PHA112 Micro 10 (Immunology 1) 2020 PDF

MPharm Programme Immunology Dr Callum Cooper [email protected] Recommended text books Kindt. et al. Kuby Immunology. (6th ed.) Publisher: W. H. Freeman Lydyard et al. Immunology 2nd ed. Publisher: BIOS Scientific Learning Objectives Gain awareness of basic Immunological principles Diffe...

MPharm Programme Immunology Dr Callum Cooper [email protected] Recommended text books Kindt. et al. Kuby Immunology. (6th ed.) Publisher: W. H. Freeman Lydyard et al. Immunology 2nd ed. Publisher: BIOS Scientific Learning Objectives Gain awareness of basic Immunological principles Difference between innate and adaptive immunity Different cell types Describe and provide example of areas in which the Immune system plays an important role Human health and wellbeing Allergy Vaccination Immunodeficiency Transplant rejection Autoimmunity Pharmaceuticals and biotechnology Immunosuppression Immunology and The Immune System Evolved to protect multicellular organisms from pathogens The fully functional immune system is vastly complex Involves numerous organ systems and cell types Has interconnecting cell types, signalling pathways The study of the immune system initially grew from the observation of people who had survived particular infectious disease Goes far beyond infectious diseases The Lymphatic System Lymphatic system consists of; Lymphatic organs Primary (bone marrow, thymus) Secondary (Lymph nodes, spleen) Lymphatic vessels Lymph (protein rich fluid from plasma) Part of the vascular system and important in the immune system Carries lymph fluid towards the heart via lymph nodes Filters bacteria etc at lymph nodes Site of some immune responses Not a closed system Blausen.com staff (2014). "Medical gallery of Blausen Medical 2014". WikiJournal of Medicine 1 (2). DOI:10.15347/wjm/2014.010. Immune cell generation Generation of blood cells is called Haematopoiesis Occurs in the bone marrow Hematopoietic stem cells Cells can migrate to different sites to mature T cells mature in thymus Cytokines have a role in determining cell type Innate Vs Adaptive Immune System Innate immune system; “Older” in evolutionary terms compared to adaptive immune system Present in all multi-cellular organisms Generally recognises lipids and carbohydrates Defence against any pathogen Adaptive Immune system; Evolved ~400 million years ago and only present in vertebrates with a jaw e.g. mammals etc Driven against specific pathogens and adapts over time Recognises protein conformation/peptides Has a memory Innate Vs Adaptive Immune System Immune System Innate/Natural Immunity 1st Line Intact skin Mucous membranes Normal microbiota 2nd Line NK and phagocytic WBCs Inflammation Fever Antimicrobial substances Adaptive/Acquired Immunity 3rd Line Specialised Lymphocytes: T and B cells Antibodies Anatomical barriers: The Skin Epidermal cells act as a barrier to prevent the passage of pathogens Pathogens can circumvent or can colonise skin Often work in combination with other factors Production of Sebum Often highly effective Infection can occur if one or more of these barriers is breached Skin possesses two main layers: Epidermidis Dermis By Madhero88 and M.Komorniczak https://en.wikipedia.org/wiki/File:Skin_layers.png, CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=21986708 Microbiota The human microbiota is an ecological community of commensal, symbiotic and pathogenic microorganisms Includes bacteria, viruses, fungi and archaea Microbiota exist for different human anatomical areas Skin Conjunctiva Gut Urethra and bladder Composition suggested to be important in noninfectious diseases By Darryl Leja, NHGRI http://www.genome.gov/dmd/img.cfm?node=Photos/Graphics&id=85320, Public Domain, https://commons.wikimedia.org/w/index.php?curid=29534265 Bacterial metabolites influence host signalling pathways Some links to IBD (not conclusive yet) Type 1 diabetes Asthma Cancer Inflammation Tissue damage produces an inflammatory response Does not have to be as the result of a microorganism 3 major events to inflammatory response Vasodilation Capillary permeability increase Phagocyte influx One of the principle mediators of this response is histamine Physiological barriers Physiological barriers which contribute to innate immunity include; Temperature pH Most pathogens grow best at physiological pH (~7) Some can survive passage through stomach (pH 2) Various soluble and cell associated molecules Lysozyme Cleaves peptidoglycan layer in bacterial cell walls Interferon Produced by virus infected cells Complement The complement system Straddles both innate and Microorganisms adaptive immune systems Lectin Complement system activated pathway by 3 paths; Classical (antigen/antibody) Lectin (MBL binding to pathogen) Alternative (spontaneous) Highly regulated process Activation can lead to; Cell lysis Opsonization Immune clearance Binding specific receptors on immune cells Alternative pathway C3 Antigen-antibody complexes Classical pathway C3b C3a C5b-9 membrane attack complex Pattern recognition receptors Receptors expressed mainly by cells of the innate immune system Classified according to ligand specificity, function etc Broadly defined as Membrane bound (e.g. TLRs and CLRs) or Cytoplasmic (NLRs) Germ-line coded DNA Identify 2 classes of molecules Pathogen associated molecular patterns (PAMPs) Associated with microbial pathogens LPS recognised by TLR4 Peptidoglycan recognised by TLR2 Damage associated molecular patterns (DAMPs) Associated with host cell components as a result of damage or death Damaged RNA from UV-B exposed keratinocytes activates TLR3 on intact keratinocytes Mitchell JA, Paul-Clark MJ, Clarke GW, McMaster SK and Cartwright N (2007). Critical role of toll-like receptors and nucleotide oligomerisation domain in the regulation of health and disease. Journal of Endocrinology 193, 323-330 Innate Immunity: White blood cells White blood cells also known as Leukocytes Neutrophil Eosinophil Basophil (mast cells) Lymphocyte Monocyte Identify and eliminate pathogens Blausen.com staff (2014). "Medical gallery of Blausen Medical 2014". WikiJournal of Medicine 1 (2). DOI:10.15347/wjm White blood cells: Mast Cells Type of granulocyte (contains granules) that resides in tissue Basophil is the blood equivalent Has granules that contain Histamine and Heparin Makes it the most inflammatory cell in the body Also a major target for anti inflammatory drugs Once activated, degranulates and releases inflammatory mediators White blood cells: Eosinophil Designed to combat multicellular parasites and certain infections Has role in allergy & asthma as well Resides in blood Accounts for about 1-3% of WBCs Not overly phagocytic Functions by releasing basic and cationic proteins Superoxide, peroxide, hypobromite etc White blood cells: NK cells Natural Killer (NK) cells are a type of cytotoxic lymphocyte Similar in function to T cells Can recognise stressed cells in the absence of MHC Reacts a lot quicker Plays important role in anti-viral and anti-tumour defences Functions by binding to cells and releasing cytotoxic granules White blood cells: Neutrophils A type of phagocytic granulocyte Most abundant WBC (60-70%) in most mammals Short lived and highly mobile Can get to places that other cells cant reach Among 1st responders to inflammation Attracted by cytokines Predominant cells in pus. Can directly attack microorganisms in 3 different ways Phagocytosis Degranulation Generation of neutrophil extracellular traps (NETs) Phagocytes and Phagocytosis Phagocytes are cells which specialised “eating” cells Consist of 2 types of cells Neutrophils and Macrophages Contain granules which contain “killing” compounds Peroxidase, acid and alkali phosphatases Process generally goes as following; 1. 2. 3. 4. 5. Pseudopodia attach to bacteria Bacteria ingested into phagosome Lysosome fuses with phagosome to produce phagolysosome Lysosomal enzymes degrade bacteria Degraded material released from cell Ref: Volker Brinkmann - (November 2005). "Neutrophil engulfing Bacillus anthracis". PLoS Pathogens 1 (3): Cover page. DOI:10.1371 Cytokines Cytokines are a broad and loose category of small proteins(~5–20 kDa) Important in cell signalling Immunomodulating Local or systemic scale Can be produced by multiple classes of cells Mainly helper T cells and macrophages Different sub classes Stimulus Stimulated cell produces cytokine Cytokine secreted Activation of cytokine specific receptor on target cell Cell activation Biological effect Cytokines Cytokines General action Interferons (IFN) Antiviral proteins Specific example Specific action IFN-γ Activates macrophages and induces Class II MHC. Can inhibit viral replication directly Tumour necrosis factors (TNF) Regulate inflammatory and immune responses TNF-α Proinflammatory cytokine that is produced in response to infection, inflammation etc. Produced by multiple cell types Interleukins (IL) Various actions (IL and cell type) dependent IL-10 Decrease or regulate inflammatory response THERE ARE MANY MANY MORE Adaptive Immunity System which recognises and specifically removes Displays 4 main characteristics Antigenic specificity Diversity Immunologic memory Self/nonself recognition Relies on use of highly specialised systemic cell types T Cells (Cell mediated immunity) B Cells (Humoral immunity) These cell types express receptors on their surfaces TCR: T cell receptor BCR: B cell receptor Immunological diversity and clonal selection Receptors have to recognise and differentiate between these different antigen epitopes Humans able to produce >1 trillion different antibody molecules without stimulation Should require millions of genes to store this information Humans have