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Introduction

Definitions

  • Self is the term used to describe the molecular makeup of the host. We do not NORMALLY mount an immune response against ourselves. This is called “self tolerance”. Autoimmunity is when self-tolerance breaks down. This is a disease state
  • Non-self is the term used to describe the molecular makeup of the universe outside our bodies, especially the molecular makeup of microbial invaders. The immune system recognises and responds to molecules that are foreign to the body
  • Innate or Natural immunity is broadly directed protection resulting from the genetic constitution of the host, and is not improved by repeated encounters with the same invader
    • Doesn’t get better over time
    • Blocks everything
  • Adaptive or Acquired immunity is specific for the invader, and is marked by an enhanced response on repeated encounters with the invader (immunological memory)
    • Gets better and different over time, with repeated exposure
  • Antigens are foreign macromolecules, which are “seen” by the immune system, which responds with the production of cells and molecules that specifically target the antigen.
    • “Antibody generator”
  • Antibodies are molecules produced by B cells, in response to antigen, and they can bind to the antigen that induces their formation (and they are specific for this antigen). Also called immunoglobulin (Ig)
    • Y shaped
  • Mucosal immunity describes the special defences that are found at mucosal surfaces (the respiratory, gastrointestinal and genitourinary tracts).
    • Most of our infections at mucosal sites, so we need our defence sitting there ready to go
  • Systemic immunity defends other tissues, including the blood. The white cells of the blood (leucocytes) are cells of the immune system

Microbial virulence factors

  • The mammalian immune system has evolved to detect and destroy invading microorganisms. Bacteria and viruses constantly mutate and evolve to evade immunological defences
    • They evolve quickly, we evolve slowly
  • Factors that contribute to the ability of an organism to evade defences and to cause disease are called virulence factors
  • They dodge our immunological “bullets”

Innate immunity

  • The first line of defence is usually sufficient to prevent infection – diverse components
    • Physical barriers
    • Mechanical processes (including reflexes)
      • Sneezing
      • Blinking (washing with microbials)
      • Coughing
      • Urinating (problem urinating → microbes build up. Without flushing out the urinary tract, we get an ascending infection)
      • Defecation (e.g. diarrhoea gets rid of a lot of microbes etc)
      • Peristalsis (rhytmic contractions of gut)
    • Biochemical defences (e.g. complement proteins)
    • Cellular defences
    • Acute inflammatory response

Non-specific barriers to infection, before entry into the tissues

  • Microbes are flung against mucus in the airways
  • Cilia push mucus and particles to the mouth → swallow → die in stomach acid
    • Smoking destroys cilia → respiratory tract infection
  • Commensalist organisms exist in the gut/vagina
    • Stability, symbiosis
    • They exclude pathogenic organisms (in terms of space and available niches)
    • Compromised when we use antibiotics. The ones that aren’t killed proliferate, giving us an upset tummy

Innate defenses “recognise” the different generic biochemistry of bacteria

  • For instance, Lysozyme (an enzyme in tears etc) attacks gram-positive bacteria.
    • The biochemistry of gram-positive bacteria is different to ours. The lysozymes can target and attack the cell walls of invaders.

Phagocytosis

  • Performed by cells of the innate immune system
    • Macrophages
    • Neutrophils
    • Lymphocytes do NOT phagocytose… T cells kill in other ways (complex process)
  • Stages include:
    • Migration
    • Attachment
    • Engulfment
    • Destruction (respiratory burst)
    • Recruitment of additional defences
  • Invader triggers a cascade that produces C5a and drifts away from the invader, producing a concentration gradient. Phagocytes detect C5a to get to the site of invasion

Acute inflammatory response

  • Blood capillaries dilate and blood flow increases, with a local rise in temperature
  • Plasma leakage into tissue space
  • Increased output of phagocytic cells from bone marrow
  • Cells migrate from blood to tissue, where they build up
  • Signs: Redness, swelling, heat, pain, loss of function

Adaptive immunity

  • Also called Acquired or Specific immunity. Involves T and B cells
  • Highly specific for the “inducing agent” – that agent that stimulated the activity of the T and B cells
  • Improves over time (with repeated exposure)
  • Displays immunological memory
  • Secondary response is better in every way:
    • develops faster
    • is stronger
    • lasts for longer
    • develops improved characteristics over time

Brief view of the antibody

  • An antibody is a polypeptide, programmed by a gene
    • One gene → one polypeptide (via central dogma)

T cells

  • Cytotoxic T cells kill
    • Very important in viral infections, when T cells must kill cells that have been virally-infected
    • [How do they kill non-APCs???]
  • Other T cells regulate the immune response
    • Helper T cells

Clonal selection theory of antibody production (McFarlane Burnet)

  • “An individual, from the moment of birth, has the ability to make antibodies against molecules never before seen in the universe”
  • There are ~2 million lymphocytes per mL of blood. One third of these are antibody-producing B cells. The rest are T cells
  • The clonal selection theory applies to both T cells and B cells. B cells (which produce antibodies) are easier to understand
  • Each B cell has ONE AND ONLY ONE specificity
  • Each individual has millions of different B cells, each with a different specificity. Hence we have the ability to recognise very many different types of antigens
  • Each specificity is generated randomly at the “birth” of the cell. (Specificity = Random(t) in B cell construction)
  • Every day, B cells are born in the bone marrow
  • The receptors on B cells are membrane-bound antibodies (essentially the same as those found in the blood). There are around 250,000 expressed on the B cell surface and act as “antigen receptors”
  • Each surface antibody in the membrane of a B cell has the same specificity, and that is the single random specificity with which it was “born”
  • A single B cell will wander the body, moving many times between the circulation and the lymph nodes, with its surface antibodies ready to bind antigens of its specific type
  • One day, it meets its antigen: it is selected
  • Antigen “SELECTS” a specific cell, by binding to its surface antibody
  • This “chosen cell” is then activated.
  • Cell activation results in cell division and the formation of a clone of specific cells
    • There are two types of B cells produced in this process of 1) division and 2) differentiation:
      • Plasma cells: pump out free antibody
      • Memory cells: with antibodies on their surfaces

In summary

  • There are B cells of many specificities
  • Specificities arise PRIOR to antigen exposure
  • Selection causes rapid cell division and differentiation into plasma cells and memory cells

Good fit and poor fit

  • The first response may be associated with a poor fit between antigen and antibody
  • Although it is a poor fit, it works, but the binding between antigen and antibody is relatively weak
  • In the second response, the new antibodies fit better, etc
  • In each subsequent response, antibodies have a stronger binding to the antigen
  • During clonal expansion, there is a targeted mutation of the genes that improve the fit of the antibody to the antigen
    • It occurs by trial and error. If the mutation leads to a loss of specificity (a poor fit) then the cell dies. If we have improved binding, then this clone is SELECTED
    • This rapid evolution occurs within the lymph nodes
    • We end up with practically a perfect fit between the antibody and the antigen
  • The massive cell division associated with clonal proliferation of B cells can be observed clinically in the form of swollen lymph nodes

How do antibodies help us?

Flagging
Antibody binding to an antigen “flags” the antigen as something that needs to be dealt with by the immune system
Complement cascade
Immune complex formation forms clumps and triggers the complement cascade
Steric hindrance
If the antibody binds to and blocks certain sites on the antigen, this might be directly beneficial to the host
Neutralisation of toxins
Toxins must bind to cellular receptors to be endocytosed and to enter the cell (and cause damage). If an antibody binds the toxin, then it protects the cell because the toxin can no longer bind the appropriate receptors on the cell’s surface
Opsonisation (overlaps with 1)
Antibodies facilitate phagocytosis of the antigen by macrophages and neutrophils.