Sept15_lecture8a_immunology

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Lecture 8Immunology and disease how vertebrate
immunity works
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Today

• Lymphocytes
• How does the right lymphocyte arise?
• Lymphocyte receptor diversity
• Clonal selection
• Different types of T-cells
• Architecture of immunity
• Origins of adaptive immunity (next time)

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Lymphocytes
Lymphocytes, like wasps, are genetically
programmed for exploration, but each of them
seems to be permitted a different, solitary idea.
They roam through the tissues, sensing and
monitoring. Since there are so many of them,
they can make collective guesses at almost
anything antigenic on the surface of the earth,
but they must do their work one notion at a time.
They carry specific information in the surface
receptors, presented in the form of a question
is there, anywhere out there, my particular
molecular configuration? Lewis Thomas, 1974
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Lymphocytes

• The phenomena of antibody formation,
  immunological memory, and the success of vaccines
  were well known before 1900
• It wasnt until the 1950s that it became clear
  that they were all due to lymphocytes
• Lymphocytes make up about a third of the white
  blood cells and are very different from other
  leukocytes like phagocytes
• They are very long lived (years/decades)
• They recirculate from blood to tissues and back
  again

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Lymphocytes

• Each endlessly searches for its unique target
• When a new pathogen appears somewhere in the
  body, only one or a few out of the millions and
  millions of lymphocytes will be able to recognize
  it
• (Think Holmes and Moriarty)

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Lymphocytes

• To increase the chance of seeing its nemesis,
  there are special locations where pathogens and
  lymphocytes are likely to meet
• These are the lymphoid organs, most importantly
  the lymph nodes (or glands)
• When you have swollen glands, say in your throat,
  theres a lot going on
• Lymphocytes recognizing the invading virus or
  bacteria home in to do battle

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Lymphocytes

• Unless it takes extraordinary precautions, a
  pathogen cannot avoid coming into contact with
  the right lymphocyte sooner or later
• That marks the beginning of the end for most
  invaders
• At this point, via antibody production (B-cells)
  and/or various killing devices mediated
  (T-cells), the lymphocytes wage all out war on
  the pathogen
• What is meant by the right lymphocyte?
• How does a lymphocyte get to be right?
• How many sorts of lymphocyte are there?

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The right lymphocyte

• By right were talking about receptors
• Protein molecules on the surface of the
  lymphocytes that can bind tightly to suitably
  shapes molecules (think lock/key or cinderellas
  slipper and foot)
• Slipper receptor
• Foot some tiny portion of the pathogen
  (epitope)
• Sort of similar to phagocytes, but with a crucial
  difference
• What?

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Phagocyte
Lymphocytes

• Each lymphocyte carries thousands of copies of a
  single receptor
• It can recognize only one single shape, unique to
  that lymphocyte

• The cells of innate immunity (like phagocytes)
  carry many different types of receptor
• All phagocytes carry the same set of 15 or more
  receptors of PAMPs

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The right lymphocyte

• Paul Ehrlich (1854-1915)
• Put forward the fundamental immunological idea of
  unique receptors on cells in 1890!
• 70 years before it was confirmed
• He thought the bonds would be chemical but they
  turned out to be physical--just like a slipper
  and foot.
• The indefatigable industry shown by Ehrlich
  throughout his life, his kindness and modesty,
  his lifelong habit of eating little and smoking
  incessantly 25 strong cigars a day, a box of
  which he frequently carried under one armhave
  been vividly described.

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The right lymphocyte

• The lymphocyte type of recognition is often
  referred to as specificity (specific immunity
  and so on)
• To refer to the phagocyte type of innate immunity
  as non-specific is a bit unfair since they can
  distinguish perfectly well between most pathogens
  and normal body cells
• Thats actually more than lymphocytes can do
  they have no way of knowing if the shape they
  bind to is part of a pathogen, a harmless
  symbiont, or one of the bodys own cells
• It is shape-directed millions of shapes,
  millions of receptors
• So, where does the diversity come from?

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Lymphocyte receptor diversity

• Humans have about 30,000 genes, so theres
  clearly not one gene for each of the tens of
  millions of different receptors on our T-cells
• Instead we have a combination of three things
• Receptors (at least B-cell ones) are composed of
  two protein chains, each different

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Lymphocyte receptor diversity

• Each chain is built of multiple segments that are
  combined by specially controlled recombination
  (somatic recombination)
• Heavy chains have three regions that affect
  recognition (receptor binding), variable (V),
  diversity (D), and joining (J)
• Light chains have only V and J regions
• In humans there are about 100 different V genes,
  12 D genes, and 4 J genes

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Lymphocyte receptor diversity

• Each progenitor of a B-cell clone undergoes
  somatic recombination that brings together a
  V-D-J combination for the heavy chain
• There are 100X12X4 4,800 V-D-J combinations
• Similar recombination events lead to the light
  chain
• How many possible light chain combinations are
  there?
• And heavy plus light chain combinations?

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Lymphocyte receptor diversity

• 4,800 V-D-J combinations for the heavy chain
• 400 V-J combination for the light chain
• 1,920,000 different B-cell receptors (aka
  immunoglobulins, aka antibodies)
• Plus there are random DNA bases added between
  segments, so the possible diversity is pretty
  much infinite
• There are lymphocytes with around 100 million
  specificities floating around inside each of us

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Lymphocyte receptor diversity

• 3. Finally, the six areas of the genes that code
  for the parts of the receptor that do the
  recognizing can undergo further small changes due
  to mutations within individual lymphocytes
• The V-D-J shuffle will be different for each
  lymphocyte, and is then locked in for that
  lymphocyte
• The glass slipper doesnt changemuch. But it
  changes a bit through somatic hypermutation
  (Haldanes idea)
• Somatic recombination gives a combinatorial pool
  of diversity which is then fine tuned

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Lymphocyte receptor diversity

• Upon infection, one of the clones generated by
  VDJ recombination of might fit a pathogen epitope
  like Cinderellas slipper
• This stimulates amplification of that clone
• The new generation of clones increase their
  mutation rate at recognition site
• This creates slight variation in the clone
  population, and variants with tighter binding are
  stimulated to divide more rapidly affinity
  maturation
• Remind you of anything?

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Lymphocyte receptor diversity
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Clonal selection

• The process that underlies lymphocyte specificity
  and differentiation is akin to natural selection
• only those lymphocytes that encounter an antigen
  to which their receptor binds will be activated
  to proliferate and differentiate into effector
  cells
• This selective mechanisms was first proposed in
  the 1950s by the Australian biologist Frank
  MacFarlane Burnet
• at a time when nothing was known about
  lymphocyte receptors, or even that lymphocytes
  were important

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Clonal selection

• It wasnt until the 1960s that James Gowans
  removed lymphocytes from rats and noticed that
  their adaptive immunity disappeared
• Peter Medawar removed the last conceptual problem
  in the 1950s by showing how the problem of immune
  responses to self is solved
• How?

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Clonal selection

• Exposure to foreign tissues during embryonic
  development of mice caused them to become
  tolerent of those tissues later (I.e. no immune
  response)
• Led to the idea that developing lymphocytes that
  are potentially self-reactive are removed before
  they can mature clonal deletion
• these sorts of experiments are why we call MHC
  MHC
• (major histocompatibility complex)

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Figure 1-15
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Figure 1-14 part 1 of 2
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Figure 1-14 part 2 of 2
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Clonal selection

• The proliferation of lymphocytes after clonal
  selection leads to immunological memory
• After a lymphocyte is activated, it takes 4-5
  days of proliferation before clonal expansion is
  complete
• Thats why adaptive responses occur only after a
  delay of several days
• After this primary response, some
  antigen-specific cells persist and lead to a more
  rapid and effective secondary response, and
  lasting immunity immunological memory

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Clonal selection, adaptive immunity, and
diversity generation

• The proliferation of lymphocytes after clonal
  selection leads to immunological memory (and
  vaccines)

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Types of lymphocytes

• B-cells produce immunoglobulins, molecules
  produced by adaptive immunity to dispose of
  particular threats
• Antibody immunoglobulin free-floating B-cell
  receptor.
• B-cells main job is to produce humoral immunity,
  to neutralize pathogens floating anywhere outside
  of cells (extracellular)
• Thats enough about them