li><p>NK cells patrol and kill virally infected cells with low MHC I - ADCC</p></li><li><p>Complement can damag viral envelope</p></li></ul><p></p><p>Adaptive immune response: </p><ul><li><p>antibodies limit viral spread and reinfection; Ab mediated complement activation </p></li><li><p>CD8  T cells destroy virally infected cells → release IFN-y</p></li></ul><p></p>
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Which group of virus does HIV belong to and what are the cellular targets?

Belongs to retrovirus - group: lentivirus, lentus =slow

Infect CD4 T cells, DC, macrophages

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Cellular tropism of HIV - via which receptor does it gets into the cell?

Lymphocyte-tropic virus - X4 viruses - uses CXCR4, needs high level of CD4 on T cells

Macrophage-tropic virus - R5 viruses - uses CCR5 as co-receptor that is expressed on DC, M, and activated T cells

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What are some treatments of HIV infection?

HAART: highly active antiretroviral therapy, protease inhibitor combined with 2 or more RT inhibitors

nucleoside analogues RT inhibitor (eg. AZT attached to the base which stops transcription

non-nucleoside analogues RT inhibitor - binds to RT enzyme

24
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Typical course of untreated HIV infection

Primary (acute) infection is often asymptomatic or causes flu-like illness

HIV first infect DC which gets carried to the lymph node

T cells clustered with DC becomes highly activated - vigorous HIV replication

Drop in circulating CD4 T cells and activation of CD8+ cells

Asymptomatic phase

Cytotoxic CD8 cells and Th1 cells are responsible for decline of virus after initial infection

HIV generates humoral immune response (sero-conversion, important for diagnosis) that decrease the no virus but does not fully deplete it (HIV stay at low steady state)

Viral replication in lymphoid tissue (patients feel OK)

During the asymptomatic phase, no CD4 T cells gradually decline due to:

  • Direct viral killing

  • Increased susceptibility to apoptosis

  • Killing by CD8 CTL that recognise viral peptides

Throughout the pathway, CD4 drops slowly, once it drops to a critical number, the cell mediated immunity is lost, leading to the development of opportunistic infections

Quasi species - escape variants are formed from mutation of HIV once infected, worsen the prognosis because escape from the immune recognition - needs to go through the process again

<p>Primary (acute) infection is often asymptomatic or causes flu-like illness</p><p><strong>HIV first infect DC which gets carried to the lymph node</strong></p><p>T cells clustered with DC becomes highly activated - vigorous HIV replication</p><p>Drop in circulating CD4 T cells and activation of CD8+ cells</p><p></p><p><strong>Asymptomatic phase</strong></p><p>Cytotoxic CD8 cells and Th1 cells are responsible for decline of virus after initial infection</p><p>HIV generates humoral immune response (sero-conversion, important for diagnosis) that decrease the no virus but does not fully deplete it (HIV stay at low steady state)</p><p>Viral replication in lymphoid tissue (patients feel OK)</p><p>During the asymptomatic phase, no CD4 T cells gradually decline due to:</p><ul><li><p>Direct viral killing</p></li><li><p>Increased susceptibility to apoptosis</p></li><li><p>Killing by CD8 CTL that recognise viral peptides</p></li></ul><p></p><p>Throughout the pathway, CD4 drops slowly, once it drops to a critical number, the cell mediated immunity is lost, leading to the development of opportunistic infections </p><p></p><p>Quasi species - escape variants are formed from mutation of HIV once infected, worsen the prognosis because escape from the immune recognition - needs to go through the process again</p><p></p>
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HIV - escaping the immune system

Neutralising antibodies: control HIV particles in blood, but cannot eliminate virus altogether

High replication and mutation rate (quasi species develop into escape variants

Antigenic variation: immunogenic surface proteins (gp41 and gp120) develop new epitopes, not recognised by CTLs

Provirus hides inside the cell on host chromosome (latent infection)

HIV interferes with synthesis of MHC class I proteins

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What is the influenza virus?

What is the role of its

Hemagglutinin (HA) 

Neuraminidase (NA) 

8 single stranded - negative sense virus

Hemagglutinin (HA): binds to sialic acid-containing receptors on epithelial cells of host 

Neuraminidase (NA): cleaves sialic acid at the end of virus life cycle to allow mature virions to be released

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Influenza virus

What is the innate response and adaptive response against this virus?

Innate response

  • Type 1 Interferon a and b to provide resistance against the virus

  • Viral replication/ cell lysis leads to production of IL-1, IL-6 and IL-8, TNF, IFNy

→ disease symptoms ( fever, cough, etc)

Adaptive response

viral clearance correlates with appearance of HA and NA specific - CD8 T cells

efficient clearance and protective immunity requires CD4T cell

Production of IgG and IgA primarily - neutralisation of HA

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Antigen drift

Change in one specific viral genome

Neutralising antibody binds to the old virus so it cannot perform viral replication or enter the cell

Introduce point mutation to change the epitope, therefore the antibody cannot neutralise it and therefore can escape antibody binding

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What are the subtypes of NA that infects human? What are the subtypes of HA that infects human?

What do they bind to?

H1, H2, H3

binds 2-6 sialic acid receptors

N1, N2

All subtypes are found in aquatic birds (natural reservoir for Influenza A virus)

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Avian HA types binds to…

Pig HA types bind to …

Bind 2-3 sialic acid receptor

PIG Both 2-6 and 2-3 sialic receptor

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Antigenic shift

Two strands of influenza virus infect the same cell, so they exchange RNA segments (in PIG) , which leads to formation of a new strand that once could not bind human but now can bind human

  • genetic reassortment between human and avian forms in pig- emergence of new virus with high transmission

eg

H5N1 bird flu: highly pathogenic but low transmission - dont infect human (however pandemic possible if stran mutates and rearange with human chain)

H1N1: highly transmissive (binds human receptor) but not very pathgenic

<p>Two strands of influenza virus infect the same cell, so they exchange RNA segments (in PIG) , which leads to formation of a new strand that once could not bind human but now can bind human</p><ul><li><p>genetic reassortment between human and avian forms in pig- emergence of new virus with high transmission</p></li></ul><p>eg </p><p>H5N1 bird flu: highly pathogenic but low transmission - dont infect human (however pandemic possible if stran mutates and rearange with human chain) </p><p>H1N1: highly transmissive (binds human receptor) but not very pathgenic</p><p></p>
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Most protective method against Influenza…

vaccination! live attenuated

changes each year based on viral type