pennock - innate immunity
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Pennock - Innate ImmunityTRANSCRIPT
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Innate Immunity
Dr Joanne Pennock
School of Translational Medicine
www.ucl.ac.uk
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Innate barriers to infection
Mechanical
Chemical
Microbiological
Epithelial cells joined by tight junctions
Flow of air or fluid over epithelial surface
Movement of mucus by cilia
Fatty acids (skin)
Enzymes: lysozyme (saliva, sweat, tears)
Pepsin and low pH (stomach)
Antibacterial peptides; cryptidins (intestine)
Normal flora compete for nutrients and
attachment to epithelium and can
produce antibacterial substances
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1. Immediate 0 - 4 hr - preformed mediators
2. Early 4 - 96 hr - recruitment of innate immune cells
3. Late > 96 hr - adaptive immune response
When a barrier is breached
Effective protection relies on cooperation
between innate and adaptive immune
response
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2006 Encyclopedia Britannica
Innate cells in blood and lymph:
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In the blood:
In the lymph nodes:
In the tissues:
Innate cells in blood and lymph:
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www.butler.org
Innate cells arise in the bone marrow
Active sites of hemopoiesis in an adult
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Innate cells arise in the bone marrow
www.mhhe.com
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Granulocytes: Neutrophil
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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)
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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)
Granulocytes: Neutrophil
Watch a neutrophil chasing a bacterium in real time
http://www.youtube.com/watch_popup?v=I_xh-bkiv_c&vq=small
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Granulocytes: Neutrophil
NET formation
Dr. Volker Brinkmann
Max Planck Institute for
Infection Biology
Journal of Cell Biology,
online, January 8, 2007
A single neutrophil enulfing anthrax
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Granulocytes: Neutrophil
Watch diapedesis of neutrophils from blood into tissue
http://www.youtube.com/watch_popup?v=I9zSe0qmXGw&vq=small
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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
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CGD caused by delayed neutrophil apoptosis and defective superoxide production
Boxer L A Blood 2009;113:1871-1872 Illustration Paulette Dennis
2009 by American Society of Hematology
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
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Granulocytes: Eosinophil
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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)
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Granulocytes: Eosinophil
Associated with a Th2 immune response
Release reactive oxygen species (bactericidal)
Release prostaglandins and leukotrienes
Release proinflammatory cytokines eg TNFa, IL1
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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: Eosinophil
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Granulocytes: Basophil
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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
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Granulocytes: Mast cell
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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
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Regulation of mast-cell and basophil function and survival by IgE
Toshiaki Kawakami & Stephen J. Galli
Nature Reviews Immunology 2, 773-786 (October 2002)
Granulocytes: Mast cell Degranulation is an antigen-specific event although the mast cells themselves
are not able to recognise antigen
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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 antigen-specific immune response
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Monocyte to macrophage
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www.britannica.com
Monocyte to macrophage
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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
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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
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Adaptive Immunity
Dr Joanne Pennock
School of Translational Medicine
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Innate immune system provides vital early
response but is often not enough
Generation of new effector cells and molecules
Immediate response of phagocytes NK response
Specific immune system
Generation of new effector cells and molecules
Immediate response of phagocytes NK response
Specific immune system
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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
Develop from a common progenitor
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Lymphocytes: T and B cells
B cells develop in the bone marrow
T cells develop in the thymus
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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
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Lymph nodes provide sites for antigen
presentation to occur
Dendritic cell
Lymphocyte T B
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Class I MHC
Peptide
TcR
The TCR binds to peptide and MHC
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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
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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
Antigen presentation to lymphocytes
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Class I MHC
Peptide
TcR
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The generation of B and T cell antigen receptors
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
Each receptor chain is the product of several genes combined
together during B or T cell development
Germline DNA
TCR b chain
Rearranged DNA
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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
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Self-reactive T cells are removed during cell
development
1st To select T cells recognising MHC class I or II
2nd To remove self-reactive T cells (self peptide + MHC)
Immature T cells undergo 2 rounds of selection in the thymus:
No MHC recognition
MHC recognition
Self peptide Foreign peptide
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Lymph nodes are full of antigen specific T and
B cells ready for clonal expansion
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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
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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
Normal:
B cell areas brown Normal
Germinal centre
Defects in T-B interaction prevent B cell proliferation
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Plasma cell
Images from: Bayer-Garner IB, Korourian S Mod.Pathol. 2001;14:877
Gaspal et al., Eur.J.Immunol. 2006;36:1665
Activation by
antigen Unstimulated B cell
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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
All antibody molecules produced by a single B cell or plasma
cell are identical
Fc
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Different antibody classes have different heavy chains and
functions
IgG IgA IgM
IgE IgD
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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
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The antibody response to infection (humoral response)
high levels of specific IgG
antibodies are produced
the affinity of IgG
antibodies
increases
With repeated infection:
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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
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http://www.youtube.com/watch_popup?v=G7rQuFZxVQQ&vq=medium
An overview of immune response (Janeway)