Evasion of Immunity I

1
Evasion of Immunity I

• Vertebrate and invertebrate immune systems.

Dr. Jo Hamilton Parasitology BS
2
Introduction.

• Successful parasites have evolved strategies for
  survival development in both invertebrate and
  vertebrate hosts.
• The goal of a parasite is to propagate within the
  host and be transmitted to the next host.
• The goal of the parasitised host is to cure or
  limit the infection.
• During the next three lectures we will
  investigate strategies used by parasites to evade
  the host immune response.
• In this session we will revisit the immune system
  of both vertebrates and invertebrates.

3
Objectives and learning outcomes.

• By the end of this session students should be
• Familiar with fundamental biology of vertebrate
  invertebrate immune systems.
• Familiar with the concept of innate and acquired
  immunity in vertebrates.
• Recognise that there is only innate immunity in
  invertebrates.
• Recognise the key players in both vertebrate and
  invertebrate immune systems.

4
Immunity.

• Resistance to infection is called immunity.
• The term immunity is derived from the Greek
  word immunis meaning exempt.
• There are two types of immunity in vertebrates.
• Innate immunity present from birth.
• Acquired immunity result of infection or
  vaccination.
• Invertebrates only posses innate immunity.

5
Innate immunity in vertebrates (also known as
non-specific or natural immunity).

• Characteristics
• Present from birth.
• Non-specific - acts on many organisms and does
  not show specificity.
• Does not become more efficient on subsequent
  exposure to same organisms.

6
Innate immunity in vertebrates.

• Non-specific Host Defences include
• Mechanical / physical barriers skin, mucosal
  surfaces.
• Prevention of stasis peristalsis, flow of
  urine, upward movement of secretions in bronchial
  tree, coughing, vomiting.

7
Innate immunity in vertebrates.

• Chemical defences - Low pH of stomach contents,
  secretion of fatty acids in the skin.
• Biological defence complement, lysozyme,
  interferons, antimicrobial peptides, kinins,
  adhesion molecules, hormones, lactoferrin.
• Cellular defence - e.g. phagocytes.

8
Innate immunity in vertebrates.

• Some of the key players in innate immunity to
  consider in more detail are
• Complement.
• Opsonization.
• Phagocytosis the oxidative burst.
• Inflammation.

9
Innate immunity in vertebrates complement.

• Complement. - complex of 17 proteins present in
  normal serum.
• 2 pathways classical alternative.

10
Innate immunity in vertebrates classical
complement pathway.

• Antigen-antibody complex forms, constant region
  of antibody changes shape.
• Activates C1, acquires esterase activity.
• Activated C1 activates C2 C4 which activates
  C3, etc.
• Eventually, C8 C9 activated forming membrane
  attack complex (MAC) - pores in target cell
  membrane - lysis.

11
Innate immunity in vertebrates - alternative
complement pathway.

• Alternative pathway - C3 can interact directly
  with certain chemicals (teichoic acids, LPS)
  found in bacterial cell walls and activate the
  alternative pathway.

12
Innate immunity in vertebrates opsonization.

• Opsonization - process of coating micro-organisms
  with plasma proteins to make them more easily
  phagocytosable.
• It is stimulated by complement bound to
  antibody-antigen targets.
• Opsonization promotes adhesion between opsonized
  cell macrophages. The opsonin binds to
  receptors on phagocyte membrane.
• Opsonization and phagocytosis are more efficient
  in immune individuals.

13
Innate immunity in vertebrates cellular defence.

• Cellular defence involves
• Granulocytes (also known as the polymorphonuclear
  leukocytes e.g. eosinophils, basophils etc).
• The reticulo endothelial system (e.g.
  macrophages, Kupffer cells of the liver and
  natural killer (NK cells).

14
Innate immunity in vertebrates White blood
cells.

• Role of white blood cells in cellular defence.
• White blood cells (WBCs) are major components of
  immune system.

15
Innate immunity in vertebrates phagocytosis.

• Certain WBCs highly mobile carry out
  phagocytosis.
• WBCs chemotactically attracted to foci of disease
  or tissue damage.
• Phagocytosis begins with engulfment of
  particulate matter (e.g. bacteria, clumps of
  virions, cell debris, etc.) into a phagosome.

16
Innate immunity in vertebrates phagocytosis
contd.

• The phagosome fuses with lysosomes to form the
  phagolysosome.
• Lysosomes contain number of enzymes including
  acid hydrolases, lysozyme, neutral proteases,
  myeloperoxidase, lactoferrin, phospholipase A.
• These enzymes can degrade biomolecules.

17
Innate immunity in vertebrates oxidative burst.

• Once engulfed, the white cell must kill the
  organisms by some means such as the respiratory
  (or oxidative) burst".
• Many pathogens and parasites succeed because they
  are able to avoid phagocytosis.

18
Innate immunity in vertebrates inflammation .

• Inflammation - (or inflammatory response)
  mechanism by which phagocytes and complement are
  recruited to site of tissue invasion.
• Non-specific reaction to tissue damage. Cell
  damage initiates a complex series of steps
  leading to inflammation.

19
Innate immunity in vertebrates inflammation.

• Inflammation involves
• Vasodilation - swelling.
• adhesion of leukocytes to endothelial cells of
  post-capillary venule, emigration of phagocytes
  into tissues.
• redness (blood flow).
• pain (prostaglandins bind to nerve receptors).
• heat (pyrogens).
• Inflammation localised to area of infection /
  injury by release of substances from
  micro-organisms or chemical mediators released
  from cells in tissues, e.g. histamine from mast
  cells.
• Once organisms are destroyed inflammation
  settles down (resolves).

20
Acquired immunity (only in vertebrates).

• Also known as adaptive immunity / specific
  immunity.
• Develops as response to an infection.
• Called adaptive as immune system adapts itself to
  previously unseen molecules.
• The induction of immunity by infection, or with a
  vaccine, is called active immunity.

21
Acquired immunity.

• Induction of immunity by infection, or with
  vaccine, called active immunity.
• Non-immune individual can be made immune by
  transferring serum or lymphocytes from immune
  individual. This is know as passive immunity and
  demonstrates that serum constituents (antibodies)
  and lymphocytes are involved in immunity.

22
Acquired immunity.

• Characteristics of acquired immunity
• Immunological recognition.
• Discrimination between self and non-self.
• Immunological specificity.
• Immunological memory.

23
Acquired immunity.

• Immunity mediated by immune system, responds to
  infection by mounting immune response. An immune
  response must
• Recognise a micro-organism or parasite as foreign
  (non-self) as distinct from self.
• Respond to the presence of a foreign organism by
  production of specific antibodies and specific
  lymphocytes.
• Mediate the elimination of such organisms.

24
Acquired immunity.

• There are two types of acquired immunity.
• Cell-mediated immunity - this is immunity
  mediated by T-cells. T cells secrete lymphokines
  (e.g. interleukin-2) which interact with other
  cell types, and either activate or repress an
  immune response.
• Humoral immunity - this is blood-specific
  immunity mediated by antibodies (Abs).

25
Acquired immunity cell mediated immunity.
26
Acquired immunity cell mediated immunity.

• Key cells involved in acquired immunity response
  are lymphocytes.
• Two types lymphocyte develop in bone marrow from
  common precursor.
• Each different response mediated by different
  sets of lymphocytes.
• Following invasion by a foreign organism,
  lymphocytes proliferate (i.e. divide) and
  differentiate (i.e. specialize).

27
Acquired immunity cell mediated immunity, B
lymphocytes.

• B lymphocytes (B cells)
• Found fixed in the lymph nodes, liver and spleen.
  
• They are bone marrow-derived lymphocytes, mature
  in Peyers Patches of the pancreas.
• During maturation, antigen-specified antibody is
  displayed on the cell surface.
• If the cell is activated by an antigen, the B
  cells excrete antibody.

28
Acquired immunity cell mediated immunity, T
lymphocytes.

• T lymphocytes (T-cells)
• Found in lymph nodes, liver, spleen, also freely
  circulating in the blood.
• Matures in thymus. They have cell surface
  receptor of a pre-determined specificity.
• These cells regulate cellular immunity.
• Two main T cell types helper T cells (Th cells
  have the CD4 receptor) suppressor / cytotoxic
  T cells (Tc cells display the CD8 receptor).

29
Acquired immunity cell mediated immunity,
macrophages.

• A third important cell type are
• macrophages.
• These cells play essential role in processing
  presenting immunogens to lymphocytes.
• Also important effector cells (i.e. they carry
  out destruction of foreign material e.g.
  phagocytosis).
• Carry receptors for antibody molecules which
  allows them to attach to antibody-antigen
  complexes before phagocytosing them.

30
Acquired immunity generation of immune
response.

• In order for an immune response to be activated,
  an object must first be recognised as foreign.
• An immunogen is any molecule that stimulates an
  immune response. In general, proteins are the
  best immunogens, followed by carbohydrates and
  then nucleic acids. Lipids are very poor.
• An antigen is any molecule that is capable of
  generating an antibody response (antigen
  antibody generating).

31
Acquired immunity generation of immune
response.

• Upon an initial infection, it takes about 4-7
  days to generate an immune response.
• After seven days get primary immune response.
  Initially, IgM produced but B cells differentiate
  further into IgG producing cells. After about
  three weeks primary immune response turned off.
• During this initial period Ab producing cells and
  memory B cells are formed.
• When same agent encountered by host again, body
  recognises it, stimulates the memory cells to
  secrete Abs. This is called the secondary immune
  response.
• Memory can last for few weeks or can last for
  years.

32
Acquired immunity generation of immune
response.

• There are three types of effector immune
  response.
• Humoral (blood) - antibody response mediated by B
  cells regulated by T cells.
• Cell-mediated (cellular) - delayed-type
  hypersensitivity and cytotoxicity mediated by
  CD4 and CD8 T cells.
• Tolerance - non-specific response mediated by T
  cells. Healthy individuals tolerant to own
  tissues, sometimes immune response fails to
  recognise self giving rise to autoimmune diseases
  or transplant rejection in transplantation
  surgery.

33
Humoral immunity antibodies.

• Large glycoproteins released by B cells.
  Antibodies (Abs) specifically interact with
  antigens. Body can produce millions of antibody
  specificities genetically as the B cells mature.
  There are five classes of Ab
• IgM largest first Ab to be made antibody
  response. IgM can mediate neutralisation, fix
  complement, agglutinate and immobilise antigens.
• IgG - this is the main serum Ab. This is
  synthesized during the secondary immune response.
  Able to do all Ab mediated functions.

34
Humoral immunity antibodies contd.

• IgA - is mucosal antibody. Sometimes called
  secretory Ab as mucosal cells secrete them when
  mucosal pathogens begin to establish colonies.
• IgD - is receptor antibody found on the surface
  of immunocompetent cells. This functions in the
  afferent response.
• IgE - binds to the surface of mast cells causing
  degranulation of the cell and release of
  histamine into circulation. This ab is involved
  with allergies.

35
Humoral immunity antibodies contd.

• Abs are important for us in five ways.
• neutralisation - an Ab molecule covers up sites
  on toxic molecule or virus.
• opsonization - this is Ab-mediated phagocytosis.
  Macrophages have antibody receptor sites on
  surface, able to bind to antigen-antibody
  complexes before phagocytosing them.
• complement fixation - a complicated system that
  reacts to antigen/antibody complexes (see also
  complement notes in innate immunity).

36
Humoral immunity antibodies contd.

• agglutination/precipitation - Abs cross-link
  antigens into large complexes making them easier
  to phagocytose destroy.
• immobilization - Abs bind to flagella etc.
  prevent organisms from escaping macrophage death.
  

37
Cellular immunity Th and Tc cells.

• Often directed against intracellular parasites
  cancer. Infected cells killed by macrophages
  under directions of CD4 Th cells. Cytotoxic T
  cells (CD8 directed) also participate by
  releasing toxic components which kill the cell.
• Cells involved in cellular immunity must be able
  to recognise self, especially as many of their
  targets are cells infected by agents that are
  within them. This means killing ones own cells in
  an effort to rid the infection. Self recognition
  is mediated by the Major Histocompatibility
  Complex antigens (MHC antigens). All our cells
  display these MHC antigens in specific patterns
  on the cell surface.

38
Cellular immunity Major Histocompatibility
Complex.

• Macrophages must process the antigen then
  display pieces of the antigen on its cell
  surface. They then present this antigen to T
  cells, which recognize the antigen as being
  foreign as well as recognising the MHC antigens.
  If the T cell sees both antigen and MHC it
  becomes activated if it sees only the MHC
  antigen nothing happens.
• When macrophages display antigen plus Class I MHC
  they stimulate CD8 cells (i.e. they make
  cytotoxic T cells) when they displayed antigen
  plus Class II MHC they stimulate CD4 cells (i.e.
  helper T cells).

39
Invertebrate immune system.

• Comparison of vertebrate invertebrate immunity.
• Vertebrates Invertebrates
• Innate Immunity Innate Immunity
• (e.g. antimicrobial peptides) (e.g.
  antimicrobial peptides)
• Acquired immunity ---------------------
• Phagocytic cells Phagocytic cells
• (Macrophages neutrophils etc) (Haemaocytes)
• ----------------------------------- Melanization
  
• ----------------------------------- Phenoloxidas
  e cascades
• Cytokines Macrokines
• Immune competent tissues Immune competent
  tissues
• N.B. Invertebrate immune system comprises only
  innate system it is non-specific and has no
  memory component. Vertebrate immune system both
  innate and acquired components.

40
Invertebrate immunity.

• The invertebrate immune system is comprised of
  two branches
• The humoral response (N.B. this is not antibody
  mediated) is concerned with soluble components
  such as antimicrobial peptides (AMPs),
  agglutinins (lectins) and macrokines (these are
  similar to cytokines).
• The cellular response includes phagocytosis
  (haemocytes), encapsulation and nodulation.

41
Invertebrate immunity humoral response.

• Antimicrobial peptides. Wide range including
  defensins, cecropins, andropins, ceratotoxins,
  drosomycin penaeidins etc. Their action leads
  to lysis of invading organism e.g. bacteria
  protozoa.
• Macrokines. There is growing evidence of these
  cytokine-like molecules. Haemolymph preparations
  have been shown to stimulate vertebrate immune
  effector cells (e.g. macrophages).
• Agglutinins (lectins). Agglutinate invading
  organisms making them easier to phagocytose.

42
Invertebrate immunity cellular response.

• Phagocytosis - Haemocytes (amoebocytes) front
  line of invertebrate cellular. Foreign (non-self)
  invaders are taken into a phagocytotic vacuole
  where proteolytic enzymes free oxygen radicals
  destroy the pathogen (in a similar way to
  vertebrate macrophages). Bacteria and yeast
  (lt10microns) can be phagocytosed.

43
Invertebrate immunity cellular response contd.

• Encapsulation - If invader too large for
  phagocytosis (e.g. the egg of a parasitic wasp),
  encapsulation might ensue. Invader is compacted
  under layer of haemocytes. This is accompanied
  by melanization. The melanized capsule adheres to
  host tissues but is walled off from the host.
  Phenoloxidases mediate melanization reaction but
  also have other tasks including wound healing,
  cuticle pigmentation sclerotisation.

44
Invertebrate immunity cellular response contd.

• Nodulation - Microaggregates of haemocytes
  bacteria encased in haemocytes are melanised
  removed from circulation.
• Phagocytosis, encapsulation and nodulation
  mediated by eicosanoids (prostaglandins,
  leukotrienes).

45
Invertebrate immunity mechanical / physical
barriers.

• In addition to the cellular humoral defences,
  invertebrates also have mechanical or physical
  defences.
• These include the cuticle, epithelia and in the
  case of insects the peritrophic membrane.

46
Summary.

• By the end of this session you should be
• Familiar with fundamental biology of vertebrate
  invertebrate immune systems.
• Familiar with the concept of innate and acquired
  immunity in vertebrates.
• Recoginise that invertebrates have only innate
  immune system.
• Recognise the key players in both vertebrate and
  invertebrate immune systems.

47
Next session.

• We will
• Describe immunity to particular parasites.
• Explore the strategies that parasites use to
  evade the hosts immune system.