Pennock - Overview and Barriers

8/9/2019 Pennock - Overview and Barriers

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Basic Clinical Immunology

Overview

Dr Joanne PennockSchool of Translational Medicine

[email protected]


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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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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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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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specific defence.


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specific defence.


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specific attack, quickly followed by antigen-specific, site-specific defence.

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