The Complement System and the Integration of Innate and Acquired Immunity

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The Complement System and the Integration of
Innate and Acquired Immunity

• David J. Kusner, M.D., Ph.D.

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The Integrated Immune Response

• Objectives
• 1. To understand the mechanisms by which the
  distinctive characteristics of innate and
  acquired immunity are integrated into a diverse
  and multifunctional immune system
• 2. To understand the complement system as the
  primary soluble component of innate immunity and
  characterize its interaction with phagocytes and
  the adaptive immune system.

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The Diversity of Microbial Challenges

• Classes of Microbes Viruses, Bacteria, Fungi,
  Parasites (Protozoa, Helminths)
• Size - 20 nm (Parvoviruses)
• 25 meters (Tapeworms)
• Composition - Protein (Prions), Nucleic acid
  protein (Viruses) Eukaryotes

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The Diversity of Microbial Challenges

• Presence/Absence of reservoirs/vectors
  Tuberculosis, Malaria, Lyme disease,
• Mode of Transmission aerosol (Measles), blood
  and body fluids (HIV)
• Extracellular / Intracellular Pathogenesis
  Staph. aureus, M. tuberculosis

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The Diversity of Microbial Challenges

• Rapidity of disease onset Meningococcal
  meningitis, Prion-induced neurodegenerative
  disease
• Severity of disease Localized vs. Systemic
  inflammation

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Epithelial barrier defenses

• Epithelial barriers
• - Skin and mucous membranes (GI, Respiratory,
  Urogenital tracts)
• - Physical barrier inhibit establishment of
  infection, block spread through tissues
• - Clearance mechanisms mucus, cilia

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Epithelial barrier defenses

• - Secretions
• Acid, enzymes stomach
• Antimicrobial peptides Defensins
• - Normal (non-pathogenic) flora
• Competition for nutrients
• Production of antimicrobial compounds
• - Epithelial turnover and cell sloughing

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Disruption of epithelial defenses

• - Extremely common feature of infection.
• - Provides microbes with access to tissues,
  blood and lymphatic vessels potential for
  systemic spread of pathogen/ products
  wounds, burns
• - The consequences of disruption of epithelial
  barrier defenses can often be prevented or
  minimized.

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Infection of an Epithelial Surface and the
Integrated Immune Response
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The Complement System

• A group of gt 30 plasma proteins which comprise
  the primary soluble component of innate immunity.
• Rapidly activated in response to infection,
  without induction or recall of adaptive immunity.

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The Complement System

• However, in the presence of an adaptive immune
  response, complement proteins interact with both
  its soluble and cellular components (antibodies,
  lymphocytes, activated macrophages, dendritic
  cells).
• Complement proteins circulate in plasma as
  inactive precursors.

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The Complement System

• Infection results in activation of complement
  proteins via a series of proteolytic reactions
  that yield biologically active fragments.
• These coupled proteolytic reactions result in an
  amplification cascade, in which limited
  stimulation of proximal complement components
  results in massive activation of distal
  complement proteins.

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Complement System Overview
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Complement proteins opsonize microbes and
promote their phagocytosis.
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Complement receptors on the surface of leukocytes
bind complement proteins

• Phagocytic receptors CR1, CR3, CR4 -
  present on neutrophils, monocytes,
  macrophages, dendritic cells.
• - Bind C3b / C3bi that are attached to
  microbial surfaces (as opsonins)
  phagocytosis

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Complement receptors on the surface of leukocytes
bind complement proteins

• CR2 surface of B cells and dendritic cells.
  Binding of activated complement fragments to CR2
  amplifies antigen-induced cellular activation -
  provides a link between the innate and acquired
  immune systems.

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The Complement System kills microbes via the
Membrane Attack Complex (MAC).
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Activation of the Complement System

• 2 activation pathways are components of innate
  immunity Alternative pathway, Lectin pathway
• The Classical pathway of complement activation
  is part of the adaptive immune response -
  dependent on Abs.

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Activation of the Complement System

• All 3 activation pathways result in generation of
  an enzyme complex which can cleave C3, called the
  C3 convertase.
• C3 C3a C3b
• - Integration point of the complement system
• (Innate and Adaptive immunity)
• - Major amplification point

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Activation of the Classical Pathway

• Requires Antigen - Antibody complexes
• Complement component C1 binds to the Fc region of
  the Ab (IgM- most potent activator)
• C1 is a protease that cleaves C2 and C4 to form
  the C3 convertase of the classical path.

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Activation of the Alternative Pathway

• Soluble proteins of the Alternative Pathway
  (B,D,P) bind to repetitive structures on
  microbial surfaces, such as components of the
  cell wall.
• The complex of B, D and P forms the C3
  convertase of the Alternative Pathway.
• Recognition is selective for microbes, but not
  highly specific (pattern recognition).

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Activation of the Lectin Pathway

• The soluble plasma protein, Mannan-Binding
  Protein (MBP or MBL) binds to the sugar mannan
  which is restricted to the surface of certain
  microbes (not on vertebrate cells)
• This leads to attachment of other complement
  proteins (C4,C2) to form the C3 convertase of the
  Lectin Pathway.

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Regulation of Complement System

• Due to its potential for rapid amplification, and
  the ability of activated complement proteins to
  damage host tissue as well as microbes, strict
  regulation is needed.

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Soluble Inhibitors of Complement

• C1 inhibitor (C1 INH, C1 esterase inhibitor) -
  binds and inactivates C1 inhibition of
  Classical Pathway.
• Lack of C1 INH (hereditary angioneurotic edema) -
  spontaneous activation of complement and kinin
  systems, inflammation of the skin and critical
  organs.
• - Symptoms are completely reversed by
• administration of C1 INH.

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Cellular Inhibitors of Complement

• Decay accelerating factor (DAF) and CD59 are
  proteins present on mammalian cells, inhibit the
  assembly of the MAC on host cells.
• Deficiencies of DAF and CD59 occur in the disease
  Paroxysmal Nocturnal Hemoglobinuria (PNH) -
  intermittent hemolysis of RBCs due to unregulated
  deposition of activated complement components on
  the cell surface.

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Complement Deficiencies

• Congenital Deficiencies of C7, C8, C9 -
  terminal complement components. Markedly
  increased incidence of Neisserial infections.
• - N. meningitidis meningitis, bacteremia
• - N. gonorrhoeae STDs, bacteremia
• Acquired consumption of complement proteins
  during extensive activation of the complement
  system.

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Complement System - Summary

• Plasma proteins Complement Receptors on
  leukocytes Regulatory proteins
• Integral to innate immunity, also functions with
  the adaptive immune system.
• Amplification cascade that proceeds via coupled
  proteolytic reactions.

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Complement System - Summary

• Functions
• Recruit inflammatory cells C3a, C5a
• Opsonizes pathogens C3b, C3bi
• Directly microbicidal MAC

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General Biomedical Principles

• In addition to its intrinsic biochemical beauty
  and physiologic importance, the complement system
  illustrates several principles which are
  fundamental to the biomedical sciences.
• 1. Amplification - coagulation, fibrinolytic,
  kinin systems
• 2. Multiple levels of compensatory regulation
• 3. Receptor - ligand interactions determine
  specificity
• 4. Inflammation - both beneficial / deleterious

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Cytokines

• Cytokines are essential soluble mediators of both
  the innate and adaptive immune systems. In fact,
  cytokines are one of the major integrators which
  bridge these complementary systems.
• 1. recruitment of leukocytes (chemokines)
• 2. activation of phagocytes augment innate
  immunity
• 3. absolutely required for the maturation and
  activation of lymphocytes

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Activated Macrophages Secrete Cytokines that
Stimulate both Innate and Acquired Immunity
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• Cytokines Exhibit Both
• Immunoprotective and Tissue-
• Damaging Effects

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Integrators of Immunity

• Components which are responsible for the
  interdependence of innate and acquired immunity
• 1. Complement system
• 2. Cytokines/chemokines
• 3. Macrophages
• 4. Dendritic cells
• 5. Antibodies

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The Integrated Immune Response
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