IMED1004 - The Immune Response (L6)

Practice Question 1

DIAGRAM ON SLIDE 2

Practice Questions Lecture 2

DIAGRAM ON SLIDE 3

Threshold of disease is rarely reached

Many infections are controlled before they have a chance to cause damage (symptoms) and disease

LIKELIHOOD OF DISEASE DEPENDS ON:

- number of pathogens

- virulence of pathogen

- status of hosts immune defences

Requirements for infection - the host perspective

Best outcome for a host: complete clearance of pathogen

- resolution of any damage

- development of immune memory

Host response to infection

Plan A = block invasion = barrier protection

- when infections cant be blocked, first innate and then adaptive immunity is activated

Plan B = destroy invaders

- innate immunity - containment

- adaptive immunity - specific killing and development of memory

Innate Immunity

FIRST TO SECOND LINE OF DEFENCE AGAINST PATHOGENS

- acts rapidly (hours/days) vital to triggering adaptive responses

- Triggered by threat/damage

- Activated by shared microbial (PAMPs) or damage (DAMPs) patterns

- soluble and cellular components

- no recall response on subsequent exposure to same threat

- initiates process of tissue repair

Adaptive Immunity

SECOND-TO-THIRD LINE OF DEFENCE AGAINST PATHOGENS

- Relatively slow to develop (days/weeks)

- triggered by exposure to specific antigen

- very focused, targets a specific pathogen (antigen)

- soluble and cellular components

- rapid recall response on subsequent exposure to same antigen (memory)

Innate Immune Response

white blood cells (WBCs) or leucocytes at site of infection:

- recognise invading pathogen

- release chemical messenger proteins (chemokines recruit more WBCs; cytokines activate more WBCs

Phagocytic cells engulf invading pathogens and destroy them in large numbers

- Tissue resident macrophages - first responders

- Recruited neutrophils - professional killers

Phagocytes recognise microbes through pattern recognition

- Shared structures unique to subsets of microbes = pathogen associated molecular patterns (PAMPs) e.g

- LPS of Gram-negative bacteria

- bacterial flagella

- viral RNA or DNA

- toll-like receptors (TLRs) are pattern recognition receptors (PRRs)

- recognition sends danger signal

- stimulates production and secretion of cytokines

.

- basically its a signal that makes it to release more cytokines or chemokines depending on requirements

• green: toll like receptor

• blue: cytokines

• pink: PAMP

Chemotaxis of neutrophils

- when tissue resident macrophages are making lots of these chemical signalling molecules these chemokines, they're going to be at highest concentration at the site of infection and then be diluted out as you get further away from the infection

- so these neutrophils and other monocytes that are whizzing around in the blood will get signals that there is a dilute something going on, these chemokines, and they will migrate towards the higher of the chemokines

- so these chemokines tell the blood vessels at the site of infection to expand a little bit and get ready to let the neutrophils that are whizzing around to come out here and they will move towards the high concentration of chemokine, and that process is called chemotaxis

- it is the movement towards a high concentration of chemokine

Inflammation is key component of innate immunity

- cytokines induce inflammation

- series of events in reaction to tissue damage - injury and/or infection

- site becomes swollen, red, hot and painful - part of normal healing process

- underlying mechanisms explain the symptoms

- Vasodilation - increase in blood vessel diameter and permeability - brings more WBCs to site of infection

Fever, another key component of innate immunity

- Cytokine, Interleukin-1 (IL-1) induces fever

- Phagocytic cells more efficient at elevated body temperature

- some pathogens unable to reproduce at higher temperatures (e.g influenza virus)

- if fever gets too high - dangerous and life threatening

- many disease symptoms are not the result of direct damage caused by the pathogen, but rather are the unpleasant side effects of your immune response

Interferons

Cytokines that interfere with viral replication and spread

- IFNs made by infected cell in response to viral replication

- Act on neighbour to induce an antiviral state

- cell in antiviral state donot allow viral replication

- contribute to flu-like symptoms of aches, headaches, chill

.

- basically to get rid of a virus we have to kill the host cell, which isn't always viable since that means we kill everything

- hence we use interferons, which are a cytokine that interfere with viral replication

The aim of the immune response is to resolve/clear the infection BUT

- the pathology/disease state may also be a result of the immune response

- Primary symptom of gonorrhea = pus in urethra = accumulation of dead neutrophils that have tried to destroy and clear the infection

- Fever, fatigue in response to viral infection is also a host response

- LEFT: dark areas = parts of lung unaffected by tuberculosis. White areas = damaged areas of lung mostly due to inflammation in response to infection

Antigen Presenting Cells (APCs) activate immune cells of the adaptive system

- at sites of infection, macrophages and dendritic cells (DCs) use TLRs (Toll-like receptors) to recognise and digest a pathogen and then send signals to amplify the immune response

- recruits more innate WBCs and initiate adaptive immune response

- macrophages and dendritic cells are both antigen presenting cells (APCs) which means they can 'talk' to adaptive immune cells with antigen receptors

How APCs activate lymphocytes diagram

- following digestion, small protein fragments of pathogen are bound on major histocompatibility complex (MHC) proteins for activation of adaptive immune cells

- antigen presentation on MHC

- antigen = pathogen fragment that adaptive immune cells specifically recognise and respond to

- basically pathogen is engulfed, and pathogen is digested into small fragments within vesicle

- at the same time the APC creates MHC and it fuses to the vesicle

- vesicles containing MHC and digested protein fuse

- a pathogen fragment (antigen) binds the MHC

- antigen-MHC complex is transported to the cell surface, where the antigen is presented

- basically becomes an antigen once the MHC binds with it (previously it was just a part of the pathogen)

Lymphatic System

- APCs that have picked up antigen at site of infection migrate to nearby (local, draining) lymph nodes (strategically located where they concentrate components for adaptive immune response

- activate adaptive immune cells responsible for microbial clearance and memory - T and B cells/lymphocytes

- Lympathic System - network of vessels returning fluid that has leaked out of blood back to circulation

- lymph = fluid in lympathics

Spleen

- blood is filtered through the spleen

- like a lymph node for blood-borne pathogens

- other specialised lympathic structures exists in areas of high pathogen exposure e.g gut and respiratory tract

Lymphocytes

- WBCs of adaptive immune response

- T and B cells

- Initially formed in bone marrow

- circulate through blood

- can leave blood and enter lymph nodes looking for antigen presented by APCs

- if they find APC presenting foreign antigen that they are specific for, they will become activated (if they don't, they keep moving)

- activated lymphocytes undergo rapid proliferation and lymph nodes swell

-

T cells mature in the thymus

- T cells migrate from bone marrow to thymus

- Complete development in thymus

- Mature (but naive) T cells that have not seen foreign antigen before leave the thymus and begin to circulate

Upon activation by APC and antigen, they become effector T cells:

- Helper CD4+ T cells (Th) coordinate entire adaptive response - activate CTLs and B cells

- Cytotoxic/killer CD8+ T cells (Tc cells or CTLs) are professional killing cells - viruses and tumours

- during activation, some Th cells and Tc cells develop into relatively inactive - long-lived memory T cells

T cells have surface protein complexes = T cell receptors (TCRs)

- APC releases cytokines that attract naive CD4+ T cells

- TCRs recognise foreign antigen presented on MHCs by APCs

- each naive CD4+ T cell has lots of identical TCRs (same specificity)

- different CD4+ T cells have different TCRs and antigen specificities

- Naive CD4+ T cell specific for presented antigen (C in this case) is activated and begins to divide

- Results in many activated effector CD4+ T-helper (Th) cells, all bearing TCRs specific for the activating antigen

- process takes several days to complete = clonal expansion (lymph node swelling)

Th cells support Tc cels to achieve microbial clearance

- APCs present antigen to CD4+ and CD8+ T cells activating them > effector Th cells and Tc cells

- Th cell responding to same infection secrete cytokines that further stimulate/help Tc cells

- Tc cells can then go looking for host cells infected with virus, displaying viral antigen on MHC

Tc cells recognising antigen on MHC

- Tc cells recognising antigen on MHC of infected host cell release toxic chemicals to cause infected cell to die = targeted cell killing

- uninfected cells not displaying antigen are not affected/killed

Th cells also activate B cells to initiate humoral (antibody) responses

- B cells complete development in bone marrow

- Each B cell has its own specificity for antigen (B cell receptor (BCR) = antibody = immunoglobulin

- Mature, but naive, B cells leave bone marrow and begin circulation

- Antibodies are secreted by BCRs - protein molecules that recognise specific foreign antigen

- Bind free floating antigen - no need for MHC processing/presentation

- Two antigen binding sites

- Composed of 4 proteins joined by covalent bonds

- Two smaller proteins = light chains are identical

- Two larger proteins = heavy chains, also identical

.

- basically antibodies are secreted B cell receptor

B cell action

- Mature, naive B cells pass through lymph organs looking for specific antigen

- Antigen-antibody binding + cytokines from Th cell = B cell activation

- Plasma cells are activated/effector B cells that secrete antibody into blood, lymph

- Memory B cells are also produced

Antibody functions

(a). coat surface of viral particles preventing them from attaching to host cell receptors = neutralisation (pink)

(b). each antibody has two antigen binding sites - large agglutinated clumps of antigen and antibody may form = agglutination (green) Complexes are phagocytosed

(c). Enhances phagocytosis by acting as opsonin/physical connection for phagocytic cell with receptor for antibody tail = opsonisation (blue) (example of adaptive immune responses helping innate cells)

.

- basically for 3, when the antibody binds its antigen binding sites to the pathogen, the tail of that antibody can be recognised by phagocytic cells that have receptors for the tail of that antibody. this makes phagocytosis efficiently since its not gonna get away

Several different classes/isotypes of antibody

- Ig = immunoglobulin

- different Ig classes have different functions

- IgD also membrane bound (important in B cell development)

- IgE is secreted (important in allergy)

- isotype/class switching from IgM to IgG and IgA requires further signals from Th cells

Primary vs Secondary Response

- IgM first antibody produced in primary response (first exposure to pathogen)

- Larger amount of IgG - with same antigen specificity - produced later

- During secondary exposure (to same antigen), memory cells are activated that quickly differentiate itno IgG producing plasma cells

.

- threshold of disease is when you start to see symptoms

Successful adaptive response culminates in elimination of pathogen

- 5-7 days required to activate and clonally expand T and B cells = inductive period

Vaccines induce immune memory without causing disease

- vaccination exploits the ability of the immune response to mount ever stronger responses with each antigen exposure

- primary immune response stimulated by exposure to dead/inactivated, weakened/attenuated, or component of pathogen

- Subsequent exposure to live pathogen immediately triggers secondary adaptive response

Putting it together = likelihood of disease

1. more virulent pathogen has lower threshold of disease

- if immune response to both pathogens is same, less virulent pathogen does not reach threshold = contained by immune response

- only most virulent pathogen causes illness

2. two pathogens have same threshold of disease but reproduce at different rates

- more rapidly producing pathogen reaches its threshold before inductive period is complete

- more slowly replicating pathogen is contained by immune response

- only fast replicating pathogen causes illness

3. Time-course of adaptive immune response

Summary

DIAGRAM ON SLIDE 40

Good series of videos

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