pennock - overview and barriers
TRANSCRIPT
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Basic Clinical Immunology
Overview
Dr Joanne PennockSchool of Translational Medicine
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Recommended reading:
Essential of Clinical Immunology
Chapel, Haeney, Misbah & Snowdon (Authors)
5th Ed 2006, Blackwell Scientific Publications
Janeway’s Immunobiology
Kenneth Murphy
Garland Science 2011
http://www.amazon.co.uk/Janeways-Immunobiology-Kenneth-Murphy/dp/0815342438/ref=sr_1_1?s=books&ie=UTF8&qid=1318926114&sr=1-1http://www.amazon.co.uk/gp/reader/1405127619/ref=sib_dp_pt
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Immunology timeline:
Ancient
Civilisations
430BC –
8 th Century
accination
GermTheory1800’s 1900’s
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•Sprang from the study of bacteria and
smallpox
•Bacteria first observed…. •Idea of ‘contagion’ gradually evolved
•1718 Lady Mary Wortley Montagu
innoculated her children against smallpox
(Constantinople)
•1798 Edward Jenner successfully
demonstrated innoculation against smallpox
•1884 Koch’s postulates – definition of a
contagious disease
GermTheory
1800’s
Vaccination
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1900’s •Discovery of mouse MHC
• Advances in microscopy
•Louis Pasteur developed rabies
and anthrax vaccines – first
example of attenuating bacteriato induce immunity
• Antigen:antibody theory
established
•Hypersensitivity and allergy
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Clonal selection theoryHLA
Antibody structure
Thymus
T & B cells
Dendritic cells
HIVcytokines
Immune response to intra/extracellular
pathogens (Th1 vs Th2)
Regulatory T cells
Danger model
pattern recognition (TLR)
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•37 interleukins•Th17 cells
•Native and inducible T reg cells
•Human papillomavirus vaccine
•Regulatory macrophages and DCs…….
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Barriers to infection
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The skin:
3 layers protect the body from infection.
Collagen
between
layers
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Epidermolysis bullosa
Caused by a defect in collagen formation
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Atopic dermatitis
Often associated with mutations in Filaggrin
Secondary infections cause ‘flare ups’ due to
breach of skin barrier
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The lungs:
Dr Keith Wheeler/ Science photo library
Healthy lung
tissue
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The lungs:
Cystic fibrosis
A severe disease causingexcessive mucus production in
the lungs and pancreatic ducts.
Life expectancy 30 years.
Normal CF
Excessive mucusimpairs bacterial
clearance resulting in
congestion and severe
infection.
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The gastrointestinal tract:
Saliva, mucus, antibodies
and constant surveillance
protect the body frompathogens
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The stomach:
Gastric/duodenal ulcers
caused by:NSAIDS (20%)
H pylori (80%)
Protection of gastric
epithelium by mucusand secretion of
neutralising
bicarbonate
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The colon:
In the GI tract, a single layer of cells separates our
immune system from the outside world
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The firm mucus layer is devoid of bacteria.
Johansson M E V et al. PNAS 2008;105:15064-15069
©2008 by National Academy of Sciences
The colon:
A protective layerof mucus is
essential for
health
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Johansson M E V et al. PNAS 2008;105:15064-15069
The colon:
Mucus is secretedby goblet cells
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Muc5ac: a critical component
mediating the rejection of entericnematodes.
J Exp Med. 2011 May 9;208(5):893-900. Epub 2011 Apr 18.
Hasnain SZ, Evans CM, Roy M, Gallagher AL, Kindrachuk KN, Barron L,
Dickey BF, Wilson MS, Wynn TA, Grencis RK, Thornton DJ.
Wellcome Trust Centre for Cell Matrix Research, Faculty of LifeSciences, The University of Manchester, Manchester M13 9PT,
England, UK.
http://www.ncbi.nlm.nih.gov/pubmed?term=%22Hasnain%20SZ%22%5BAuthor%5Dhttp://www.ncbi.nlm.nih.gov/pubmed?term=%22Evans%20CM%22%5BAuthor%5Dhttp://www.ncbi.nlm.nih.gov/pubmed?term=%22Roy%20M%22%5BAuthor%5Dhttp://www.ncbi.nlm.nih.gov/pubmed?term=%22Gallagher%20AL%22%5BAuthor%5Dhttp://www.ncbi.nlm.nih.gov/pubmed?term=%22Kindrachuk%20KN%22%5BAuthor%5Dhttp://www.ncbi.nlm.nih.gov/pubmed?term=%22Barron%20L%22%5BAuthor%5Dhttp://www.ncbi.nlm.nih.gov/pubmed?term=%22Dickey%20BF%22%5BAuthor%5Dhttp://www.ncbi.nlm.nih.gov/pubmed?term=%22Wilson%20MS%22%5BAuthor%5Dhttp://www.ncbi.nlm.nih.gov/pubmed?term=%22Wynn%20TA%22%5BAuthor%5Dhttp://www.ncbi.nlm.nih.gov/pubmed?term=%22Grencis%20RK%22%5BAuthor%5Dhttp://www.ncbi.nlm.nih.gov/pubmed?term=%22Thornton%20DJ%22%5BAuthor%5Dhttp://www.ncbi.nlm.nih.gov/pubmed?term=%22Thornton%20DJ%22%5BAuthor%5Dhttp://www.ncbi.nlm.nih.gov/pubmed?term=%22Grencis%20RK%22%5BAuthor%5Dhttp://www.ncbi.nlm.nih.gov/pubmed?term=%22Wynn%20TA%22%5BAuthor%5Dhttp://www.ncbi.nlm.nih.gov/pubmed?term=%22Wilson%20MS%22%5BAuthor%5Dhttp://www.ncbi.nlm.nih.gov/pubmed?term=%22Dickey%20BF%22%5BAuthor%5Dhttp://www.ncbi.nlm.nih.gov/pubmed?term=%22Barron%20L%22%5BAuthor%5Dhttp://www.ncbi.nlm.nih.gov/pubmed?term=%22Kindrachuk%20KN%22%5BAuthor%5Dhttp://www.ncbi.nlm.nih.gov/pubmed?term=%22Gallagher%20AL%22%5BAuthor%5Dhttp://www.ncbi.nlm.nih.gov/pubmed?term=%22Roy%20M%22%5BAuthor%5Dhttp://www.ncbi.nlm.nih.gov/pubmed?term=%22Evans%20CM%22%5BAuthor%5Dhttp://www.ncbi.nlm.nih.gov/pubmed?term=%22Hasnain%20SZ%22%5BAuthor%5D
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Johansson M E V et al. PNAS 2008;105:15064-15069
The colon:
Upper layer ofmucus is
colonised by
bacteria
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The colon:
Gut flora provides additional barrierEssential for health and development
Different composition between individuals
Thought to ‘out compete’ potential pathogens
•‘Mutaflor’
•Ulcerative Colitis
•Gastroenteritis
•IBS
•Pouchitis
•Crohn’s disease
Each capsule 2.5-25x10(9) viable cells
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The colon:
Gut flora is actively involved in thehomeostasis and maintenance of health in the
gut
http://iai.asm.org/
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World's largest E. coli outbreak
kills 14 in Germany (May 2011)3,500 infected
855 developed rare haemolytic uraemic syndrome
53 died
Enteroaggregative
strain of E. co li had
acquired Shiga toxin
which caused HUS
E. Coli is a commenal bacterium
•Species is highly diverse
• Acquisition of virulence genes canlead to pathogenicity
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The gastrointestinal tract:
IgA is a GI specific
antibody
responsible for
primary defenceagainst bacteria
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http://www.calier.es/
The gastrointestinal tract: IgA
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•1 in 700 Europeans are IgA deficient
•The most common immunodeficiency
•Many have no symptoms…. BUT
Role of IgA in the defense against
respiratory infections: IgA deficient mice
exhibited increased susceptibility to
intranasal infection with Mycobacterium
bovis BCG
Vaccine
Volume 23, Issue 20, 8 April 2005, Pages 2565-2572
•IgA deficient patients suffer more episodes of:
•bronchitis•pneumonia
•chronic diarrhea
•conjunctivitis
•sinusitis
•IgA deficiency often presents with IgG2 deficiency
•Increases susceptibility to certain bacteria
http://www.sciencedirect.com/science/journal/0264410Xhttp://www.sciencedirect.com/science?_ob=PublicationURL&_hubEid=1-s2.0-S0264410X00X03271&_cid=271205&_pubType=JL&view=c&_auth=y&_acct=C000228598&_version=1&_urlVersion=0&_userid=10&md5=faaf8c6c12a88c4ae410f96ac8fd1e0bhttp://www.sciencedirect.com/science/journal/0264410Xhttp://www.sciencedirect.com/science?_ob=PublicationURL&_hubEid=1-s2.0-S0264410X00X03271&_cid=271205&_pubType=JL&view=c&_auth=y&_acct=C000228598&_version=1&_urlVersion=0&_userid=10&md5=faaf8c6c12a88c4ae410f96ac8fd1e0bhttp://www.sciencedirect.com/science/journal/0264410X
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The bladder:No mucosal layer
‘Umbrella’ cells provide barrier function alongside 5to 6 cell-deep epithelium
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Leonardo da vinci 1510 Circulatory system
Discovery of blood & lymph systems
Lymphatic system
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©2006 Encyclopedia Britannica
Lymph and blood systems are separate
Antigen: substance which provokes an immune responseMay have several antigenic determinants (epitopes)
which can be recognised by antibody
Therefore a single antigen may provoke many antibody molecules
Antibody: Soluble factor secreted by plasma cell in large quantities
Prevents antigen from causing damage (inflammation)
Cytokine: Protein secreted by cells of the immune system to
orchestrate the immune response (activate, suppress,attract)
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…But lymph and blood interact at lymph nodes
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http://effleurageholistictherapies.co.uk
Lymph nodes are the defence hub during infection
e.g. Head and neck lymph nodes during flu
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Swelling of lymph nodes during infection is due
to cellular proliferation, and antibody production.
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Any immune response is very much an
orchestrated event involving early non-
specific defence, quickly followed by non-specific attack, then antigen-specific, site-
specific defence.
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Any immune response is very much an
orchestrated event involving early non-
specific defence, quickly followed by non-specific attack, then antigen-specific, site-
specific defence.
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Any immune response is very much an
orchestrated event involving early non-
specific defence, quickly followed by non-specific attack, then antigen-specific, site-
specific defence.
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Any immune response is very much an
orchestrated event involving early non-
specific attack, quickly followed by antigen-specific, site-specific defence.