Transcript A rough guide to the immune system - UK

A rough guide to the immune
system
Dr Adrian Palfreeman
Senior Clinical Scientist MRC CTU
Stem cells –why they matter
Stem cells
Neutrophil (polymorph)
• Multi-lobed nucleus.
• Commonest leucocyte (2500-7500/mm3 of
blood).
• A short-lived phagocytic cell whose granules
contain numerous bactericidal substances.
• leave the blood to go to tissues where
infection or inflammation is developing
Eosinophil
• A leucocyte whose large refractile granules
contain a number of highly basic or ‘cationic’
proteins,
• possibly important in killing larger parasites
including worms.
• Bind avidly to IgE-coated particles (i.e.
Helminthic parasites) .
• Abundant at sites of allergic reactions.
Components of the immune system
• Monocyte
– The largest nucleated cell of the blood (16-20μm
– diameter), developing into a macrophage when it
– migrates into the tissues.
• Macrophage (A professional antigen presenting
cell)
–
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The principal resident phagocyte of the tissues.
Strongly phagocytic of particles and microbes.
Has receptors for Ig and complement.
CNS – “microglia”
Liver – “Kupffer cells”
Lungs – “alveolar macrophages”
Bone – “osteoclasts”
T lymphocyte (T cell)
• A thymus-derived (or processed) lymphocyte.
• 1500 - 4000/mm3 blood
• 6-15μm diameter (red blood cell 7.2μm
diam.)
• 2 main subdivisions
– CD8 (cytotoxic T cells)
- CD4 (helper T cells)
• B lymphocyte
– A bone marrow- (or in birds, bursa-) derived
lymphocyte, the precursor of antibody-forming
cells. In foetal life, the liver may play the role of
‘bursa’.
• NK (Natural Killer) cells
– do not have to recognise a specific antigen
before acting against it
– are effective against a wide range of infectious
microbes.
The 2 arms of the adaptive
immune response
1. Humoral immunity (antibodies)
2. Cellular immunity (T-cells)
• Sub-divided into T helper cells (CD4+) and
• Cytotoxic T cells (CD8+)
CD4 Lymphocytes (T helper cells)
• coordinate much of the immune response to
micro-organisms
• help B-cells respond to foreign proteins
• secrete substances that enable CD8 T-cells to
proliferate
• activate macrophages so that they can kill
certain organisms, including some organisms
associated HIV infection.
CD8 Lymphocytes (Cytotoxic T cells)
• kill cells in the body identified as abnormal or
foreign
• tumour cells
• cells that have been infected by viruses.
How does HIV reduce CD4 Cells?
• Increased turnover of cells in response to
infection
• Trapping of HIV in lymph nodes
• Shortened survival of CD4 cells
• Reduced production of new cells
• Reduction of T cell progenitor production from
bone marrow
Sites of the
principal
lymphoid tissues
within the human
body.
Primary lymphoid
organs
Secondary lymphoid
organs
Human
lymphoid organs
Primary lymphoid
organs
Secondary
lymphoid
organs
• Lymphoid tissues
– Immune system compartmentalised into
organs/tissues.
– Funtionally unified via blood and lymph systems.
– Lymphocytes recirculate.
– In total, equivalent in weight to brain or liver.
• Primary lymphoid organs
– Bone marrow where T and B lymphocytes are made.
– Thymus where T lymphocytes mature/are selected.
• Secondary lymphoid organs
– e.g. spleen, lymph nodes and Peyer’s patches.
– Contain T cells, B cells, antigen presenting cells (APCs)
T cell precursors
(thymocytes) migrate
from the bone marrow
to the thymus to mature.
Mature T cells leave the
thymus and migrate to
secondary lymphoid tissues
where they may encounter
foreign antigen.
Thymus
Lobules show - a lymphocyte-dense outer cortex
- an inner lighter-staining medulla.
Stromal framework with specialised epithelial cells, DCs
and macrophages (APCs).
T cell precursors arrive from the bone marrow.
Cortex and medulla ‘educate’ thymocytes into mature,
competent T cells (1 to 3% of T cells survive education).
Mature T cells are released into the peripheral
circulation.
THYMUS
Developing
thymocytes
occupy the
interstices of
an extensive
network of
epithelial cells
Clusters of Differentiation (CD)
• CD3 T cells
• CD4 Helper T cells
• CD8 Cytotoxic T cells
• CD16 Macrophages
• CD19 B cells
Maturation of T lymphocytes in the thymus
Circulating
lymphocytes
meet
lymph-borne
pathogens
in draining
lymph nodes.
Lymph node
Cytokines
• Il2 stimulates division of B and T cells and
killing of HIV infected cells by NK cells
• IL2 levels reduced in HIV infection
IL2
•
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Does administration of IL2 help?
Raises CD4 numbers
Significant side effects
Injectable
Short term benefit in clinical trials
Does it reduce mortality and morbidity in the
long term?
Summary
• B cells recognise antigens (antigenic epitopes) via their monomeric IgM
receptor
• T cells recognise antigens (small peptides)via the T cell receptor (TCR) which
is always associated at the cell surface with CD3 11
• The monomeric B cell receptor (and, in fact, all antibodies) recognise
antigens in solution – in their native (folded) state
• The TCR does not recognise soluble antigens but only small antigenic
peptides associated with the Major Histocompatibility (MHC) molecules I
& II
• For a T cell or B cell to be activated 2 appropriate signals are always
required
• T cells need binding of the TCR to peptide/MHC plus specific cytokines from
the APC (notably IL- 1 and IL-2) and interaction between B7 and CD28
• B cells need binding of mIgM surface receptor plus signals from TH cells
(notably IL-4 and IL- 10) and interaction of CD40/CD40L.
• This process has evolved to prevent unwanted activation of immune cells
which can lead to harmful responses such as allergies and autoimmunity