The innate immune response

Levels of Defence

• Organisms must continually defend themselves against pathogens of many kinds

• A variety of defence mechanisms have evolved to increase the chances of survival in the face of these external challenges

• Defence mechanisms operate at all levels – external and internal, and involve molecules, cells and organ systems.

Non-specifc Defences

• Non-specific defences are found in all organisms.

• They are non-specific because they protect against a wide variety of pathogenic organisms.

• They are innate – meaning that they are always present and are not produced by prior contacts with a pathogen.

Invertebrate Defences

• Invertebrate animals have only innate non-specific defence mechanisms.

• They may respond to any foreign material (including a parasite) by producing a capsule of connective tissue around the material. Within the capsule, phagocytic cells may ingest the invader.

• Some species of crustaceans produce broad spectrum bacteriocidal agents in response to infection by bacteria.

• Both these reactions require the ability to recognise and reject ‘non-self’ materials, but it is not known how this occurs in inverterbrates.

Plant Defences

• Like animals, plants have both molecular and cell-mediated defences, and are able to distinguish ‘self’ from ‘non-self’.

• Unlike other organisms, plants have no circulatory system or wandering phagocytic cells so each cell must fend for itself.

• Cell wall is first line of defence – it provides a physical barrier against pathogens.

Plant Defences• Secondary substances – these are chemicals produced by plants,

e.g.:– Antibiotics to protect against bacterial and fungal infections– Protease enzymes that disrupt the digestive functions of herbivores– Cellulases and chitinases that kill fungal cells by digesting their cell

walls– Ecdysome – insect moulting hormone. Disrupts the hormonal balance

of parasitic insect larvae– Specific examples from textbook include the toxic compounds produced

by Eucalypt leaves and the cytotoxic chemicals produced by some species of Acacia

• Cell mediated defences can involve self-destruction of infected or damaged cells.

• Isolation and encapsulation are also important mechanisms for defending against plant parasites such as fungi, nematodes, bacteria, viruses and insects.

The immune system has evolved to protect eukaryotes from microbes

SARS virus

Parasite in red blood cell

Fungus

Bacteria

Us and them – ‘self’ and ‘non-self’

• Microorganisms – protozoans, bacteria, viruses, helminths (worms) all express unique molecules (proteins, carbohydrates and lipids) that distinguish them from other species.

• These molecular differences are the basis by which the immune system discriminates microbes from self components.

Recognition of ‘Self’ and ‘Non-self’

• Some microbial molecules are shared with us.

• Some microbial molecules are unique to microbes but are shared within discrete taxonomic groups e.g. LPS in gram negative bacteria. These shared molecules are called PAMPs (pathogen associated molecular patterns).

• Some microbial molecules are unique to a particular organism e.g. those displayed by one strain of influenza virus but not another strain.

• Unique molecules that can be recognised by the immune system are called antigens.

• The immune system has separate sets of receptors for recognising shared and unique molecular patterns that are distinct from ‘self’ molecules.

Muscle cell

Nervecell

Epithelialcell

Leukocyte

Class I MHC self-marker protein

Every cell in your body carries the same set of distinctive surface proteins that distinguish you as “self.” This set of unique markers on human cells is called the major histocompatibility complex (MHC) proteins. There are two classes: MHC Class I proteins, which are on all cells, and MHC Class II proteins, which are only on certain specialized cells.

Markers of self

Markers of non-self

Non-self leukocyte

Antibody

Epitope Class I MHC protein

Epitope

Antibody

Antigen

Antigen

Bacteria

Non-self nerve cell

SARS virus

Markers of self:Major Histocompatibility Complex

Antigenic peptide

Antigen-presenting cell uses MHC Class I or II

Cell membrane

MHC Class II

Antigenic peptide

Viral infection

Infected cell

MHC Class I

Antigenic peptide

MHC Class I

Your immune cells recognize major histocompatibility complex proteins (MHC) when they distinguish between self and non-self. An MHC protein serves as a recognizable scaffold that presents pieces (peptides) of a foreign protein (antigenic) to immune cells.

Requirements for an effective defence against pathogens

1. Response should not harm the host – recognition of pathogen presence by recognition of ‘non-self’

2. Should be present as soon as exposure to pathogens occurs (i.e. at birth)

3. Response must be rapid (pathogens can replicate rapidly)

4. Response must be appropriate for the pathogen (pathogens vary in size, environment, etc)

These features evolved early in the development of life on Earth and are displayed by the innate immune system.

Outcome of the response to microbial invasion by the innate

defences1. Innate defences remove or control invading microbes;

thus infection resolvesOR

2. The microorganism persists and replicates – because some microbes have evolved to overcome the defences of the innate immune system. These are pathogens.

Additional effector mechanisms are required to remove pathogens

These are provided by the more recently evolved adaptive (specific, acquired, cognate) immune system

What is immunity?

• Protection and resistance from infection by microrganisms.

• Innate and adaptive immunity have overlapping but distinctly different roles in this process.

Where are immune defences required?

Sites of microbial infection and normal flora– Skin– Nose and mouth– Respiratory tract– Eye– Scratch, injury– Circulation– Urogenital tract– Anus

Interactions with microbes

• Not all microorganisms cause disease – some microbes colonise their host and aid normal body functions.

• Suppression of the immune system allows microbes that are normally harmless to become pathogenic – “opportunistic infections”.

• Some microbes have evolved to evade the innate immune system (pathogens) so the adaptive immune system developed later in evolution.

Innate Immune System

• The innate immune system controls the early stages of infection.

• Characteristics:– Relatively non-specific – receptor molecules on cells and in

serum recognise PAMPS– Rapid – because components already present– Magnitude constant– Acts as a first line of defence (sentinel function)

• Comprises:– Physical barriers– Biochemical barriers– Serum factors (complement, cytokines etc)– Cells (neutrophils, macrophages, NK cells, other)

Physical and biochemical barriers of innate immunity

• Physical barriers prevent microbial entry.• Biochemical barriers control pathogen growth.• Normal flora compete with potential pathogens.

– Skin = barrier. Sweat (acidic pH)– Clotting = also helps protect skin– Lysozyme = enzyme in saliva, sweat, tears. Attacks bacterial cell

walls– Mucous (respiratory, digestive, urinary & reproductive tracts) =

traps pathogens – Cilia = little hairs that help clear mucous (and pathogens) from

respiratory tract– Alimentary canal = lysozyme in saliva, stomach HCl kills many

pathogens, specialised immune areas in the GI tract, very high turnover of epithelial cells, antibodies

– Movement e.g. peristalsis, cough reflex, blinking

Soluble factors – the complement system

• The complement system (complement) is a group of plasma proteins which interacts with pathogens to mark them for killing.

• The proteins are activated sequentially in a cascade.

• Multiple triggering events activate the cascade, e.g.– Binding certain PAMPs on microbial surfaces.– Binding antibodies which have bound microbial surfaces

(associated with the adaptive immune response).

• Outcomes:– Migration of phagocytes to site of infection.– Phagocytosis of microbes.– Lysis of some microbes.

Complement

C9Enzyme

C2

C5C3b

C3aC3

C4Antigen

IgG

C1C8

C7

C6

C5b

C5b

C5a

Other soluble factors

Cytokines (including interferons)• Small glycoproteins released by body cells a s a means of communicating

with the immune system• Coordinate many aspects of the immune response• Usually act locally and only remain active for a short time• Cytokines act on target cells by attaching to a cytokine receptor in the

membrane, which sends a signal to the nucleus changing the behaviour of the cell

• Different cytokines trigger a variety of responses, both non-specific and specific e.g. they promote growth and proliferation of lymphocytes, induce fever, promote antibody responses, activate macrophages

Interferons• Set of proteins produced by virally infected cells to limit the spread of viral

infections, by inducing a state of resistance in healthy cells. • Induced by viruses, bacteria and other signals from the immune system

Cells of theinnate immune response

• Phagocytic white blood cells (leukocytes) attracted to a site of infection (chemotaxis) by chemicals released by injured cells.

• Three types– neutrophils (short lived)– monocytes (short-lived..in blood)– macrophages (long-lived..in tissue)

• Cytotoxic cells – eosinophil and natural killer (NK cells)

• Inflammatory cells – basophil, polymorphonuclear granulocytes

• All are derived from pluripotent stem cells in bone marrow.

• All induce inflammation.

Phagocytes and Granulocytes

• Some immune cells have more than one name:– “Phagocytes” are large immune cells that can

engulf and digest foreign invaders– “Granulocytes” refers to immune cells that

carry granules laden with killer chemicals.

Phagocytes

• Phagocytes include: – Monocytes – circulate in the blood– Macrophages – are found in tissues throughout the body– Dendritic cells – are more stationary, monitoring their

environment from one spot such as the skin– Neutrophils – are cells that circulate in the blood but move into

tissues when they are needed.

• Macrophages are versatile cells; besides acting as phagocytic scavengers, they secrete a wide variety of signaling cytokines (called monokines) that are vital to the immune response.

Phagocytes and their relatives

Monocyte

Dendritic cell

Eosinophil

Neutrophil

Basophil

Mast cell

Macrophage

Functions of Phagocytes• Enter an infected site from the circulation• Bind, engulf and kill a wide variety of microbial agents• Produce immunomodulatory substances e.g. cytokines, chemokines, which regulate the immune response• Act as first line of defence against infection

Phagocytes in the body

Brain: microglial cells

Joint:synovial A cells

Precursors in bone marrow

Lymph node: resident and recirculating

macrophages

Blood: monocytes

Kidney:mesangial

phagocytes

Spleen: macrophages

Liver: Kupffer cells

Lung:alveolar

macrophages

Phagocyte killing mechanisms

Acidification pH 3.5-4.0Antimicrobial peptides defensins, cationic proteinsEnzymes lysozyme, acid hydrolasesCompetitors lactoferrinToxic nitrogen intermediates nitric oxideToxic oxygen intermediates O2-, H2O2, OH, OCl

Granulocytes

• Neutrophils are both phagocytes and granulocytes: they contain granules filled with potent chemicals. These chemicals, in addition to destroying microorganisms, play a key role in acute inflammatory reactions.

• Other types of granulocytes are:– Eosinophils and basophils – these degranulate by spraying their

chemicals onto harmful cells or microbes.

– Mast cells – are twins of the basophil, except they are not a blood cells. They release granules containing inflammatory mediators to augment the action of immune cells and are responsible for allergy symptoms in the lungs, skin, and linings of the nose and intestinal tract.

– Blood platelets – are cell fragments. These fragments contain granules which promote blood clotting and wound repair, and activate some immune defenses.

Cytotoxic cells

• Target infected or altered cells, and release granules whose contents are toxic.

• These include:– Natural killer (NK) cells (kill tumours, virus

infected cells)– Eosinophils (kill parasites)– Macrophages (release cytotoxic mediators)

Protective processes

Inflammation

• Infected cells (mast cells) release histamine, which is a vasodilator.

• Causes localised swelling, redness, heat, pain. Can also cause high temperature.

• Brings white cells to the area of infection

• Phagocytes that invade damaged tissue do their work, and are removed by programmed cell death

• Resolvins (derived from omega-3 fatty acids) are a group of naturally occurring substances that have been identified as signalling molecules involved in dampening down the inflammatory response

Protective Processes

Preventing blood loss

• Any injury that damages blood vessels is potentially very dangerous, so very efficient mechanisms have evolved to prevent the loss of blood

– Small arteries constrict in the area around the wound to reduce the amount of blood escaping from damaged vessels (this involves a nervous response)

– Blood platelets become sticky and fragile. They clump together to plug the broken part of the vessel.

– Blood coagulates (clots) as a result of a series of chemical reactions triggered by the damage to cells and the release of platelet contents. Soluble blood proteins are converted into insoluble protein fibres which entangle blood cells and slowly shrink, forming a a more permanent seal over the wound.

– New tissue grows to permanently heal the wound.

Protective Processes

Fever

• Fever is an increase in body temperature resulting from a resetting of the body temperature set-point in the hypothalamus of the brain to a higher level. Temperatures above 37.8oC are regarded as fever.

• Fever can be triggered by bacterial toxins called pyrogens acting directly on the brain or by cytokines released from macrophages stimulated by the presence of bacterial substances.

• Bacteria that infect humans grow best at 37oC so fever reduces the growth rate of most bacteria.

• Moderate increases in temperature increase enzyme activity, so fever often improves many aspects of the inflammatory response.