Innate Immunity

Dr Joanne Pennock

School of Translational Medicine

Joanne.pennock@manchester.ac.uk

www.ucl.ac.uk

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

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

2006 Encyclopedia Britannica

Innate cells in blood and lymph:

In the blood:

In the lymph nodes:

In the tissues:

Innate cells in blood and lymph:

www.butler.org

Innate cells arise in the bone marrow

Active sites of hemopoiesis in an adult

Innate cells arise in the bone marrow

www.mhhe.com

Granulocytes: Neutrophil

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)

Granulocytes: Neutrophil

Watch a neutrophil chasing a bacterium in real time

http://www.youtube.com/watch_popup?v=I_xh-bkiv_c&vq=small

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

Granulocytes: Neutrophil

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

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

Granulocytes: Eosinophil

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)

Granulocytes: Eosinophil

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: Eosinophil

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

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

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

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

Monocyte to macrophage

www.britannica.com

Monocyte to macrophage

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

Joanne.pennock@manchester.ac.uk

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

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

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

Lymphocyte T B

Class I MHC

Peptide

TcR

The TCR binds to peptide and MHC

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

Antigen presentation to lymphocytes

Class I MHC

Peptide

TcR

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

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

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

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

Normal:

B cell areas brown Normal

Germinal centre

Defects in T-B interaction prevent B cell proliferation

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

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

Different antibody classes have different heavy chains and

functions

IgG IgA IgM

IgE IgD

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)

high levels of specific IgG

antibodies are produced

the affinity of IgG

antibodies

increases

With repeated infection:

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

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

An overview of immune response (Janeway)