Partridge L1-10 Flashcards
What is immunology?
Study of the immune system. Provides defence against infection, distinguishes between self and non self and recognises danger signals.
What are the two types of the immune system?
Innate and adaptive
What are characteristics of innate immunity?
Broad specificity, not affected by prior contact. Immediate response is rapid and within hours.
What are characteristics of adaptive immunity?
Highly specific and enhanced by prior contact. Response is slow and takes days to weeks.
What is involved in innate immunity?
Barriers (physical and chemical), soluble proteins (complement, interferons), local and systemic responses (inflammation, fever), leukocytes.
What is involved in adaptive immunity?
B and T lymphocytes. B cells respond by secreting soluble antibodies in humoral immunity. T cells develop into cytotoxic T cells that kill infected host cells (important in viral infections) or helper T cells which secrete cytokines acting on other cells, in cell mediated immunity. Both B and T cells develop into memory cells.
How is infection recognised in adaptive immunity?
B and T lymphocytes express specific antigens receptors.
How is infection recognised in innate immunity?
Pattern recognition receptors recognise pathogen associated molecular patterns on cells of innate immune system. PAMPs include LPS or peptidoglycan and are conserved due to being essential for survival.
What is the clonal selection hypothesis?
B lymphocytes have a preformed receptor on the surface that recognises a particular microbe. Upon contact with an antigen it undergoes clonal selection where the parent divide as clones. Those that recognise “self” are deleted early in development and so they cannot cause harm to body. Healthy lymphocytes can then go onto become plasma cells and memory cells.
What is primary lymphoid tissue?
Where lymphocytes reach maturity and acquire their specific receptors (bone marrow + thymus).
What is secondary lymphoid tissue?
Where mature lymphocytes are stimulated by antigens.
What do dendritic cells in the lymph node?
Presents microbe to T cell and if it has the right antigen it will differentiate into Helper or Cytotoxic. Same with B cells but these will form plasma cells.
What do the elements of the innate immune system do?
Barriers = prevent establishment of infection.
Preformed mediators = Proteins with broad specificity that damage pathogens, induce inflammation or recruit innate immune cells.
Innate immune cells = Recognise and activated by pathogen, eliminated pathogen, cell communication and activate/steer adaptive immune response.
How do mechanical barriers prevent infection?
Secretes chemicals, anti microbial and commensals to create an unfavourable environment for pathogens.
What are examples of preformed mediators?
Lysozyme. Antimicrobial peptides. Complement.
What is lysozyme?
Present in secretions such as tears, saliva and mucous. Breaks a bond in peptidoglycan so more active against gram +ve bacteria where peptidoglycan is exposed.
What are antimicrobial peptides?
Such as defensins which are evolutionary ancient. Produced by epithelial cells and neutrophils. Cationic meaning they insert into pathogenic membranes and disrupt lipid bilayers.
What is complement?
Discovered as a heat – sensitive substance that complemented antibodies in killing bacteria. There are >20 soluble proteins found in the blood and other bodily fluids. Components usually inter but activated by presence of pathogens or antibody bound to the pathogen. Proenzyme is activated on by infection forming a working enzyme which can further go on to form other proenzymes and enzymes.
What is the classical pathway for complement activation?
C1,4,2,3,5,6,7,8,9
What do activated complement components act as?
Proteases so act on one another to generate a large and smaller fragment. C3 -> C3b + C3a. Where b denotes the bigger fragment and a denotes the smaller fragment. Cleavage of C3 exposes a reactive thioester in C3b which can covalently bind to adjacent proteins.
What are the three pathways for complement activation?
Classical = C1,4,2,3,5,6,7,8,9.
Mannose binding lectin pathway = MBL binding to mannose.
Alternative pathway = LPS to factor B to factor D to factor P.
What is the alternative pathway for complement activation?
If C3b generated binds to LPS on a pathogen surface, factor B binds. Factor B is cleaved by factor D -> C3 convertase (C3bBb). The C3bBb convertase is stabilised by factor protein P (properdin). This became known as the alternative pathway. C3b generated by classical/MBL pathway can also bind factor B.
What are the three major biological activities of complement?
- C5a (C3a) recruits phagocytes and induces inflammation. They act as chemo attractants and anaphylatoxins. Phagocytes have C5a and C3a receptors and undergo chemotaxis in response to C5a/C3a peptide.
- C3b promotes opsonisation. Pathogens coated with C3b peptides are recognised by phagocytosis with C3b receptors, facilitating binding and phagocytosis.
- C5b – C9 form the Membrane Attack Complex, leading to lysis. Activation of C5b – C9 results in C9 polymerisation, forming a pore in the membrane, disrupting it and killing the pathogen. This is important in the killing of gram negative bacteria.
Why is complement inactivation important?
To prevent host damage
How is complement inactivated?
Components are rapidly hydrolysed in the fluid phase. Soluble and membrane bound regulator proteins also aid regulation -> C1 inhibitor inactivates C1 ; Factor H inhibits alternative pathway by competing with Factor B ; carboxypeptidase N inactivates C3a and C5a ; CD59 on host cells binds C9, preventing MAC formation.
What diseases are caused by deficiencies in complement inhibitors?
age related macular degeneration which causes blindness in the elderly (lack of Factor H) and paroxysmal nocturnal hemoglobinuria which is a type of anaemia caused by MAC formation on RBC (lack CD59)
What are the characteristics of eosinophils?
Few in blood but also beneath mucous surfaces. Contain receptors for C3b, IgG, IgA and IgE. Release toxic proteins and free radicals to defend against multicellular parasites. Play role in allergy and asthma
What are the characteristics of basophils?
Very few in blood containing receptors for C3a, C5a and IgE. They release heparin and histamine defending against parasites with a role in allergy.
What are the characteristics of mast cells?
Restricted to tissues and protect mucosal surfaces. Contain receptors for C3a, C5a and IgE. Release histamine etc.
What is the role of sentinel cells?
Such as macrophage and dendritic cells. Come into first contact with a pathogen and defend against parasites.
What are the characteristics of macrophages?
Derived from monocytes during infection. Long lived and act as sentinel cells. Phagocytose 100 bacteria per cell containing receptors for C3b, IgG and IgA. Produce pro inflammatory mediators and can present antigen to T lymphocytes.
What are characteristics of dendritic cells?
Found in skin and lymphoid tissues. Take up foreign material by phagocytosis. Digest foreign material and display fragments on cell surface. Specialised for presenting antigen to T cells. Constitutively express high level of Major histocompatibilty type 2 (MHC II) proteins.
What is the sequence of events for phagocytosis?
- Bacterium binds to the surface of phagocytic cell. Antibody or complement can aid binding.
- Phagocyte pseudopods extend and engulf organism.
- Invagination of phagocyte membrane traps organism within a phagosome.
- Lysosome fuses and deposits enzymes into phagosome. Enzymes cleave macromolecules and generate ROS destroying species.
What is oxygen dependent killing in phagocytosis?
Done by an “oxidative burst” where a transient increase in oxygen consumption occurs following phagocytosis due to an activation of a membrane bound NADPH oxidase.
What are the characteristics of NK cells?
Kill infected host cells by recognising altered self due to changes in MHC I proteins. Contains receptors for IgG (allowing killing of antibody coated infected host cells).
How does NK cells kill infected host cells?
Activated NK cells produce a pore forming protein called perforin which inserts into the membrane of the infected host cells. Granule contents (granzymes) are released into target cell to activate the apoptosis pathway. Target cells then undergo apoptosis.
What do pattern recognition receptors recognise in pathogens during innate immune responses?
- Microbe associated molecular patterns (MAMPs) = Shared by many microbes and distinct from self. Critical for survival/function of pathogens and so are often conserved.
- Damage associated molecular patterns (DAMPs) = Host components released during injury and cell damage.
What are classes of PRRs?
- Soluble receptors such as mannose binding lectin
- Membrane receptors such as lectin receptors which bind carbs, chemotactic receptors and toll like receptors
- Cytoplasmic receptors like NOD receptors.
What do chemotactic receptors recognise?
Chemoattractant
What are toll like receptors?
Sensors that signal the presence of microbial components - upon signal of infection, a change is induced in gene expression. They can be on the cell surface or endosomal but always membrane associated.
What is the structure of toll like receptors?
The extracellular domain of TLR3 has a horseshoe shape formed by leucine-rich repeats. The inner surface has βsheet structure and forms the ligand binding domain. Ligand induced dimerization triggers signalling.
What are the two cytoplasmic receptors in innate immunity?
Nod like receptors and RIG-I-like receptors
What are NOD like receptors?
Large group of cytoplasmic receptors that recognise bacterial components. Signal expression of pro inflammatory cytokines to trigger assembly of inflammasomes - a multi subunit complex that cleaves inactive cytokine precursors into active cytokines.
What are RIG-I-like receptors?
Viral sensors that detect viral RNA produced within host cells and signal interferon expression.
What are the four classic signs of inflammation?
- Release of inflammatory mediators (Redness)
- Dilation of local blood vessels (Swelling)
- Increased permeability and blood flow (Heat)
- Immune cell migration into inflammatory site and stimulation of nerve endings (Pain)
What are examples of inflammatory mediators?
- Lipid mediators like prostaglandins in pain reaction
- Vasoactive amines like histamine to stimulate blood vessel dilation
- Chemo-attractants to aid phagocyte movement
- Complement proteins
- Cytokines
What are the two types of inflammation?
Acute - Generally beneficial in dealing with infection, comes and leaves rapidly
Chronic - Caused by chronic infection like TB and can be damaging