Download Innate Immune Response

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
Bacteria
Parasite in red blood cell
SARS virus
Fungus
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.
Markers of self
Epithelial
cell
Muscle cell
Leukocyte
Nerve
cell
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 non-self
Bacteria
SARS virus
Epitope
Antigen
Antibody
Non-self nerve cell
Non-self leukocyte
Antigen
Epitope
Class I MHC protein
Antibody
Markers of self:
Major Histocompatibility Complex
Viral
infection
Antigenic
peptide
Antigenic
peptide
Antigenic
peptide
MHC
Class I
MHC
Class I
MHC
Class II
Antigen-presenting cell
uses MHC Class I or II
Infected cell
Cell
membrane
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
defences
1.
2.
Innate defences remove or control invading microbes;
thus infection resolves
OR
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
C2
C3
C3a
C5a
C1
C7
C6
C8
C5b
IgG
C5b
Antigen
C4
Enzyme
C3b
C5
C9
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 the
innate 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
Eosinophil
Mast cell
Macrophage
Dendritic cell
Neutrophil
Functions of Phagocytes
Basophil
• 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
Lung:
alveolar
macrophages
Liver:
Kupffer cells
Kidney:
mesangial
phagocytes
Lymph node:
resident and
recirculating
macrophages
Spleen:
macrophages
Blood:
monocytes
Precursors in bone
marrow
Joint:
synovial A cells
Phagocyte killing mechanisms
Acidification
Antimicrobial peptides
Enzymes
Competitors
Toxic nitrogen intermediates
Toxic oxygen intermediates
pH 3.5-4.0
defensins, cationic proteins
lysozyme, acid hydrolases
lactoferrin
nitric oxide
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.