Pennock - Innate Immunity

Innate Immunity
Dr Joanne Pennock
School of Translational Medicine
[email protected]
www.ucl.ac.uk
Innate barriers to infection

Mechanical
Epithelial cells joined by tight junctions

Flow of air or fluid over epithelial surface
Movement of mucus by cilia
Chemical
Fatty acids (skin)

Enzymes: lysozyme (saliva, sweat, tears)
Pepsin and low pH (stomach)
Antibacterial peptides; cryptidins (intestine)
Microbiological
Normal flora compete for nutrients and

attachment to epithelium and can
produce antibacterial substances
When a barrier is breached

1. Immediate 0 - 4 hr - preformed mediators
2. Early 4 - 96 hr
- recruitment of innate immune cells
3. Late > 96 hr
- adaptive immune response
Effective protection relies on cooperation

between innate and adaptive immune
response
Innate cells in blood and lymph:
2006 Encyclopedia Britannica
Innate cells in blood and lymph:

In the blood:
In the lymph nodes:
In the tissues:
Innate cells arise in the bone marrow
Active sites of hemopoiesis in an adult
www.butler.org
Innate cells arise in the bone marrow
www.mhhe.com
Granulocytes: Neutrophil
Make up ~70% of white blood cells

Constantly being made in bone marrow
Phagocytes: first line of defence against
bacteria
Short life span if not activated (approx 5
days)
The predominant cell in pus!
Essential to limit bacterial spread
Phagocytosis (requires antibody &
complement)
Degranulation (eg myeloperoxidase)
NET formation when dying
(externalisation of nuclear contents to
trap bacteria)
Watch a neutrophil chasing a bacterium in real time
http://www.youtube.com/watch_popup?v=I_xh-bkiv_c&vq=small
NET formation
Dr. Volker Brinkmann

Max Planck Institute for
Infection Biology
Journal of Cell Biology,
online, January 8, 2007
A single neutrophil enulfing anthrax
Watch diapedesis of neutrophils from blood into tissue

http://www.youtube.com/watch_popup?v=I9zSe0qmXGw&vq=small
Chronic Granulomatous Disease

Characterised by persistent chronic infections
Pneumonias
Absesses
Impetigo
Joint infections
Perianal absesses
Swelling of multiple lymph nodes
Acute infections treated aggressively with antibiotics
Only cure is bone marrow transplant
CGD caused by delayed neutrophil

apoptosis and defective superoxide
production
Neutrophils live longer
and fail to be engulfed
by macrophages.
Persistent release of
proteases etc promote
sterile inflammation.
CGD patients may be
misdiagnosed with
Crohns
Boxer L A Blood 2009;113:1871-1872

Illustration Paulette Dennis
2009 by American Society of Hematology
Granulocytes: Eosinophil
Most often associated with parasitic
infection and allergy
In health, make up 1-6% of blood cells
Exit from bone marrow into blood in
response to acute infection / injury
Short life span (recorded up to 12 days)
Associated with a Th2 immune response
Release reactive oxygen species
(bactericidal)
Release prostaglandins and leukotrienes
Release proinflammatory cytokines eg
TNFa, IL1
Here we show that polarized type-2 immune responses

are initiated independently of adaptive immunity. In the
absence of B and T cells, IL-4-expressing eosinophils were
recruited to tissues of mice infected with the helminth
Nippostrongylus brasiliensis, but eosinophils failed to
degranulate.
Granulocytes: Basophil
Granulocytes: Basophil
Distinct from eosinophil basic granules

Mature in the bone marrow and stay in the blood
Important in parasite infection and allergy
Could be an early source of IL4
Granules contain histamine, leukatrienes
Actively secrete cytokines
Granulocytes: Mast cell
Once thought to be tissue dwelling basophils

Now known that arise from distinct precursor in bone
marrow
Circulate in blood in immature form
Enter tissue (connective tissue mast cells) or mucosa
(mucosal mast cells)
Central role in allergy, asthma, anaphylactic shock
Coated in antigen specific IgE

Degranulation is an antigen-specific event although the mast cells themselves
are not able to recognise antigen
Regulation of mast-cell and basophil function and survival by IgE

Toshiaki Kawakami & Stephen J. Galli
Nature Reviews Immunology 2, 773-786 (October 2002)
Monocyte to macrophage
Monocytes are blood dwelling imature macrophages

Macrophages are tissue dwelling monocytes
Are able to engulf invading microbes and present antigen
on the cell surface to advertise invasion
Key cell linking innate and adaptive immune responses
Present antigen to lymphocytes to begin clonal antigenspecific immune response
www.britannica.com
Dendritic cell
Phagocytes
Key antigen presenting cells of the immune
system
Trigger an antigen-specific immune response
Several different types, subtly different, but all
interact with T cells
Dendritic cell
In this picture a mature
dendritic cell (the cell on the
right with dendrites) is moving
towards a T lymphocyte (little
rounded cell). The contact
between a mature dendritic cell
and a T lymphocytes is the
initial step of an immune
response
Adaptive Immunity
Dr Joanne Pennock
School of Translational Medicine
[email protected]
Innate immune system provides vital early

response but is often not enough
Immediate
response of
phagocytes
Generation of
new effector
cells and
molecules
NK response
Specific immune
system
system
Lymphocytes: T and B cells

Develop from a common progenitor
Transcription of BCR or TCR genes into
mRNA
Translation, assembly and expression of
receptor proteins on cell surface
Removal of self-reactive immature cells
Migration of mature B and T cells to the
blood and tissues
Lymphocytes: T and B cells

B cells develop in the bone
marrow
T cells develop in the thymus
There are two main populations

of T cells
CD8 cytotoxic (Tc) cells
kill virus-infected cells
CD4 helper T (Th) cells

activate macrophages (Th1)
activate B cells to produce

high affinity antibodies (Th2)
help activate Tc cells
Lymph nodes provide sites for antigen

presentation to occur
Dendritic cell
B
Lymphocyte
The TCR binds to peptide and MHC
TcR
Peptide
Class I MHC
Antigen presentation to lymphocytes

Major Histocompatability complex antigens
Also known as HLA Human Leukocyte antigens

Highly complex and variable
Most unrelated individuals have different HLA
Although many matching haplotypes
Require match for successful transplantation
Two major types MHC Class I and Class II
Antigen presentation to lymphocytes

Dendritic cells
Dendritic cells engulf pathogens
Pathogen proteins are digested into peptides
Peptides are placed in MHC class I or II
MHC + peptide is transported to the cell
surface
TcR
Peptide
Class I MHC
The generation of B and T cell antigen receptors

Each receptor chain is the product of several genes combined
together during B or T cell development
1. Each receptor chain gene is composed of:
- 2-3 different V gene segments (V, D, J)
- 1 C gene segment
2. During V-D-J recombination gene segments
are selected randomly from a large gene pool
Germline DNA
TCR b chain
Rearranged DNA
Random recombination of V gene segments can

generate self-reactive antigen receptors
Immature B cells binding self Ag in bone marrow die by
apoptosis
Removal of self-reactive immature cells is called negative

selection
Self-reactive T cells are removed during cell

development
Immature T cells undergo 2 rounds of selection in the thymus:
1st
To select T cells recognising MHC class I or II
2nd To remove self-reactive T cells (self peptide + MHC)
MHC recognition
No MHC recognition
Self peptide
Foreign peptide
Lymph nodes are full of antigen specific T and

B cells ready for clonal expansion
Th2 cells against soluble antigens

and extracellular pathogens
Th2 cells secrete:
IL-4
IgE
IL-5
eosinophilia
Eosinophils secrete inflammatory mediators
Chronic asthma
Chronic allergic rhinitis
B cell activation occurs in the B cell area of the lymph node

Two signals are necessary for B cell
activation:
1. Specific antigen-antibody binding on
the B cell surface
2. Antigen-specific help from effector
Th2 cells
Defects in T-B interaction prevent B cell proliferation
Germinal centre
Normal:
B cell areas brown
Normal
Unstimulated B cell
Activation by
antigen
Plasma cell
Images from: Bayer-Garner IB, Korourian S

Mod.Pathol. 2001;14:877
Gaspal et al., Eur.J.Immunol. 2006;36:1665
The structure of antibodies (immunoglobulins)

Each antibody is composed of:
2 heavy chains
2 light chains
Each chain has a:

variable region binds antigen
constant region effector functions
Fc
All antibody molecules produced by a single B cell or plasma

cell are identical
Different antibody classes have different heavy chains and

functions
IgM
IgE
IgG
IgD
IgA
How do antibodies
protect from infection?
1. Block binding of
pathogens and toxins
2. Facilitate phagocytosis
by neutrophils
(opsonisation)
3. Kill bacteria by
activating complement
The antibody response to infection (humoral response)

With repeated infection:
high levels of specific IgG

antibodies are produced
the affinity of IgG

antibodies
increases
Clinical deficiency in humoral immunity
Inability to clear pyogenic bacteria:

Staphylococci, Streptococci,
Hemophilus
Opsonisation is essential for phagocytosis by
neutrophils
Brutons X-linked agammaglobulinaemia (XLA)

Recurrent respiratory infections
Middle ear infections, sinusitis,
skin infections
An overview of immune response (Janeway)

http://www.youtube.com/watch_popup?v=G7rQuFZxVQQ&vq=medium

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Innate Immunity

Innate barriers to infection

Epithelial cells joined by tight junctions

Fatty acids (skin)

Normal flora compete for nutrients and

When a barrier is breached

- recruitment of innate immune cells

- adaptive immune response

Effective protection relies on cooperation

Innate cells in blood and lymph:

2006 Encyclopedia Britannica

Innate cells in blood and lymph:

In the lymph nodes:

Innate cells arise in the bone marrow

Active sites of hemopoiesis in an adult

Innate cells arise in the bone marrow

Make up ~70% of white blood cells

Dr. Volker Brinkmann

A single neutrophil enulfing anthrax

Watch diapedesis of neutrophils from blood into tissue

Chronic Granulomatous Disease

CGD caused by delayed neutrophil

Boxer L A Blood 2009;113:1871-1872

Here we show that polarized type-2 immune responses

Distinct from eosinophil basic granules

Granulocytes: Mast cell

Granulocytes: Mast cell

Once thought to be tissue dwelling basophils

Granulocytes: Mast cell

Regulation of mast-cell and basophil function and survival by IgE

Monocytes are blood dwelling imature macrophages

Innate immune system provides vital early

Lymphocytes: T and B cells

Lymphocytes: T and B cells

There are two main populations

CD4 helper T (Th) cells

activate B cells to produce

Lymph nodes provide sites for antigen

The TCR binds to peptide and MHC

Antigen presentation to lymphocytes

Also known as HLA Human Leukocyte antigens

Antigen presentation to lymphocytes

The generation of B and T cell antigen receptors

Random recombination of V gene segments can

Removal of self-reactive immature cells is called negative

Self-reactive T cells are removed during cell

To select T cells recognising MHC class I or II

2nd To remove self-reactive T cells (self peptide + MHC)

Lymph nodes are full of antigen specific T and

Th2 cells against soluble antigens

Eosinophils secrete inflammatory mediators

B cell activation occurs in the B cell area of the lymph node

Images from: Bayer-Garner IB, Korourian S

The structure of antibodies (immunoglobulins)

Each chain has a:

All antibody molecules produced by a single B cell or plasma

Different antibody classes have different heavy chains and

The antibody response to infection (humoral response)

high levels of specific IgG

the affinity of IgG