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Immunology/Immunometabolism, Humoral Immunity = Immune response mediated…

- - - - altered self: cancer (tumour immune cell infiltration), injury (tissue injury - release of cellular contents to instruct repair), metabolic disturbance e.g. gout (accumulation of metabolites -> inflammation)
      - immune system fights at the cellular level e.g. with killer t cells - terminates cancer cells and cells infected by a virus or bacterium ->> bodies have innate defences to infection but this is NOT immunity
        
        immune response features: SPECIFICITY, TOLERANCE, MEMORY
        
        innate immunity = instant, immediate, integrates w/ adaptive immune system
        
        invading microbes have general pathogen-associated molecular patterns (PAMPs) such as LPS, dsRNA -> are recognised by pathoge recognition receptors (PRRs) such a TLRs, CLRs
        
        associated with myeloid immune system which is nonspecific - contained cellular (pahagocytic cells, dendritic cells, mast cells, basophils etc) and humoral (complement system, coagulation system, lyzozyme, cytokines etc) components
        
        adaptive immunity = acquired, no immediate response (slow), accurate and specific, autoregulation, autoimmunity
        
        invading microbes have specific antigens such as PHA and ovalbumin which are recognised by B/T cell recptors and antibodies
        
        associated with the lymphoid immune system which also has cellular and humoral components (cellular - T and B cells // humoral - antibodies and cytokines)
  - - - innate immunity (immediate: 0-4 hrs) - recognition by nonspecific effectors - weak pathogens - removal of infectious agent
        
        innate immunity distinguishes self and non self - activates adaptive immune system (if pathogen bypasses innate defenses) - performs valuable delaying function to keep pathogen numbers in check while adaptive system gears up
        
        physio-chemical barriers (in skin, gut, lungs, eyes/nose)
        
        mechanical: epithelial cells joined by tight junctions (all organs), logitudinal flow of air/fluid (skin + gut), movement of mucus by cilia (lungs), tears and nasal cilia (eyes/nose)
        
        chemical: fatty acids (skin), low pH and enzymes e.g. pepsin (gut), enzymes in tears e.g. lysozyme, antibacterial peptides (skin, gut)
        
        lysozyme - attacks peptidoglycan which is present in bacterial cell walls - lsozyme cleaves the beta 1,4 linkages, weakening in cell wall and leading to osmotic lysis (bursting of cell due to external pressure - lyszyme is only effective against gram positive bacteria as it has a thick peptidoglycan layer - gram negative bacetria has a thin peptidoglycan layer with a protective outer membrane
        
        Anti-microbial peptides (AMPs) - PRE-FORMED OR INDUCED - MADE BY ENDOTHELIAL CELLS (MUCOSAL FLUID) - cause target cell lysis - 3 evolutionary conserved families : Defensins, Cathelicidins, Lecticidins
        
        AMPs have a cationic portion and hydrophobic core - therefore they repel eukaryotic memnbranes (neutral-cationic) - insert into bacterial membranes (anionic-hydrophobic) - cause pore formation and target cell lysis // E.G. electrostatic attraction and transmembrane electric field bring defensin AMP into lipid bilayer - defensin peptides form a pore
        
        microbiological : normal flora (skin, gut)
        
        commensals (bacteria) - 10x more microbial cells at barrier surface - co-evolved alongside human body - have mutualistic relationship - if there is a disruption in homeostasis comensal bacteria can become pathogenic
        
        skin: - disruption to host homeostasis -> opportunistiuc microbes // dysbiosis of microbial communities - > host disease
        
        gut - dysbiosis (abnormal ratio of ebneficial and aggresive bacterial species ) key charcteristic of IBD
        
        epidermis vs mucosal surfaces: epidermis has multiple cell layers, is lipid rich and therefore a wtare tigt barrier, its glands produce anti-microbial peptides /// mucosal is 1 cell layer thick - covered in mucus and cilia
        
        importance of musus in host defense - cystic fibrosis (CF) patients have defects in mucus production in respiratory endolthelium - therefore uniquly susceptible
        
        tight junction proteins: maintain epithelial integrity - include: claudins, occludins, JAMs (junctional adhesion molecules) and tricellulins - some viruses use them as co-receptors for entry
      - early induced innate response (4-96 hrs) - recognition by MAMPs - inflammation recruitment and activation of effector cells - removal of infcetious agent
        
        ONCE ENTRY HAS OCCURED - 2 RESPONSES
        
        INFLAMMATION
        
        characterised by: redness, swelling, heat, pain
        
        proteins in inflammatory exudate: Clotting proteins (fibrinogen), fibrinolytic proteins (includes plasminogen which degrades clot when wound has healed), Complement system (plasma proteins that stimulate immune response and destroy bacteria), Kinin cascade (kinins cause vasodilation, increase permeability of blood vessels and stimulate pain receptors)
        
        Neutrophil and Macrophage - both recognise and ingest pathogens - helped by opsonisation - activated macroohage releases two important inflammatory mediators: pro-inflammatory cytokines and prostaglandins (pro-inflammatory lipid mediators)
        
        eicasanoids: prostaglandins, prostacyclin, thromboxanes, leukotrienes --> are locally active and are mediated through g-protein linked signalling pathways to decrease/increase cAMP levels - derived from arachidonate - dietary precursor is linoleic acid (FA which is essential to diet)
        
        prostaglandin production: phospholipase A2 releases arachidonic acid from membtrane phsopholipids when stimulated - arachidonic acid is converetd to prostaglandins via cyclooxygenase (COX) enzymes (COX-1, COX-2) - COX nezymes convert it to prostaglandin H2 (PGH2) which is a precursor for diff prostaglandins - e.g. PGE2, PGI2, TXA2
        
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        complement = collection of soluble proteins in blood and other fluids - synthesised in liver - has defence and anti-microbial fxns - induce an inflammatory response
        
        cascade system of proteins activating one another via proteolytic cleavage
        
        3 pathways of Recognition converge in C3 activation - all pathways make C3 convertase which cleaves C3 - leaves C3b bound to microbial surface and releases C3a
        
        activation leads to: 1. phagocytosis of microbes, 2. cell lysis, 3. inflammation
        
        pathogen coated w/antibody and/or C3b -> antibody is recognized by Fc receptor omn phagocytes / complement C3b is recognized by CR1 -> promotes internalization/phagocytosis
        
        effector pathways from C3 cleavage: BOUND C3b: pathogen attaches to C3 receptor and induces phagocytosis // C3b: interacts w/C5 - complexes w/other c-proteins to form Membrane Attack Complex (MAC) - inserts onto microbial plasma membrane - forms pore to cause lysis // C3a: asscoiates w/C5a and promotes inflammation via binding to mast cells and promoting degranulation -> vasodilation
        
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        Inflammatory Mediators cause Vasodilation: bradykinin - protease casde in blood / Histamine - degranulation in mast cells/platelets
        
        COAGULATION
        
        TBC
      - adaptive immune response (late: >96 hrs) - transport of antigen to lymphoid organs - recognition by naive B/T cells - clonal expansion and differentiation to effector cells - removal of infectious agent
- - - - TCR Structure
      - gene rearrangement
      - Maturation and selection in thymus
      - t cells only recognise antigen when its presented to them by Antigen Presenting Cells (APC) in context of Major Histocompatibility Complex (MHC)
    - - peptide recognition
      - co-stimulation/role of IL-2
      - signalling
      - differentiation
    - - t cell migration
      - CD4 and CD8 effector mechanisms
  - - - cytokines regulate immunoglobulin subtypes (immunoglobulin = antibodies)
        
        immunoglobulin isotype has specialised functions and a unique distribution
        
        distribution of immunoglobulins throughout the body
      - antibodies are active against bacterial toxins
        
        virus infection can be blocked by antibodies
        
        bacterial infection can be blocked by antibodies
        
        only pathogen bound antibody is capable of crosslinking Fc receptors in macrophages and other immune cells
        
        Fc and complement receptors act together on phagocytes to take up bacteria coated with complement and immunoglobulin
        
        NK cells kill antibody coated target cells
        
        mast cells, basophils and activated eosinphils bind IgE via Fc(epsilon)
    - - origin if B cells
        
        B cell receptor
        
        B cell activation by T helper cell
        
        comparison of naive B cells and plasma cell characteristics
        
        lymph node maturation of B cells
        
        Thymus independent antigens
        
        isotype switching
    - - role of BCR (B cell receptor)
        
        Armed helper T cells activate B cells that recognise the same antigen (linked recognition)
        
        implications for vaccine development
      - antibody dependent phagocytosis
    - - generation of immunoglobulin diversity
        
        there are Ige mediated allergic reactions // hypersensitivty rxns that involve humoral immunity
    - - BCR signalling
        
        BCR signalling in chronic lymphocytic leukaemia
        
        B Cells are a target of the Epstein Barr Virus
      - autoreactive B cells are removed from the germinal centre by apoptosis
        
        autoreactive B cells do not compete effectively in peripheral lymphoid tissue to enter primary lymphoid follicles
        
        peripheral anergy of autoreactive B cells:
        
        breakdown of tolerance and emergence of autoreactive B cells
      - antivenoms
- - - - M2 (antiinflammatory): favour oxidative phsophorylation and FA oxidation - can generate more ATP - more efficient than glycolysis and helps support tissue remodelling/wound healing