Innate immunity

What does the immune systems do?

1. Recognises there’s a threat - self vs non-self

2. Deals with that threat - barrier, innate and adaptive systems coordinate

3. Resolves the response to the threat

4. Remembers the threat

What are the parts of the immune system?

• Barriers

  • Protect you so the immune system doesn’t have to get into action

• Humoral effectors

  • Anything soluble (molecules, not cells e.g. antibody, complement)

• Innate cells such as:

  • Phagocytes

  • Killer cells

  • Granulocytes - cells that pre made chemicals and enzymes to help the response

• Adaptive cells

  • Cells that respond to specific antigens (B & T cells)

  • Can change their specificity to adapt to a new challenge (B cells)

  • Cells that co-ordinate the response (helper T cells), and cells that kill (cytotoxic T cells)

Pathogens that infect individuals

1. Viruses

2. Bacteria

3. Fungi

4. Protozoa

Skin

Largest organ in the body

• Thick and dead outer layer

• Dry surface

• Impermeable (keratin)

• Anti microbial secretions

Thing that breach the skin barrier

1. Frequently acquired

• Burns, wounds, bites

2. Medical

• Surgery, needles, cannulas

3. Inherited issues

• Eczema

Internal barriers to infection

• Mucosal surfaces e.g. lungs & GI tract

  • Often only 1 cell thick to allow passage of molecules

• Respiratory tract

• Conjunctiva

• Urinogenital tract

• Anus

• Alimentary tract

Lungs

Changes that affect the lungs

• Alteration to mucosal flow

• Inherited

  • Cystic fibrosis, primary ciliary dyskinesia (PCD)

• Acquired

  • E.g. smoking

GI tract

• Chemical barriers e.g. stomach acid, bile salts, high pH in the duodenum and jejunum

• Physical e.g. mucous, peristalsis

Biological barrier

• Commensal bacteria - they are most often disrupted through antibiotics e.g. broad-spectrum antibiotics

Summary of the main physical, chemical & biological barriers of the body

Overview of innate and adaptive immune system

What is the innate immune system compromised of?

• Humoral components: plasma proteins, complement, acute phase proteins

• Cellular components

Humoral immune system: complement

• Present in high conc in plasma & tissue fluids

• Produced continuously by the liver

What is the complement system?

• Enzyme cascade

• Rapid amplification & generation of effector molecules

• 9 soluble (plasma) pro-enzymes C1-C9

What does complement do?

• Opsonisation (targeting and improved efficiency of phagocytosis) this is through C3b

• Activates cells - inflammation

• Many cells have complement receptors for C3a e.g. improves or initiates responses

  • Mast cell degranulation

  • Macrophage phagocytosis

• Attracts immune cells

  • (Activates endothelium)

  • Provides a concentration gradient to follow

• Lysis of pathogens - membrane attack complex

Acute phase proteins

• Present in low conc in plasma & tissue fluids

• Production greatly increased in response to infection

• Mannose binding lectin (MBL)

• C-Reactive protein (CRP)

How is the complement activated?

1. Alternative pathway

2. Lectin pathway

3. Classical pathway

Haematopoeisis - where immune cells come from

• All immune cells derived from bone marrow pre-cursors

• Differentiation depends on growth factors

Location of innate immune cells - 2 categories

Sentinel immune cells are in all our body surfaces

• Provide an immediate response

• Activate our adaptive immune system

Circulating immune cells provide:

• Quick ‘back up’

• Specialised roles & functions

Cells of the innate immune system - different functions

• All cells recognise threat - PRRs, DRRs, complement receptors

• Some engulf and destroy threat - phagocytes, macrophages, neutrophils

• Some use pre-made reagents - granulocytes, neutrophils, mast cells, basophils, eosinophils

• Some kill infected cells - NK cells

• Many alert and interact with T cells - APCs through MHC, dendritic cells, macrophages/monocytes

3 types of sentinel cells

1. Mast cells

2. Macrophages

3. Dendritic cells

Mast cell function

• Produce inflammatory mediators

• Contain many granules packed full of histamine and other mediators

• Vasodilation and local cell activation

• Parasite responses

• Immediate release: histamine

• Late mediators e.g. prostaglandins and leukotrienes

Vascular changes in acute inflammation

Macrophages - function and how they are activated

• Tissue resident phagocytes - kill pathogens

• Monocyte differentiate into macrophages when they enter tissues

Activated by:

• Complement e.g. C3a

• Cytokines

• PAMPs

Cytokines and chemokines

• Small protein molecules made by cells that change the behaviour of other cells

• Act though specific cytokines receptors

• Can be pro-inflammatory or anti-inflammatory

• Help ‘direct’ an immune response

Chemokines

• Type of cytokine

• Small chemoattractant proteins that stimulate the migration and activation of other cells especially phagocytes

How are the innate and adaptive response joined?

Dendritic cells

• Constantly sample the environment

• In infection - activated by pathogens (though PAMPs)

• Take in antigen, process it and migrate to the nearest lymph node to activate T cells

What type of cells do we need to recruit from the blood?

• Neutrophils - quickly infiltrate infected tissue

  • Highly phagocytise, essential for host protection and innate immunity

• Neutrophil netosis - a form of activated eutrophic cell death

  • Traps and kills microbes

• Monocytes - circulate in the blood, enter tissue, mature into macrophages

For a viral response: natural killer (NK) cells - what do they do?

• Rapid responses to infected cells and respond to tumour formation

• Detect absence of MHC molecules on infected cell surfaces that trigger granule release which induces target cell lysis or apoptosis

For parasite responses

• Eosinophils - kill antibody created parasites, release toxic granules

• Basophils - immune responses to parasite, similar in function to mast cells

Types of circulating cells

• NK cell

• Monocyte

• Eosinophil

• Basophils

• Neutrophil

Pathogens recognition

• Pattern Recognition Receptors (PRRs) That detect key microbial components

• Pathogen-associated molecular patterns (PAMPs)

• Greatest expression of PRRs on sentinel immune cells:

  • Macrophages

  • Dendritic cells

  • Mast cells

PRRs are located:

• On the cell surfaces

• In the cytoplasm

• In phagosomes

But all signal to change gene expression

Common pathogen PAMPs

Pathogens have to survive PAMPs

They can be:

• Surface structures

• Nucleic acids

• Metabolic products

Examples:

• Viral and bacterial genomes

• Fungal sugars

• Bacterial cell wall sugars

• Flagellin proteins

Surface expressed pattern recognition receptors (PRR) and where they can be found

Example of a surface expressed PRR

• Toll like receptor 4 (TLR4)

• Toll like receptor 5 (TLR5)

They can be found in endosomes such as phagosomes - endosomal PRR band to internal molecules from pathogens

PRR binding outcomes

• Cytokines - inflammation, activate cells

• Chemokines - recruit cells

• Dendritic cell activation - adaptive response

• Anti-bacterial peptides

• Interferons - anti viral response

Toll-like receptors (TLRs) - what they are and function

• A family of pattern- recognition receptors

• Each TLR binds specific pathogen-associated molecular patterns (PAMPs) of viruses, bacteria, fungi and parasites

• The activation of TLR and its associated signalling pathway leads to a broad range of inflammatory responses mediated mainly by increased secretion of cytokines and chemokines

PRRs in cell cytosine detects exposed viral genome

All cells have cytoplasmic PRRs

After activation these PRRs trigger transcription and interferon (IFN) production

What do interferons do?

• Signals to neighbouring cells to shut down protein production and degrade RNA

• Makes neighbouring cells more likely to undergo apoptosis

• Attracts immune cells

How do NK cells recognise healthy cells?

Normal levels of expression of MHC Class 1 molecules inhibits NK cells from killing healthy cells

How do NK cells recognise unhealthy cells?

Infected or malignant cels don’t express MHC Class 1, only the activators signals is left so the NK cell kills that cell

NK cells can kill virus infected cells that have antibody bound to them

Viruses that have membranes will put their proteins in cell membranes leading to binding so NK cells will kill

Key features of innate immunity

• Always present - rapid response

• A set repertoire of PRR responses to common pathogen molecules (PAMPs)

• No memory response generated

• Probably the major pathway by which invading organisms are cleared

How does the adaptive immune system are the innate better?

High affinity antibody:

• Faster phagocytosis

• Viral and toxin neutralisation

• NK cells ADCC improved

T cell helps increase:

• Cytokines production

• Killing ability of phagocytes

T cell killing:

• Reduces viral load