7.

Complement
• Complement system –
30 proteins produced by the
liver, circulate in serum
• recognize pathogens to
trigger activation
• Once activated, other
components…
– Induce inflammation
– Signal to attract immune
cells
– Bind the pathogen to
enhance destruction by
phagocytic cells via
opsonization
– Lyse the pathogen
Nature Immunology 11, 785–797 (2010)
 Opsonization

• Complement protein C3b

or antibodies bound to
the surface of an invading
bacterium act as opsons
• Promote adherence and
ultimately phagocytosis
 Complement activation: “Alternative pathway” shown here

C3
b
a

b MORE PHAGOCYTES!

MORE PHAGOCYTES!

5b

Bacterium C5

Membrane attack complex

Complement activation requires several accessory factors that are not shown here!
 Innate immunity – Summary I
AMPs/lysozyme/lipases

EAT!
TLR4 cytokines

e.g. LPS
Bacterium MAMPs phagocytic cell
(or flagellin,
HELP
LTA, CpG…)

KILL!
Complement proteins

Transmigrate, ATTACK!!!

MAMPs =
microbe-associated molecular patterns
All clear?
 Innate immune components summary II

Barriers Cellular components

Thick epithelium Phagocytic cells
Tight junctions (neutrophils,
macrophages,
Chemical attack dendritic cells)
Lysozyme
AMPs Complement proteins
C3, C5 and helpers
 Summary III
• The innate immune system is the unsung hero of our defenses
against potential pathogens
• Mechanical, chemical and microbiota barriers are the first line
of defense against microbial invasion
• Acellular responses include the production of antimicrobial
peptides by certain cell types, also complement in the serum
that can help identify and neutralize invaders
• Cellular responses include recognition of microbial molecular
signals (PAMPs or MAMPs) by receptor proteins on immune
cells. Recognition then activates and mobilizes appropriate
responses.
• One response to invaders includes the release of cytokines
and chemokines to initiate the inflammatory response.
 Adaptive Immunity
1. Adaptive immune
response introduction:
B-cells, T-cells and
antibodies
2. B cells and memory
3. T cells
4. Cell mediated immunity
 Innate immunity Adaptive immunity

500 1st exposure 2nd exposure 1st

1st exposure 2nd exposure
immune cells/functions

500
400

immune cells/functions
400
300
300
200
200
100
100

0 0
0 5 10 15 20 00 10
10 20 30
time time
Done! You know this stuff inside
and out
 1. Adaptive Immune Response – the
main players
• Lymphocytes:
• T lymphocytes (T cells), cell-mediated
response
• B lymphocytes (B cells), humoral
responses (antibody)
• Antibodies are made by B-cells
• Old friends: Cytokines (as signals)
 Antibody architecture

- Antibodies recognize diverse non-host structures.

- They contain variable regions that can bind a variety of antigens
- Each antibody recognizes a unique epitope
Antibodies recognize foreign particles

Antigen – a compound (e.g. protein)

recognized as foreign, this
recognition activates a lymphocyte
and leads to an adaptive immune
response
Epitope – tiny portion of an antigen
that interacts with and is recognized
by antibodies
 The humoral response neutralizes
threats through antibody binding
Three major ways antibodies (immunoglobulins)
clear an infective agent:

• Opsonization
• Neutralization
• Complement
activation
= ONC
Antibodies are broadly used to
neutralize toxins, for example in
snake antivenom!
 2. B-cells and the humoral immune
response
B-cells are produced in the bone marrow
and carry antibodies (“B-cell receptors”)
on their surface.

Once its BCR binds a

specific antigen, B
cells can differentiate
into Plasma cells (and
memory cells!)
Plasma cells produce
antibodies
But how does an antibody know its
antigen?
B-cells with almost infinite antibody diversity are produced in the
bone marrow

In the bone marrow, self-reactive B-cells are weeded out

through clonal deletion

new antigen
Antigen binding (+ helper cell!)
activates B-cells
Clonal propagation +
Refinement (”somatic
hypermutation”)

new antigen

differentiation

Memory B-cell
 Memory B-cells rapidly react after
second exposure to same antigen

Memory B-cell
 3. T-cells and the cell-mediated
immune response
T-cells are produced in the bone T-cells bind to special receptors
marrow and carry T-cell (MHCI and II) on Antigen
receptors on their surface. presenting cells (APCs)
T-helper Cytotoxic T-cell
Once its TCR binds a
specific antigen on
another cell,
different T-cell types
either signal
(cytokines) or kill an
infected cell
How does the T-cell meet its antigens? – by
talking to antigen presenting cells!
(APCs, e.g. phagocytes)

dendritic cell

MHC II
Major
Histocompatibility
Complex
APCs present antigens to T cells via Major
Histocompatibility complexes (MHCs)
CD4 co-receptor CD8 co-receptor
- MHC II on antigen- on T cell on T cell
presenting cells
interacts with and
activates T-helper cells
(co-receptor on T-cell:
CD4)
- MHC I on infected cells
interacts with and
activates Cytotoxic T-
cells (co-receptor on T-
cell: CD8)
APC or B cell APC or Infected cell

APC, Antigen Presenting Cell

 T cell activation

• An APC displays an antigen

on the MHCII receptor
protein on the cell surface. It
also produces signals to
CD4 CD8 attract naïve T cells.
• A helper T cell with a
receptor that recognizes the
antigen is activated. This
effector T cell divides (some
become memory T cells).
 Why do we need T-helper cells? To activate B-cells,
for example!

In order to differentiate into

Plasma and Memory cells, B-
cells need to be activated by T-
helper cells!
 Why so complicated? Why do you
need two events (recognition by B-cell
and T-helper) to elicit an immune
response?
 Cell Mediated Immunity
In cell-mediated immunity, activated effector T Cells
release cytokines to activate Cytotoxic T Cells

• Any cell can display an

antigen on the MHCI
receptor protein on the cell
surface.
• A cytotoxic T cell with a TCR
CD8
receptor that recognizes the
antigen (stabilized by CD8) is
activated. (some become
memory T cells). The
cytotoxic T cell kills the
infected cell.
But how does a T-cell receptor know
its antigen?

Self-reactive
T cells are
removed
in the
Thymus.

Naïve T-cell
Figure 27.2
Where do T-cells and APCs meet? Lymphoid Tissues
and Lymphatic Circulation

• Lymphoid precursor cells

differentiate into
B or T cells in the Bone
marrow or Thymus.
• These immature (naïve)
lymphocytes are carried
to peripheral lymphoid
organs (in blue)
• These are locations
where they can interact
with specific antigens =>
maturation.
Cytotoxic T cell – searching for target,
then delivering perforin and granzymes to target cell

Immunity (2015)
Putting it all together…
humoral response Pathogen (virus/bacterium)

B-
cells Phago
-cytes
MHCII

Th cell
memory (CD4+)
B-cell ONC:
Opsonize
Neutralize
Complement
 Putting it all together…
cell-mediated response
Pathogen (virus/bacterium)

Any
cell
MHCI

cT-cells
(CD8+)

(left out for dramatic purposes: cytotoxic T-cell activation also

requires a T-helper cell!)
 Summary
• The humoral response is mediated by B-cells and
antibodies (antibodies neutralize toxins and pathogens)
• The cell-mediated response relies on T-cells.
• T-cells come in two varieties: Cytotoxic T-cells that kill
infected cells, and helper T-cells that activate B-cells
(among other things)
• The immune system generates pathogen-reactive B-
and T-cells through a random change process
• The immune system exhibits memory function, but
differentiating some B and T-cells into long-lived
memory cells that can reactivate once they encounter
the same pathogen again