pathways to defeat infection - week 6

where is the pathogen

• outside cells

  • extracellular pathogens

• inside cells

  • intracellular pathogens

the location of the pathogen decides which parts of the immune system can reach it

the team

innate immunity

• Phagocytes: macrophages and neutrophils

• Antimicrobial defensins

• Eosinophils

• Dendritic cells

• Complement proteins

• Mast cells

• Interferons and NK cells

Adaptive immunity

• B cells and antibodies

• CD8 cytotoxic T cells

• CD4 helper T cells: Th1 and Th2

innate acts first, adaptive is slower but specific - and they help each other

key terms:

• Phagocytes: Cells that engulf and destroy microbes.

• Defensins: Small antimicrobial peptides that damage microbial membranes.

• Eosinophils: White blood cells that help defend against parasites.

• Dendritic cells: Cells that capture antigens and help activate T cells.

• Complement proteins: Blood proteins that help destroy or mark microbes for removal.

• Interferons: Proteins that help cells defend against viral infections.

• NK cells (natural killer cells): Cells that destroy infected or abnormal cells.

• Cytotoxic: Able to kill cells.

• Th1 and Th2: Types of CD4 helper T cells that coordinate different immune responses.

two ways to defeat infection

• for extracellular pathogens

• for intracellular pathogens

extracellular pathogens

Extracellular pathogens (most bacteria, fungi, parasites, toxins, and viruses before they enter cells) live in blood, tissue fluid and on mucosal surfaces – so soluble molecules and phagocytes can reach them

extracellular pathogens process

1. recognition

2. response

phagocytosis

RECOGNITION

Phagocytes engulf and digest bacteria and small particles.

Two main types:

• Macrophages

  • Live in tissues; engulf and raise the alarm

• Neutrophils

  • Arrive fast, in large numbers

phagocytes are the clean-up crew

phagocytosis in action

1. Phagocytes express a range of pattern recognition
   receptors (PRRs)

2. A microbe can bind directly to a macrophage via
   these pattern recognition receptors

3. This activates the macrophage: it releases
   inflammatory mediators (e.g. cytokines) and starts
   phagocytosis

recognizing the microbe switches the phagocyte on - it engulfs and raises the alarm

what is complement?

RECOGNITION

• ~30 proteins in blood and tissue fluid

• named for ‘complimenting’ antibodies

Complement proteins acts as:

• Activation enzymes – act on other complement proteins to activate them

• Immune defence molecules – make holes in the surface of microbes

• Control proteins – switch the system on when needed – and off when it is no longer needed

compliment punches holes, tags microbes and calls for help

B cells vs T cells

RECOGNTION

• recognition of antigen

B cells

• ‘direct recognition’

• Recognise pathogens in their native form

• Have B cell receptors on the cell surface, allowing them to bind antigens
  
  

T cells

• ‘indirect recognition

• don’t recognize pathogens in native form

• pathogen must be processed and presented on MHC class l or class ll

B cells see the whole pathogen; T cells see pieces on MHC

Immunoglobulins: two forms

Membrane-bound antibodies

• receptors on the surface of the B cell

• bind foreign antigens encountered by the host

Soluble (secreted) antibodies

• recreated by plasma cells

• presented in serum and tissue fluid

• mediate effector function to neutralise or eliminate antigen

same molecule, two jobs: a receptor on the B cell, or a free antibody in body fluids

antimicrobial defensins

• Small cationic peptides that act as host defence peptides

• Act mainly by disrupting the membrane structure of bacterial cells

• Active against bacteria, fungi and many enveloped and non- enveloped viruses

• Immune cells contain these peptides to help kill phagocytosed bacteria

• Form pore-like defects that let essential ions and nutrients leakout

Defensins are the body’s own antibiotics

Antibody isotypes: recruiting other defences

Neutralisation (all isotypes, mainly IgG and IgA): antibodies block microbes and toxins from binding host cells

isotype-specific functions:

• IgM IgG

  • compliment activation (via C1q)

• IgG IgA

  • phagocyte binding (via FcγR or FcαR)

  • helps macrophages and neutrophils engulf and digest microbes

• IgE

  • mast cell binding (via FcεR)

  • IgE on mast cells trigger release of inflammatory mediators)

different antibody classes recruit different helpers to remove the pathogen

Opsonisation

• Opsonisation is a way of marking the invading particle for the phagocyte

• Main opsonins: complement C3b and IgG antibody – phagocytes have receptors for both

• Acute-phase proteins (e.g. CRP) are another class: during infection, IL-6 triggers their release from the liver

• Acute-phase proteins then coat the surface of the microbe,
  promoting phagocytosis

opsonization coats a microbe so phagocytes can grab it easily

mast cell mediator release

• Tissue-resident cell (connective tissue, skin, mucosa) with many granules rich in histamine and heparin.

• High-affinity Fcε receptors (FcεRI) bind IgE

• Cross-linking: if an antigen binds at least 2 IgE molecules on the mast cell surface, the mast cell is activated

• C3a and C5a (complement) can also trigger mast cell activation

mast cells are alarm bells packed with histamine

local inflammatory response

Inducers of inflammation (amplifying events):

• Mast cell products – histamine (immediate release), leukotrienes (delayed release)

• Prostaglandins – e.g. from macrophages and mast cells

• Cytokines – e.g. from macrophages and T cells

• Chemokines – attract leukocytes to the site 1
  
  

inflammation brings more blood, fluid and immune cells to the site of infection

eosinophils

• defence against parasites

• Parasites such as worms are too large to be phagocytosed.

• Eosinophils bind antibody-coated parasites via Fc receptors.

• They release toxic granule proteins onto the parasite surface – extracellular digestion

too big to swallow? attack from outside

where to T and B cells meet antigen

1. Naive T cells are activated (primed) in secondary lymphoid organs – lymph nodes, spleen, mucosal lymphoid tissue

2. Dendritic cells carry antigen from the infected tissue to the lymph node

3. Effector T cells then leave and act in the infected tissue

adaptive responses start in lymph nodes

Th2 and help and B cell activation

1. Pathogen enters the body

2. Dendritic cell takes it up

3. Shows it on MHC class II

4. CD4 T cell becomes Th2 (makes IL-4)

5. Meanwhile, a B cell binds the same pathogen

6. Th2 helps the B cell make antibodies

Th2 cells help B cells make antibodies

Intracellular pathogens

Intracellular pathogens (viruses, M. tuberculosis, Listeria) hide inside host cells, out of reach of antibodies and complement – so the immune system must recognise and deal with the infected cell

intracellular pathogens

• recognition

• response

two key populations of T cells

• The CD4/CD8 co-receptors are very important – they ensure the correct type of T cell is activated.

• CD4 helper T cells (Th)

  • Help B cells (antibody production) and macrophages (phagocytosis and killing)

• CD8 cytotoxic T cells (Tc)

  • Kill infected cells
    

CD4 T cells are the helpers; CD8 T cells are the killers

why do T cells need MHC presentation?

• T cells don’t recognize pathogens in their native form

• The pathogen must be processed and presented on MHC class I or class II for T cell activation

Why is this important?

• We don’t want to kill cells that have deliberately taken up a pathogen – they need help

• We only want to kill a cell if it has an infection in its cytosol
  

MHC is the cell’s displayed window _ T cells inspect what is shown there

where is the pathogen?

• Whether the pathogen is in the cytosol or in a vesicle determines whether it is presented on MHC class I or class II

• This ensures that the right type of T cell is activated
  

where the pathogen lives decides which MHC - and which cell - responds

MHC class l presents to CD8 T cells

1. Virus has infected the cytosol of the cell

2. Virus is degraded and presented on MHC class I

3. Peptide recognised by the TCR, with CD8 as the co-receptor

4. CD8 binds directly to the α3 domain of MHC class I

5. CD8 cytotoxic T cell is activated and can kill the virally infected cell

MHC l + CD8 → kill the infected cell

MHC class ll presents to CD4 T cells

1. Vesicular pathogen – taken into the cell in a vesicle (e.g. M. tuberculosis in a macrophage phagosome)

2. Pathogen is degraded and presented on MHC class II

3. Peptide recognised by the TCR, with CD4 as the co-receptor

4. CD4 binds directly to the β2 domain of MHC class II

5. CD4 helper T cell is activated and makes cytokines that help the APC kill the pathogen it has ingested

MHC ll + CD4 → help the cell that swallowed the pathogen

innate defence against intracellular pathogens

T cell responses take days to develop. Meanwhile, the innate system already limits infection inside cells:

Type I interferons (IFN-α, IFN-β)

• Released by virus-infected cells

• Make neighbouring cells resist viral replication

• Increase MHC class I expression

• Activate NK cells

Natural killer (NK) cells

• Innate lymphocytes that kill infected cells

• Detect cells that have lost MHC class I (‘missing self’) or show stress signals

• Kill using perforin and granzymes – the same mechanism CD8 T cells use

• Release IFN-γ, which activates macrophages

the innate system holds the line during the days before T cells arrive

T cell activation - putting it together

For a T cell to be activated, the peptide must be processed and presented on MHC class I or II

• MHC class l + CD8 : ensures CD8 T cells respond to virally infected cells

• MHC class ll + CD4 : ensures CD4 T cells respond when an APC needs help

Right MHC + right co-receptor + the right T cell responds

T cell activation - the three signals

Signal 1

• Recognition

  • The TCR recognises its specific peptide presented on MHC

Signal 2

• Co-stimulation

  • CD28 on the T cell binds B7 (CD80/CD86) on the antigen- presenting cell

Signal 3

• Polarising cytokines

  • Decide what type of T cell develops

No co-stimulation, no activation - a built-in safety check

helper T cell subsets and cytokines

• Th0 = naive CD$ T cell

• signal 3 cytokines decide what it becomes

Th1

• activates macrophages

Th2

• helps B cells

cytokines decide what a helper T cell becomes

helper T cell subsets - Th1, Th2, Th17, and Treg

Th1 - intracellular

Th2 - parasites

Th17 - bacteria & fungi

treg - calms

CD8 cytoxic T cells

• killing infected cells

1. Naive CD8 T cells are activated by dendritic cells in the lymph node
   and proliferate

2. Effector CD8 T cells travel to the infected tissue

3. They recognise viral peptide on MHC class I and kill the infected cell by apoptosis (perforin and granzymes)

CD8 T cells make infected cells self-destruct - taking the virus down with them

Th1 cells

Th1 cells activate macrophages so they can kill the microbes they
have ingested

two activating signals:

• IFN-γ (cytokine)

• CD40L (cell contact)
  
  

Result: activated macrophages fuse phagosomes with lysosomes and make more reactive oxygen and nitrogen species, killing intracellular bacteria

Th1 cells switch macrophages into killing mode

two pathways one team

Extracellular

where it lives: blood, tissue fluid, mucosa

Recognized by: PRRs, compliment, B cells

Main weapons: Antibodies, complete, phagocytes

Helper T cell: Th2 → B cells

Example: Streptococcus pneumoniae

Intracellular

where it lives: cytosol or vesicles

Recognized by: T cells via MHC l or ll

Main weapons: Interferins, NK cells, CD8 T cells

Helper T cell: th1 → macrophages

Example: Mycobacterium tuberculosis

overview

Location decides the strategy
Outside: antibodies & phagocytes.

Inside: target the infected cell

Innate first, adaptive next
Innate acts in hours; B and T cells take days but are specific.

The two arms work together
Antibodies help phagocytes; T cells help B cells and macrophages.

It matters clinically
Vaccines build antibodies; immune gaps open the door to infection.