P1254413703UvWQd

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Genetics of the Immune system   Immune system -
protects us against foreign material proteins,
viruses, bacterial infections   Immune system
has two major divisions. Non-Specific
Response - block entry of foreign agents into
the body - block the spread of foreign agents if
they get into the body   Specific Responses -
antibody-mediated immunity - humoral response -
cell-mediated immunity cellular response
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Foreign versus Self

• To protect the body from harmful organisms, the
  immune system identifies foreign molecules as
  nonself and destroys those cells.
• Molecules recognized by the immune system are
  called antigens. Antigens are usually protein
  fragments or carbohydrates.
• During development, the immune system removes
  components that recognize self.
• Immune response to ones own body is called
  autoimmunity.

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1. Physical barriers - skin, mucous membranes
and their secretions - infection fighting
chemicals,in tears, saliva, other body
fluids 2. Nonspecific - Innate defenses -
phagocytosis - (engulfing cells) - inflammatory
response - fever - anti-microbial proteins
complement, collectins, cytokines 3. Specific
response - Acquired Immunity - Humoral immune
response - B cells, antibodies, memory
cells - Cellular immune response - T cells,
cytokines, memory cells
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Acquired response
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Inflammatory response A non-specific response
triggered by - injury - penetration of
bacteria -skin, respiratory, digestive, urinary
or reproductive tract   Two main players -
histamine - complement  
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Histamine - dilates local blood vessels -
increases capillary permeability Result is
redness, heat and swelling heat - unfavorable
to microorganisms - mobilizes white blood cells
(monocytes) - raises metabolic rate of
surrounding cells Complement - chemotaxsis
agent - recruits in WBC to injury site The
Inflammatory Response - starts with release of
histamine and other chemicals - ends with WBC
cleaning up the debris
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Complement System - chemical defense system
that kills microorganisms - named the complement
system because of the way it works together
with the immune system - are a series of
proteins, C1, C2 , etc   - C5-C9 - form a large
multi-protein complex - MAC - membrane-attack
complex MAC - inserts itself into the membrane
of invading microorganisms - creates a
pore - disrupts control of ion balance -
cells burst
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Anti-microbial chemicals on the non-specific
response   - collectins - recognize the sugar
moieties present on the surface of foreign
cells - cytokines - interferons (chemical
scouts), alert other cells to the presence of
invaders - also anti-viral - interleukins
(fever) - high temp - kills some infecting
bacteria - lowers blood iron levels - tumor
necrosis factor
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Specific, Adaptive Immunity - Acquired Response

• Invoked when the inflammatory response and
  complement systems fails
• - Requires stimulation.
• - Response time is in days.
• Major features
• Diversity - many different pathogens
  recognized
• Specificity - distinguishes particular
  molecules
• Memory - responds faster with subsequent
  exposure
• Primary immune response is reaction to first
  exposure.
• Secondary immune response is reaction to exposure
  using memory of first response.

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Antibodies   - antibodies are proteins that bind
to antigens - antigens - a protein or other
molecule that causes antibody production antibo
dy generators - antibodies are produced by B cell
B-cells - type of lymphocyte - matures in
the bone marrow - circulates in the blood and
lymph system - encounters an antigen - makes a
specific antibody - each B-cell produces only
one antibody - clonal   B- cells are the
lymphocytes that mediate the Humoral response
(antibody-directed immunity).
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T cell lymphocytes. - target and destroy
infected body cells - develop in the bone
marrow - differentiate into mature T cells in the
Thymus gland - T cells move in the circulation
and the lymphatic system - are responsible for
the Cellular Response (cell- mediated immunity).
Antibody-mediated and cell-mediated immune
systems work together.
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Humoral response -Antibody-directed
Immunity   Three basic steps - detect the
antigen - activate helper T cells - make the
antibodies  
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Antigens activate B cells directly and
indirectlyHOWEVER - indirect is the major
pathway.
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Antigen-presenting macrophage activates helper T
cell
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Role of helper T cells in the humoral response

• - Recognize antigens presented by macrophages
• - Stimulate B cells to produce antibodies

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Antibodies - several different classes - known
as immunoglobulins, IgG, IgM, IgE, etc
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Antibody structure

• Antibodies minimally consist of four proteins
• Two long proteins heavy chains
• Two shorter proteins light chains
• Constant region of each protein is similar in all
  antibodies.
• Variable region of each protein is diverse.
• Antigen binding sites are pockets where antigen
  is held.
• Idiotypes are sites in direct contact with
  antigen.
• The portion of the antigen contacting the
  antibody is called the epitope.

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Problem - humans produce billions of different
types of antibodies - Where are the genes? - B
cell antibody genes undergo a tremendous number
of recombination events   - recombination occurs
during B cell maturation
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Simplest antibody 2 H (heavy) and 2 L (light)
chains random recombination can make 30,000
different H chains random recombination can make
about 3600 light chains 30,000 x 3600 108
million combinations - other processes generate
more than 100 trillion   - a particular B cells
produces only one antibody - as it divides -
its daughter cells produce the same antibody -
it is these mature daughter cells that are
circulating
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Cell-mediated immunity   - helper T cells -
recruit and activate B cells to make
antibodies - suppressor T cell - inhibit
immune reaction - are off switches - killer T
cells - destroy infected body cells - cytotoxic
T cells - a subset of killer T cells - memory
T cells - T cells ready to respond to make
other T cells when antigen is
reintroduced  
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Cytotoxic T cells can destroy cancer cells
Join T cell surface receptors to bind antigen
Cell transport is disrupted and cell dies
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The immune system is capable of memory -
referred to as secondary immunity Vaccines -
work by triggering a primary immune response -
with development of secondary immunity -
boosters - increase the number of memory cells
present - vaccines present an antigen that is
derived from, or is highly related to that of,
potential bacterial and viral invaders
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 Blood types - are determined by cell surface
antigens   - more than 30 known antigens on RBC
plasma membranes - blood transfusions -
certain antigens must be matched are you elicit
an immune response - being treated like the
massive foreign invasion - two groups of
antigens are of major significance - ABO system
- Rh
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ABO blood group

• The I gene encodes enzymes that attach cell
  surface molecules on the sugar chains of red
  blood cells.
• A allele attaches antigen A
• B allele attaches antigen B
• O allele no attachment performed
• Blood type incompatibility
• A person with type A blood who is transfused
  with type B blood will have antibodies that
  recognize and destroy the red blood cells
  carrying type B.

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Type O is the universal donor. Type AB is the
universal recipient.
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Rh factor

• Rh factor or rhesus factor is another blood group
  affecting cell surface molecules.
• Phenotypes Rh - produces Rh factor on RBC
• Rh- - no Rh factor on RBC
• Rh incompatibility occurs when an Rh- mother has
  an Rh child.
• - hemolytic disease of the newborn - HDN
• - HDN occurs with the second pregnancy
• - preventable through screening and anti-Rh
  therapy

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Human leukocyte antigens (HLA)

• HLA proteins are produced by major
  histocompatibility complex (MHC) class I and II
  genes.
• Link sugars to form branched glycoproteins on
  cell surface of white blood cells.
• HLA glycoproteins can recognize bacterial and
  viral proteins, marking them for immune system to
  target, a process called antigen processing.

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Antigen Presenting Cells
Cells which bind antigens with HLA glycoproteins
are called antigen presenting cells. Two types
of antigen presenting cells are Macrophages Ly
mphocytes
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• Organ transplants
• - need to match histocompatibility antigens
  between donor and recipient
• only 1 in 10,000 unrelated people will share a
  HLA type by chance at the six major HLA genes.
• (twins 100, siblings 25)
• - matching at least 4 major HLA genes is needed
  for most transplants to succeed.
• - HLA genes account for about 50 of the genetic
  impact on immunity.

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HLA gene complex - consists of several gene
clusters - class I HLA-A, HLA-B, HLA-C - class
II HLA-SR, HLA-DQ, HLA-DP - each gene in each
class has multiple alleles - haplotype - this
is a set of alleles at a specific location -
each of us has an specific array of HLA alleles
on a given copy of chromosome 6 - since we
have two copies of chromosome 6 - each have two
HLA haplotypes - population has millions of
haplotypes (allele combinations)
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• 18,000 organ transplants/yr in US
• - about 40,000 qualified patients (on the list)
• - about 3000/yr die while on the waiting list
• estimated about 50,000 transplant/yr is what is
  need
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• xenotransplants
• - animal human transplant
• - transgenic pigs
• therapeutic cloning

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Xenografts
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• HLA and disease
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• There is a relationship between certain HLA
  antigens and specific diseases
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• Ankylosing spondylitis
• Inflammatory condition in which the vertebrae are
  inflamed and deformed, leading to fusion of the
  joints in the spine.
• - Those with HLA-B27 are 100 times more likely to
  have this disease.
• - 90 of those afflicted carry HLA-B27 (versus 5
  of general pop)
• - maybe triggered by a bacterial infection
  Klebsiella
• However,
• - 10 of cases do NOT have B27.
• - Not all with B27 allele get disease.
• gt HLA-B27 is a significant factor but not the
  sole factor in ankylosing spondylitis.

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Why do we have a complicated HLA system? Need
to be able to recognize self from
non-self During development - immune system
learns who is self - a large group of diseases
is related to the inability to differentiate
self - immune system has decided that a cell
of our body is not of our body
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Autoimmune Diseases

• When the immune system attacks the tissues of an
  individuals own body it is called autoimmunity.
  Autoantibodies recognize self proteins.
• Some mechanisms include
• - Viruses use host proteins on the viral cell
  surface. These host proteins become the target
  of the immune system which responds as if they
  are viral proteins.
• - Thymocytes which recognize self antigens
  survive instead of apoptosing.
• - Nonself antigen may coincidentally resemble
  self antigens.

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Autoimmune disorder Symptoms Target of Antibodies
Glomerulonephritis Lower back pain Kidney cell antigen that resembles Streptococcus antigen
Graves disease Restlessness, weight loss, irritability, increased heart rate and blood pressure Thyroid gland antigen
Myasthenia gravis Muscle weakness Nerve message receptors on skeletal muscle cells
Pernicious anemia Fatigue and weakness Binding site for vitamin B on cells lining stomach
Rheumatoid arthritis Joint pain and deformity Cells lining joints
Systemic lupus erythematosus Red rash on face, fever, weakness and kidney damage DNA, neurons, blood cells
Type I diabetes Thirst, hunger, weakness, emaciation Pancreatic beta cells
Ulcerative colitis Lower abdominal pain Colon cells
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Inherited immune deficiencies

• Mutations in genes encoding proteins used in
  immunity result in impaired immune response.
• 20 types of inherited immune deficiency
• Chronic granulomatous disease mutation of
  oxidase enzyme results in neutrophils that cannot
  kill bacteria.
• Severe combined immune deficiency (SCID) impacts
  both humoral and cellular immunity due to lack of
  mature B cells and/or T cells.

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• X-linked agammaglobulinemia (XLA)
• - usually boys
• - characterized by having multiple serious
  bacterial infection during childhood (20 or more
  in 5 years).
• - have normal T cells
• - patients dont have any mature B cell
• - can't make antibodies
• protected for the first 6 months by maternal
  antibodies
• - rest of life always having severe infections
• pneumonia and strep

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SCID - severe combined immunodeficiency Both
antibody-mediated and cell-mediated immune
responses are non-functional - usually die at a
young age from a minor bacterial threat boy
in the bubble - David died at age 12 -
lacked of a thymus gland - Some SCID cases are
due to ADA deficiency (adenosine deaminase)
- target disease for gene therapy
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• AIDS Acquired immunodeficiency syndrome
• collection of disorders that develop as a result
  of infection with HIV
• HIV , human immunodeficiency virus
  (retrovirus).
• - virus infects macrophages and T4 helper cell
• Problem - T cell activation also activates viral
  replication
• - with time, the helper T cells are killed off
• - eventually loose ability to activate the
  antibody-mediated immune response
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• result - increased susceptibility to infection
  and certain forms of cancer - early death

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Structure of HIV
HIV is an RNA virus (a retrovirus). The RNA
molecule encodes a reverse transcriptase enzyme
which synthesizes a DNA copy of the RNA
virus. The virus is enclosed within a capsid
within a coating of envelope protein studded with
glycoproteins that can bind cell surface
molecules on the host cell.
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HIV envelope proteins gp41 and gp120 bind to CD4
and CCR5 receptors on the helper T cell.
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Final note on AIDS its not that the immune
system cant fight the HIV infection, it just
cant keep up - early HIV infections - produce
2 billion new B and T cell per day - virus does
two things - produces millions to billions of
new virus per day - it mutates very rapidly -
antibodies useful today no effect tomorrow
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Treatment of HIV infection

• Drug therapies have cut the mortality rate from
  AIDS in half since 1996.
• Two reverse transcriptase inhibitors and a
  protease inhibitor are commonly used.
• Reverse transcriptase inhibitors block conversion
  of the viral RNA into DNA.
• The protease inhibitor limits the processing of
  several viral proteins required for new particle
  formation.

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Resistance to AIDS?

• Are some individuals less susceptible to AIDS
  than others?
• People at high risk for HIV infections
  (individuals with multiple partners or
  hemophilia) who are not infected more often have
  a CCR5 receptor gene with a 32-base deletion.
  This deletion truncates the protein and prevents
  localization to the cell surface.
• Long term nonprogressors are infected but
  healthy.
• Correlated with heterozygous carriers of CCR5
  deletion.
• Correlated with milder inflammation response.

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Disorders of the Immune system   Allergies -
overreactions of the immune system - weak
antigens are called allergens - house dust,
pollen, cat dander food, medicines - up 10
of us have at least one allergy Problem relates
to Immune response memory Mast cell release
histamine - local inflammatory response - if
histamine enter blood stream in high amounts -
full body response - anaphylaxis - treat with
antihistamines- epinephrine
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• Asthma
• - a chronic disease involving contraction of the
  respiratory airways, inflammation and mucus
  production in the lungs. Breathing becomes
  difficult during an asthma attack. Some asthma
  attacks are triggered by allergic reactions.

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Allergic response

• Humoral and cellular arms respond. IgE class
  antibodies are made and bind mast cells.
• Mast cells release allergy mediators like
  histamine and heparin that cause inflammation,
  runny eyes and nose, rashes and asthma.
• Allergens activate a class of helper T cells
  which release cytokines.
• Severe allergic reaction throughout the body is
  called anaphylatic shock and can be
  life-threatening.