The innate immune response

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The innate immune response
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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.

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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.

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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.

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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.

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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.

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The immune system has evolved to protect
eukaryotes from microbes
Parasite in red blood cell
Bacteria
SARS virus
Fungus
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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.

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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.

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Markers of self
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.
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Markers of non-self
Bacteria
SARS virus
Epitope
Antigen
Antibody
Non-self leukocyte
Non-self nerve cell
Antigen
Epitope Class I MHC protein
Antibody
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Markers of self Major Histocompatibility Complex
Antigenic peptide
Antigenic peptide
Antigenic peptide
Viral infection
MHC Class II
MHC Class I
MHC Class I
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.
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Requirements for an effective defence against
pathogens

• Response should not harm the host recognition
  of pathogen presence by recognition of non-self
• Should be present as soon as exposure to
  pathogens occurs (i.e. at birth)
• Response must be rapid (pathogens can replicate
  rapidly)
• 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.

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Outcome of the response to microbial invasion by
the innate defences

• 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

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What is immunity?

• Protection and resistance from infection by
  microrganisms.
• Innate and adaptive immunity have overlapping but
  distinctly different roles in this process.

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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

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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.

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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)

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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

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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.

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Complement
C2
C3a
C3
C7
C5a
C1
C8
C6
C5b
IgG
C5b
Enzyme
C5
C3b
C4
Antigen
C9
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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

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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.

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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.

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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.

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Phagocytes and their relatives
Monocyte
Eosinophil
Mast cell
Dendritic cell
Macrophage
Neutrophil

• 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

Basophil
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Phagocytes in the body
Brain microglial cells
Lungalveolar macrophages
Liver Kupffer cells
Spleen macrophages
Kidneymesangial phagocytes
Blood monocytes
Lymph node resident and recirculating macrophages
Precursors in bone marrow
Jointsynovial A cells
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Phagocyte killing mechanisms

• Acidification pH 3.5-4.0
• Antimicrobial peptides defensins, cationic
  proteins
• Enzymes lysozyme, acid hydrolases
• Competitors lactoferrin
• Toxic nitrogen intermediates nitric oxide
• Toxic oxygen intermediates O2-, H2O2, OH, OCl

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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.

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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)

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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

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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.

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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.