Transcript No Slide Title

1. Complement System
2. Antigen Specific Receptors
K.J. Goodrum
Department of Biomedical Sciences
2005
Topic Outline
• Complement System
– Activation pathways
– Bioactive complement peptides & functions
– Complement regulatory proteins
• Lymphocyte receptors for antigens
– B cell receptor (immunoglobulin) and T cell
receptor (TcR) structure
Complement System
Composition: proenzymeg enzyme plasma
protein cascade system with >25 proteins
(enzymes, receptors, and complement
inhibitors)
Synthetic source: liver, macrophages
Function: mediates inflammation by
increasing vascular permeability, attracting
phagocytes, enhancing phagocytosis, and
causing microbial lysis
Complement Activation Pathways, their activating
signals, and common immune functions
Classical Pathway
Ag:Ab complex
C1q
C1r
C1s
MBL-MASP1-MASP2
C1
C4
C4a
C14b
C2
Lectin Pathway
MBL:microorganism
complex
MASP1
MASP2
C2a
C14b2b
C4
C4a
MC4b
C2
C2a
MC4b2b
C3
C3a + C3b
Alternative Pathway
C3
H2O
C3H2O
B
Ba
D
C3(H2O)Bb
C3
C3a
Target bound C3b
B
Ba
D
C3bBb
P
C3bBbP
C3 convertases
C14b2b
MC4b2b
C3bBbP
C3
Terminal complement
pathway common to
all activation
C3a pathways
C14b2b3b or MC4b2b3b or (C3b)nBbP
C5 convertases
C5
C6 +C7
C8 +C9
C5b
C5a
C5b67
C5b678(9)n Membrane attack complex
Bioactive Complement Peptides
• Plasma protease cascade generates peptides
active in inflammation and innate immunity
– C3a & C5a anaphylatoxins release histamine from
mast cells g hvascular permeability
– C5a chemotaxin, recruits phagocytes
– C3b & C3bi opsonins (coats microbes to enhance
recognition & uptake by phagocytes)
– C5b6789n membrane attack complex (lyses
microbial cell membranes)
Classical Complement Pathway
Classical Complement Pathway- continued
Alternative Complement
Pathway -1
Alternative Complement Pathway -2
Alternative Complement Pathway -3
Classical and Alternate
Pathway formation of
C5 convertase and
cleavage of C5
Terminal Complement Pathway and formation of the Membrane
Attack Complex
Cells detect and
respond to
complement
peptides via
cell-membrane
receptors for
complement
peptides.
Spontaneous or chronic activation of complement is prevented
by inhibitory proteins, both soluble and membrane associated.
Antigen Recognition
• B cells recognize antigens via membrane
associated immunoglobulin molecules
(antibodies)
– Antigen-activated B cells synthesize and secrete a soluble form of
this receptor (plasma antibody) which accumulates in fluids and
specifically binds and eliminates the stimulating antigen.
• T cells recognize antigens via a membrane associated
heterodimeric protein, the T cell receptor or TcR
– TcR are not secreted
Antibody Activity
• Antibodies specifically recognize and bind
to the inducing antigen
• Humoral immunity: antibody-mediated
immunity can be transferred from an
immune to a non-immune person by
transfer of serum
• The gamma-globulin protein fraction of
serum contains the antibody activity
Basic antibody
structure = 4
covalently
attached
polypeptide
chains with 2
identical heavy
(H) and 2
identical light
chains (L)
Each H and L chain
have structurally
constant (C) and
structurally variable (V)
domains.
The Fab fragment
of antibody
molecules
contains the
antigen binding
region. The Fc
fragment
determines
antibody class and
effector functions
(complement
interaction,
opsonic activity)
The
“immunoglobulin
fold” refers to the
characteristic 3D
structure of V and C
region domains.
Hypervariable amino acid residues in the H
and L chain V regions physically bind the
antigen and determine the specificity of the
antigen receptor.
Hypervariable
amino acid
residues are
located at the
exposed ends
of V domain
loops.
VH and VL domains fold to form antigen binding sites that
resemble pockets, grooves, open faces, or extrusions.
The TcR binding
site for antigen
(one site per
receptor) is also
formed by the
variable domains
of an alpha and
beta chain
polypeptide.
The structure of the T
cell receptor (TcR)
resembles that of
antibody but consists
of only 2 polypeptide
chains with a single
binding site. Each
chain has a constant
and variable structural
domain. An abTcR
and a gdTcr have been
described.
Antigen interaction with receptors is noncovalent and reversible.
There are 5 immunoglobulin classes based on
structural similarity of the H chain C domains.
IgM and IgA
are secreted as
pentamers and
dimers
respectively.
The J chain
protein
promotes
polymerization.
Nomenclature for structural differences between any 2 antibodies.
Antigen-Antibody Reactions, Definitions
and Characteristics to Know
•
•
•
•
Size of Epitope/antigenic determinant
specific,noncovalent,reversible binding
affinity vs. avidity
valency, crosslinking,
agglutination,precipitation
• multideterminant antigens,
• heterogeneous antibody responses
• cross reactions
Soluble antigens
mixed with
equivalent amounts of
soluble specific
antibody can bind to
form lattices (antigenantibody complexes)
large enough to
become insoluble and
precipitate. Insoluble
(particulate) antigens
+ antibody form
clumps (agglutinate).
Fig A.9
Protective functions of antibody reactions
with antigens.
Protective functions of antibody interactions with
antigen. -continued.
Protective functions of antibody interactions
with antigen. -continued.