Transcript Introduction to the Immune System

The Complement System
A group of > 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.
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.
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.
Complement System: Overview
Complement proteins opsonize microbes
and promote their phagocytosis.
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
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.
The Complement System kills microbes via
the Membrane Attack Complex (MAC).
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.
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
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.
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).
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.
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.
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.
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.
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.
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.
Complement System - Summary
Functions:
Recruit inflammatory cells: C3a, C5a
Opsonizes pathogens: C3b, C3bi
Directly microbicidal: MAC
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
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
Activated Macrophages Secrete Cytokines that
Stimulate both Innate and Acquired Immunity
Cytokines Exhibit Both
Immunoprotective and TissueDamaging Effects
Integrators of Immunity
Components which are responsible for the
interdependence of innate and acquired
immunity
1.
2.
3.
4.
5.
Complement system
Cytokines/chemokines
Macrophages
Dendritic cells
Antibodies
The Integrated Immune Response