6 symptomatic rabies (2009) Exploited by Edward Jenner who used - PDF document

Presentation by Dr Lindsay Nicholson LDA Conference 2011 Overview Immune Responses: The Good, the Bad and the Ugly • Where does immunology come from? • Where is the immune system? Lindsay Nicholson • How does the immune system l.nicholson@bristol.ac.uk recognise infection? www.bris.ac.uk/cellmolmed/air • What happens when this goes wrong? How old is the study of Rabies immunology? • The concept of immunity is an ancient one Number of people who have survived 6 symptomatic rabies (2009) • Exploited by Edward Jenner who used cowpox inoculation to prevent smallpox (1796) Louis ‘… here Pasteur left the field of bacteriology, itself still in its infancy, to become the first to venture into … immunology Pasteur … a new science that would provide the means of by • Modern understanding of immunology – that it understanding and manipulating natural immunity.’ depends on cells – required the formulation of the Patrice germ theory of disease towards the end of the 19 th Debré ‘At the beginning of each session, a loaded revolver was century by Louis Pasteur, Robert Koch, Eli placed within their reach. If a terrible accident were to Johns Hopkins University Metchnikoff, Paul Ehrlich and others happen to one of them, the more courageous of the two Press 1998 others would put a bullet in his head.’ The Immune Response is a Complications of the rabies vaccine Two Edged Sword • Attenuation was used to develop a rabies vaccine. Rabid rabbit spinal cords were dried in air and used to treat patients. Not enough immunity Too much immunity • Approximately 0.1% of vaccine recipients Overreact to developed an acute paralytic illness; most Destroy Live in a Recurrent harmless Normal yourself - recovered. infections bubble stimuli - autoimmunity allergy • The immune system is confusing the rabbit brain and the human brain A spectrum of possible immune responses 1

Presentation by Dr Lindsay Nicholson LDA Conference 2011 Immune function depends on Pathogens and lymphocytes cells drawn to scale Virus • How many cells are Neutrophil (60%) there in a millilitre Bacteria of blood? Lymphocyte (30%) • Red cells – 500m • White cells - 1,000,000 Lymphocyte Monocyte (5%) Macrophage (in tissues) en.wikipedia.org/wiki/White_blood_cells How does the immune system Antibodies bind directly recognise infection • 1. Antibodies recognise infection directly • 2. Lymphocytes recognise infection indirectly commons.wikimedia.org/wiki/File:Antibody_IgG2.png T cells recognise infection indirectly How T cells recognise infections T cell receptor molecule Peptide Made taken by the from the cell infection MHC molecule Made 1. Antigen presenting 2. Peptides are 3. T cell with specific by the cell digests infection shown to T cell receptor activated to to produce peptides produce helper cells cell and killer cells commons.wikimedia.org/wiki/File:TCR-MHC_II.png 2

Presentation by Dr Lindsay Nicholson LDA Conference 2011 T cells focus on a limited set of The immune system constantly amino acids patrols the body • Samples the environment for evidence of infection Pathogenic cells H S L G K W L G H P D K F • Examines cells to see if they are infected 139 140 141 142 143 144 145 146 147 148 149 150 151 • Examines cells to see if they are cancerous Non-pathogenic H S L G K W L G H P D K F cells 139 140 141 142 143 144 145 146 147 148 149 150 151 Calls for Help Primary TCR Contact Starts killing Secondary TCR Contact Produces inflammation �������������������������������������������� Inflammation of the retina Autoimmunity occurs because… • … the sufferer has a ‘permissive’ set of ������ ������ ������ genes (so it runs in families) • …the environment triggers disease (e.g. some viral or bacterial infections) • …the immune system mistakes a healthy cell for an infected or a cancerous cell Invest. Ophthal. Vis. Sci. 49 :5458 (2008) How do the T cells get Bystander Activation activated? Sympathetic Ophthalmia • In 1583 George Bartisch wrote that after injury + Danger the eye may shrink and become painful, “in Eye this case the other eye is in great danger” protein Signals • 80% of cases develop within 3 months; can occur up to 50 years after initial injury 3

Presentation by Dr Lindsay Nicholson LDA Conference 2011 What amino acid substitution Molecular Mimcry studies tell us • TCRs can be exquisitely sensitive to single amino acid changes • TCRs can accept multiple substitutions 139 140 141 142 143 144 145 146 147 148 149 150 151 without losing the ability to respond Autoantigen H S L G K W L G H P D K F • TCRs can be activated by two peptides of Bacterial antigen E Q L V K W L G L P A P I completely different sequence • A single TCR in a mouse has the potential to be stimulated by about 13 self-peptides Carrizosa, A. M et al. (1998) Journal of Immunology 161(7): 3307-3314. The Complexity of Infection What can we study • Genetics: Tissue Damage – To find all the genes that play a role and to establish the effect of individual genes on disease • Immune mechanisms: – To find out which cells are important and what molecular programmes they use to cause disease • Treatments: – To test new drugs or therapies quickly before trying them in patients Molecular mimicry Treatments for autoimmune Important questions for future disease research • Anti-inflammatory (Aspirin-like; steroids) • Understand what triggers human disease • Immunosuppressive (Killing immune cells or inhibiting their function) • Predict how bad disease is going to be • Antigen specific ‘anti-vaccination’ • Target drugs to a specific immune response not to the whole immune system • Modulate immunity selectively in the affected organ 4

Presentation by Dr Lindsay Nicholson LDA Conference 2011 Summary Acknowledgements • The ‘immune system’ is a collection of cells • Aaron • Jez Fordham Postlethwaite • Jian Liu that respond to pathogens. • Ana Anderson • Jo Boldison • Andrew Dick • This response causes inflammation • Lauren Schewitz • Ben Raveney • Markus Munder • The response can be life saving • Carly Guyver • Mercy Prabhu-Das (e.g. rabies vaccination) • Claudia Calder • Richard Lee • Dave Copland • Sarah Morwood • The response can destroy normal life • David Nicholson • Tarnjit Khera (e.g. multiple sclerosis; uveitis) • David Wraith • Vadim Turchin • Emma Kerr • Vijay Kuchroo • There is still lots to learn • Estelle Bettelli • Wei-Kang Wu • Jay Reddy • Zsolt Illes 5