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					           Genes and Immunity
Immune response system is remarkably adaptive
  defense system
  a. protects against pathogens and cancer
  b. immune recognition or specificity is the hallmark of
  IRS
  c. distinguishes between self versus non-self
  d. effect or response-calls in a variety of cells and
  proteins (B cells, T cells etc)
  e. exhibits memory--protection against second
  invasion
          eg polio vaccine

Problems with immune system
  Type I diabetes (B cells and insulin cells are killed by the
  immune system)
Pioneers:
Discipline of immunology has its roots in the early observations and
experiments by Edward Jenner and Louis Pasteur (human medicine and
veterinary medicine)

Edward Jenner, 1898---viral etiology

   country physician
   smallpox--40-50% fatality
   observations for almost 20 years--milk maids no pock marks on their
   body from small pox
   cowpox--blisters on their hands, did not get small pox
   fluid from cowpox blister--inoculated 8 year old boy, waited and inoculated
   with smallpox--did not get small pox
   established procedure for preventing smallpox throughout Europe

Louis Pasteur--chance observation--1880,

   experimenting with chicken cholera--major disease of chickens
   left preparation of cholera bacteria on shelf 2 weeks
   injected chickens--did not die--re-injected with live bacteria-did not die
   1881--injected sheep with attenuated anthrax--gave live anthrax-did not die
     Duality of the IRS:
Elie Metchnikoff, 1883 cellular immunity (T cells)

Emil von Behring, 1890--humoral immunity (Ab's)

Today's thinking is that IRS is combination of cellular and
humoral

          Thymus-----------------------T cells (cellular)
                                         (T helper/killer)
Bone Marrow -----

            Bursa Equiv-------------------B cells (humoral)

   T cells are present in all areas of the body and ask the
   question: self or non-self?

   Without T helper cells there would be not B cell response.


Take home lesson

These two systems are not independent of each other, but are in
constant communication..
Where do our immune cells come
 from?

  Formation and development of RBC’s
  and WBC’s (leukocytes)

  All blood cells arise from one type of
  cell called the hematopoietic stem
  cell

  Stem cells have the ability to
  differentiate into a number of different
  cell types.

  They are self renewing and maintain
  their populations via division.
The Major Players
          B cells (Humoral)
             produce antibodies
              which bind to pathogens
              and disable them or flag
              them for destruction

          T cells (Cellular)
           kill infected cells

           coordinate entire

            adaptive response
Humoral Branch
  Antibodies are immune system-related
  proteins called immunoglobulins.
  Antibody consists of four polypeptides– two
  heavy chains and two light chains joined to
  form a "Y" shaped molecule.
  The amino acid sequence in the tips of the
  "Y“ varies greatly among different
  antibodies.


 •This variable region, give the antibody its specificity for binding antigen.
 The variable region includes the ends of the light and heavy chains.


 •The constant region (Fc) determines the mechanism used to destroy
 antigen (secondary biological function)
five major classes, IgM, IgG, Iga, IgD and IgE
IgA about 15% of total antibody count. Found in mucous secretions and
   mother’s milk

IgD less than 1%
   Appears to have a role in activating and suppressing lymphocyte activity
   Found in large quantities in the cell walls of many B-cells. IgD has a single
   binding site.

IgE less than 1%
   Mediator in allergic responses. Most importantly activates histamine
   secreting cells. Also appears to play a role in parasitic infection.

IgG- composes 75% of our immunoglobulin pool. IgG stimulates
   high immune response. Most importantly, it is the only antibody that
   can cross the placenta and confer immunity on the fetus.

IgM - makes up 10% of our total antibodies. This is the predominant
   early antibody; the one that first activates in an initial attack of
   antigen.
   Because of its high number of antigen binding sites (5), it is an
   effective agglutinator of antigen . This is important in the initial
   activation of B-cells, macrophages, and the complement system.
Explaining Ab specificity.

  ImmunoGlobulin (Ig) molecules
    Thousands on surface of each B cell
    Ig are essentially just bound antibodies

What do Antibodies bind to?

  An antigen is defined as "anything that can be
  bound by an antibody". This can be an enormous
  range of substances from simple chemicals, sugars,
  small peptides to complex protein complexes such
  as viruses.

  In fact antibodies interact specifically with relatively
  small parts of molecules. These are known as
  antigenic determinants or epitopes.
Antibody diversity

  How is this astonishing diversity
  generated?
  This problem has been resolved over
  the past 20 years by the
  demonstration that Ig genes
  rearrange during B cell
  development.
  light chains- two types k or λ
       contain V J C gene segments
      Rearranged V J segments encode the
       variable region of the light chain.
  heavy chain family contains V D J C
  genes segments
      Rearranged V D J segments encode the
       variable region of the heavy chain.
Pairing of different combinations
of Ig heavy and light chains.
Recombination of V, D and J
segments (VJ for light chains)

Together these potentially
generate some 5x106 different
antibodies.
Cellular Branch

T cells
 T lymphocytes constitute the "cellular" arm of immunity.
 There are two major subsets of T lymphocytes that differ
 in function
      Specificity of T cells
Each T cell has a unique
surface molecule called a T
cell receptor (TCR)

Specificity through similar
process of DNA splicing...
Like Ig’s, each cell’s TCRs
recognizes a unique pattern
(10^7 TCR types)
TH cells are activated and proliferate only
 when presented with the antigen via self
 MHC.

     MHC genes are organized into regions that
      encode 3 classes of molecules
     Class I – present on the surface of nearly all
      nucleated cells.
      Major function is to present antigens to Tc cells
     Class II – present on APC’s
      Major function to present antigens to TH cells

  APC –Dendritic Cells (can present with
  either class I or class II). They are the major APC
     in our body
   Macrophages
Establishing Self Tolerance

   T cells originate in the bone marrow then migrate to the
   Thymus where they mature

   Selection of T cells through binding to common MHC-self
   peptides in thymus
      strong binders are killed (clonal deletion)
      weak binders die from lack of stimulation (clonal selection)
      They then go on to make either Tc or TH cells, but 95% of all
       cells entering the thymus undergo apoptosis.

   Remaining T cells are not self-reactive
Bringing it all together

Typical Immune
 Response

 Ex. Polio
 Initial response started
 out by IgM
 IgG activated later
Low Response
 IgM response.
 T cell independent



 Taking a closer look at
 cell involvement.


 Clonal Expansion
 High Response
  T cell dependent
  IgG now becomes
  involved
   How do T cells get
  involved in the IRS?
In order for a T cell to get involved in the IRS, it needs to be
presented the antigen in a very specific manner.

This is made possible via presentation of the antigen by an
Antigen Presenting Cell (APC)
•Macrophages
•B cells
•Dendritic cells
Sequence of Events
  Ag recognized by Ab on B cell
  Ingested by (APC), immunogen
  broken down
  Select peptides of immunogen
  presented on surface of APC via
  MHC
  Peptide is presented to T helper cell
  via TCR.
  Cytokine release (chemical signals)
  Cytokine release from T helper cell
  telling B cell to continue making
  Ab's that are specific to the
  immunogen.

				
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posted:3/5/2011
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