The Lectin Pathway Originates with Host Proteins Binding Microbial Surfaces

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The Lectin Pathway Originates with Host Proteins
Binding Microbial Surfaces Lectin proteins
that bind to a carbohydrate MBL
(mannose-binding lectin) - a
protein which binds to mannose residues on
glycoproteins or carbohydrates on the surface of
microorganisms (structurally similar to C1q)
MASP-1 MASP-II MBL-associated serine protease

(structurally similar to C1r and C1s)
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• MBL is induced during inflammatory responses.
• After MBL binds to the surface of a microbe,
• MBL-associated serine proteases, ) MASP-1 and
• MASP-2,( bind to MBL.
• The MBL-MASP-1II complex mimics the
• activity of C1r and C1s, and causes cleavage
  and
• activation of C4 and C2.
• Thus, the lectin pathway is Ab-independent.
• It is an important innate defense mechanism
  comparable
• to the alternative pathway, but utilizing the
  elements
• of the classical pathway, except for the C1
  proteins.

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Q2 Why doesnt mannose-binding lectin (MBL)
bind to host carbohydrates? A2
Mammalian cells normally have sialic
acid residues covering the sugar groups
recognized by MBL and are not a target
for binding.
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Biological Effects Mediated by Complement 1.
Cell lysis The membrane-attack complex can
lyse a broad spectrum of cells
G(-) bacteria parasites
viruses
erythrocyte nucleated cells
(tumor cells) Because the activation of
alternative and lectin pathways is
Ab-independent, these pathways serve as important
innate immune defenses against infectious
microorganisms.
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2. Inflammatory response - Various peptides
generated during activation of
complement play a role in the development
of an effective inflammatory response. -
C3a, C4a, C5a (called anaphylatoxin) bind to
complement receptors on mast cells and
basophils and induce degranulation with
release of histamine and other
mediators. - The anaphylatoxins also
increased vascular permeability,
extravasation, and chemoattraction (induced by
C5a, C3a, and C5b67)
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3. Opsonization - C3b is the major opsonin
of the complement system, although C4b also have
opsonizing activity.
binds to the surface of microbes
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Opsonization by Ab and complement
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4. Viral neutralization - Formation of
larger viral aggregates reduces the net
number of infectious viral particles. - The
deposits of Ab and complement on viral
particle neutralizes viral infectivity by
blocking attachment to susceptible host
cells and facilitates binding of the viral
particle.
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5. Clearance of immune complexes
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Innate Immunity Complement
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Comparison of 3 Pathways
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Inflammation
Inflammation is non specific response to tissue
damage resulting from a variety causes, including
heat, chemicals, ultraviolet light, cuts and
pathogens.

• There are two types
• Acute inflammation develops quickly and is
  short lived, is typically beneficial and result
  in the elimination of whatever condition
  precipitated.

• Chronic inflammation develops slowly, lasts a
  long time, and can cause damage to tissue,
  resulting in disease .

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Acute inflammation is an important part of the
second line of defense because it results in

1. dilatation and increases permeability of blood
   vessels.
2. migration of phagocytes ( diapedesis).
3. tissue repair

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Components of Innate Immunity Inflammation

• Non-specific, physiologic reaction of vascular
  tissue to injury and microbial invasion.
• The inflammatory process can be divided into two
  sequential steps
• Vascular Phase - dilation and increased
  permeability of blood vessels with the
  accumulation of fluid and cells at the site of
  injury.
• Cellular Phase - the activation of specialized
  blood and connective tissue cells that destroy or
  wall off injurious agents and clear debris so
  that tissue repair can take place.
• Cells important to inflammation include
  neutrophils, basophils, eosinophils, lymphocytes,
  monocytes, and platelets.

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• In the skin, inflammation is recognized by the
  presence of
• redness, swelling, heat, and pain.
• Without inflammation and repair, infections would
  go unchecked and wounds would never heal.

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SIGNS OF ACUTE INFLAMMATION
Heat Redness Swelling
Pain Loss of function
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Cytokines

• An important group of small molecular weight
  polypeptides that are produced by lymphocytes,
  macrophages, and other connective tissue cells.
• The function of cytokines is to regulate growth
  and differentiation of blood, lymphoid, and
  connective tissue cells.
• They help to orchestrate many aspects of innate
  and acquired immunity as well as wound healing,
  and the production of blood cells.

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• Inflammatory cytokines Interleukin-1 (IL-1) and
  Tumor Necrosis Factor (TNF)
• induce the fever, fatigue, and decreased
  appetite.
• Activate leukocytes and other inflammatory cells,
  
• increase vascular permeability.
• Activate tissue-degrading enzymes.
• Activate the connective tissue cell involved in
  tissue repair.

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Stages of Inflammation 1. Vascular Phase

• Vasoconstriction - Immediately following injury,
  tightening of blood vessels
• Complement activation and mediator release
• Activated complement opsonize microbes/injured
  tissue and release of histamine and serotonin
  from nearby mast cells
• Formation of bradykinin and initiation of
  synthesis of prostaglandins and leukotrienes
• Vasodilation
• Histamine, and other vasodilators, cause
  relaxation of smooth muscle in arteriolar and
  capillaries walls.
• Vessels dilate providing increased blood flow to
  the injured tissue.
• Causes redness/heat

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Increased vascular permeability endothelial
cells lining blood vessels contract slightly
creating gaps between the cells that allow plasma
to escape into surrounding tissues. Plasma
delivers antibodies and other antimicrobial
substances to the site of injury. Fibrinogen
from plasma also clots and serves as a temporary
barrier to bacterial invasion.
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Stages of Inflammation2. Cellular Phase

• Adhesion white blood cells (WBCs) stick to
  inner surface of blood vessel walls
• Diapedesis WBC's then to squeeze between the
  contracted endothelial cells and migrate in an
  ameba-like fashion into the extravascular space
• Chemotaxis - Once in tissue, the WBC's begin to
  migrate towards the site of injury or microbial
  invasion. WBC's are attracted by chemotactic
  agents that have been released at the site of
  injury. WBC's apparently have surface receptors
  for chemotactic agents which cause them to move
  in the direction of increasing concentrations of
  the chemotactic substance.

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Phagocytosis When WBC's arrive at the site of
tissue injury or microbial invasion they become
very active and begin engulfing bacteria (or
other foreign) that have been opsonized by
complement or antibodies through various
mechanisms, bacteria and other foreign substances
are destroyed and degraded after phagocytosis
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Increase permeability during inflammation
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MECHANISMS OF INFLAMMATION
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Emigration of Neutrophils
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Inflammation Outcome - Resolution
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Fever is a body temperature more than 37 ºC.
- Fever results due the presence of chemicals
called pyrogens.
- Pyrogens trigger the hypothalamic thermostat to
reset at high temperature.
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Pyrogens include - bacterial toxins -
cytoplasmic contents of bacteria that are
released upon lysis Ab-Ag complexes. -
interleukin-1 a pyrogen released by phagocytes
that have phogocytized bacteria
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Steps of fever
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Determinants of innate immunity
Innate immunity is genetically controlled and
varies widely with species, race and to less
extent between individuals.

• Species and race
• -Man and guinea pigs are highly susceptible to
  diphtheria while rats are not.
• -Man is susceptible to common cold while dogs
  are not.
• -American Indian and Negro are more
  susceptible to tuberculosis than white races.

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B) Individual differences Age the very young
and aged are particular liable to
infection. Nutrition Malnutrition and
starvation predispose to infection by decreasing
the total white cell count and phagocytosis. Horm
ones Some endocrine diseases cause a decrease in
resistance to infection such as diabetes
mellitus, hypothroidism and adrenal dysfunction.
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