Genetics of Immunity

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Genetics of Immunity

• Sunne Woo and Naoko Charity

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Table of Contents

• THE IMPORTANCE OF CELL SURFACES
• Pathogens
• Genetic Control of Immunity
• Blood Groups
• The Human Leukocyte Antigens(HLA)
• THE HUMAN IMMUNE SYSTEM
• Physical Barriers And The Innate Immune Response
• The Adaptive Immune Response
• ABNORMAL IMMUNITY
• Inherited Immune Deficiencies
• Acquired Immune Deficiency Syndrome (HIV)
• Autoimmunity
• Allergies
• ALTERING IMMUNE FUNCTION
• Vaccines
• Immunotherapy
• Transplants
• 5. A GENOMIC VIEW OF IMMUNITY- THE PATHOGENS
  PERSPECIVE
• Crowd diseases

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Introduction
The Immune System is more than just cells
attacking foreign bodies to prevent getting
sick.
The Immune System is a powerful tool that
consists of about 2 trillion cells and
biochemicals. Its attacking actions are
highly coordinated And multipronged with both
general and specific responses. Basic logic of
the immune system Recognize foreign or
non-self surfaces.
Click here
When the Immune system shuts down (death),
the body starts decomposition.
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Overview of the Immune System

• Immune response and cell signaling by amino acid
  sequence (LTL)
• Diapedesis occurs.
• Cell membrane begins to surround its target
• Two calcium waves begin to circulate around the
  cell.
• When the target is completely surrounded, one
  wave splits in two, with the second wave
  encircling the phagosome (sac).
• This second wave allows the digestive enzymes to
  enter the phagosome and destroy the target.

Diapedesis
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The Importance of Cell Surface
Pathogens
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Genetic Control of Immunity
Genes oversee immunity by encoding Antibodies,
Cytokins, and Antigen.

• Antibodies (protein) respond to antigen
• Antigen (protein or carbohydrates molecule)
• mark the cell surface as self
• Cytokines (protein) - released by immune cells
• to act as intercellular mediators in an immune
• response.

• Mutation of gene
  impair immune function
• Immune deficiencies - Inherited or not inherited.
  Missing or defective Immune System (e.g. Severe
  Combined Immune Deficiency (boy-in-the-bubble
  disease)).
• Autoimmune disorders - Attack of own tissue. The
  genes contribute to the susceptibility for
  developing an autoimmune disease. Maybe
  triggered by outer factor (e.g. Systemic Lupus
  Erythematosus).
• Allergies
• Cancer

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Inheritance of abnormal genes
X - linked recessive (sex chromosome. No disease
are inherited through Y). Female (XX)
carrier or affected. Male (XY)
affected. Autosomal (non-sex chromosomes).
Recessive abnormal chromosomes from both
parents are
required to cause disease. Dominant
only one abnormal chromosome is required to
cause disease.
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Blood Groups (ABO Group)

• I gene alleles encode enzymes to place
• antigens A, B, Both or Neither on red blood cells.

Clumping-agglutination

• RH factor
• (another blood group antigen)
• RH produces RH-antibodies
• RH- produces RH
• antibodies
• ABO group is one of the
• major 26 Blood groups

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Human Leukocyte Antigens (HLA)
Cell surfaces have proteins that are encoded by
genes that are part of Chromosome 6, called Major
Histocompatibility Complex (MHC).
Class I II genes encode Human
Leukocyte Antigens (HLA).
MHC 3 classes
Class III genes encode proteins in blood plasma.

• Phagocytosis (eating of an invader) by
• Macrophage cell (HLA)
• The Antigen attaches to MHC.
• MHC proteins and Antigens are displayed on the
  macrophage surface.
• Helper T cells recognize both and bind to the
  macrophage to initiate the immune events.

Macrophage
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The Human Immune System

• The immune system consists of 2 defensive
  barriers that block pathogens.
• They are the innate barrier which is generally
  immediate to phagocytes, collectins, and
  cytokines. Inflammation is part of the innate
  immune response. This process engulfs and
  destroys certain pathogens around the injury.
  Inflammaton at the site of an injury can prevent
  infection (Lewis, 2007).

• The adaptive immune response has to be stimulated
  into action. The immune response has 3
  characteristics that are diverse because it
  defeats many different types of pathogens. It is
  specific because it can distinguish the certain
  cells and molecules that are dangerous to cause
  diseases from the harmless ones. And it
  remembers so it can respond faster than the first
  time with a foreign antigen.

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• The humoral immune response is part of the
  Adaptive Immune Response. It is where the
  B-cells are stimulated and then divided into
  plasma and memory cells.

The Humoral Immune Response B-cells Antibodies

• Plasma cells secrete a bunch of antibodies of a
  single type.
• Antibodies are of Y-shaped polypeptides, that
  consist of 2 heavy chains and 2 light chains.
  Each of these chains consists of a constant and
  a variable region, and the tips of the Y form and
  antigen binding site with a specific idiotype
  (Lewis, 2007).

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In the picture below, it shows a death of a
cancer cell the cytotoxic T-cells binds to the
cancer to inject perforin. The cell then dies
and leaves debris that microphages come to clear
away.
The T-cells give cellular immune response because
the cells travel to where they need to act.
T-cells are unlike B-cells because they dont
secrete antibodies in the blood stream. The bone
marrow lets the T-cells descend from each stem
cell to travel to the thymus gland.
T in T-cells refer to the thymus!!
Perforin is a protein that punctures the cancer
cells plasma membrane.
The Cellular Immune Response-- T-cells Cytokines
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Altering Immune Functions

• This sections contains different areas of
  possible cures to bacteria and viruses. They are
  vaccines, immunotherapy, and transplants.
• Vaccines are drugs that trick the immune system
  into acting early (Lewis, 2007).
• Immunotherapy increases and redirects the immune
  response. This is done by monoclonal antibody
  technology (MAb), and cytokines that boost
  cellular immunity.
• Transplants are done after suppressing the immune
  system in order to accept the organs from another
  person, self, or animal.

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The Abnormal Immunity

• There are more than 20 types of inherited immune
  deficiencies.
• Possible causes
• Abnormal Phagocyte cells
• No thymus or natural killer cells
• Deficiencies of T cells, B cells, and
  Neutrophils

Thymus gland
Neutrophils
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Acquired Immune Deficiency
AIDS
Immune cells being attacked by HIV virus
Aids Virus
HIV enters Macrophages HIV sticks to the primary
receptor "CD4 HIV sticks to a second receptor
CCR5 CCR5 ensures HIV to dock at a helper T
cell for infection to occur.
Encountering HIV virus
The lack of CCR5 receptor by gene defect prevents
HIV infection.
CD4
CCR5
Quick replication Fast mutation Able to hide
No Cure
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Human Immunodeficiency Virus
From RNA to DNA (Reverse transcriptase)
Transcription of the viral DNA begins with the
activation of lymphocyte, resulting in the
multiple copies of viral RNA(codes) to produce
new proteins and to be packaged later as new
viruses.
Enzyme"integrase" incorporates the viral
DNA into the host cells DNA. The integrated DNA
is called a provirus.
Viral RNA is translated into chain of proteins
with polypeptide sequence (reverse
transcriptase, protease, integrase). Later,
Viral protease cuts the chain into its
individual enzyme components to facilitate the
production of new viruses.
Finally, viral RNA and proteins are packaged and
released from the lymphocyte surface with a
membrane containing viral surface proteins.
These proteins will bind to the receptors on
other immune cells and infect other cells.
HIV enzyme "reverse transcriptase" transcribes
the sequence into a complementary DNA sequence.
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Is there a cure for AIDS?
NO
But, You can slow the disease by combining drugs
with different actions, such as inhibiting
reverse transcritase, stopping the cutting action
of viral proteins that assemble to make new viral
particles, and blocking the viruss ability to
bind and fuse with the plasma membrane.


1. Inhibiting reverse transcritase (Recoding
of RNA to DNA).
2. Stopping the cutting action Of Protease.
HIV since 1991
I am on HAART or Highly Active Anti-Retroviral
Therapy that targets multiple HIV life cycles. 
3. Blocking the entry.
New Therapy for the future Structured
treatment interruption (STI) the practice of
alternating time spent on antiretroviral drugs
with time spent off drugs.
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Vaccines

• Vaccines technology was first started in China
  back in the 11th century.
• Vaccines are a pathogen that stimulate the
  B-cells in the immune system to produce
  antibodies against the disease.
• Vaccines against several different illnesses can
  be combined into only one injection so you dont
  need more than one shot per vaccine!!
• A popular vaccine was made for the smallpox
  disease. When people in China observed the
  recovery of smallpox, and that the person never
  had it again people started crushing scabs into
  a powder to inhale or rub onto the blistered
  skin.
• Vaccines are still dispensed through injections,
  but with new technology, patients can use nasal
  sprays and eat genetically modified fruits and
  vegetables.

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• To the left, a collection of pictures of
  smallpox. The black white picture shows Edward
  Jenner, the creator of the smallpox vaccine. This
  boy was the last known victim of smallpox. The
  bottom-left pictures shows the vaccine in 1798.

• The picture on the right show the difference
  between smallpox and chickenpox. When someone has
  smallpox, the blisters are more on the
  extremities the feet, hands, and face.
  Chickenpox is prominent on the abdomen with a few
  blisters on the arms and legs.

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It is important for the vaccinations to be
dispensed within the whole population because of
herd immunity. This is where the unvaccinated
population is rare, and that the pathogens may
resurface when it does, the disease wont spread
because the people will have been exposed to it
and be protected. But, when there are pockets of
people that havent been vaccinated, and the
diseases resurfaces the pathogen will have its
way and be spread throughout.
"Herd Immunity"
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MAbs

• The process was mentioned on the previous page.
• Today MAbs are used in research, veterinary
  health and human health care. It can also be
  used in agriculture, forestry, and the forensics
  fields. It can be used to diagnose everything
  spanning from strep throat to turf grass disease.
• MAbs can actually be used in home pregnancy tests
  also! It binds with the pregnancy hormone hCG on
  the paper strip of the home pregnancy applicator.
  You will know you are pregnant when the color
  changes from the MAb hits the target.

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Cytokines Boost Cellular Immunity

• Cytokines can be used to treat different
  conditions.
• These cells have short periods of activity. If
  they dont go to where they are needed right
  away, then overdose or side effects can happen.
• They can kill cancer cells!

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Timeline of Transplantation

• 1899- the 1st allograft transplant, a kidney from
  dog to dog
• 1905- the 1st corneal allograft transplant, an
  eye from a boy to man
• 1906- the 1st kidney transplant in a human body
  fails
• 1954- success of the 1st isograft transplant
  kidney from a monozygotic twin
• 1967- the 1st heart transplant leaves patient
  living for an extra 14 days
• 1984- a xenograft heart transplant from a baboon
  was transferred into Baby Fae whom was born
  with ½ a heart. She lived for 20 days before her
  body rejected the xenograft.
• 1998- scientists start transplanting hands and
  forearms
• 2003- DNA gene expression microarrays are likely
  to tell doctors which patients will have
  rejection toward kidney transplants
• Future- using stem cells from patients, embryos,
  or animals may replace transplantation

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Baboons and Pigs can transplant different organs
into the human body
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4 Different types of transplants
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These are the different parts of the body that
can have transplants done. Some of the most well
known parts of the body that can be transplanted
are the heart, cornea of the eye, kidney, liver,
blood, bone marrow, and skin.
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Rejection Reactions Or Acceptance

• In allograft transplants, the tissue in the
  recipients body can reject the newly transplanted
  part of the body. Xenograft transplants can
  cause hyperacute rejection. In hyperacute
  rejection, the blood vessels blacken and cut off
  the blood supply within minutes of the
  transplantation.
• In bone marrow transplants, the recipient can
  reject to the new bone marrow tissue. This can
  be deadly. According to Lewis, Graft versus
  Host Disease develops sometimes when bone marrow
  transplants are used to correct certain blood
  deficienceies and cancers (2007).
• According to Merriam-Webster dictionary, the
  bodily condition results when cells from a tissue
  or organ transplant mount an immunological attack
  against the cells or tissues of the host .

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Rejection Reactions Or Acceptance cont.

• When the recipient is in need of a transplant,
  the doctors need to match the HLA as closely as
  they can. If this doesnt happen, then the
  recipient will reject the donors tissue. But,
  if the HLA is matched too closely, there could be
  a chance that the disease will come back again
  because the same cell surfaces that it had
  earlier will be equally unable to fight the
  cancer. The donor bone marrow should be
  different enough to control the cancer, but no so
  different that rejection occors (Lewis, 2007).

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Side effects of GVHD
Vomitting
Nausea
Hair Loss
Jaundice
Rash
Abdominal Pain
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Bone Marrow Transplants
Bone marrow transplants are for patients that
have a deficiency of blood because the bone
marrow doesnt produces enough blood cells.
These cells are the red and white blood cells,
and platelets. Some examples of the diseases
affected by the lack of the bone marrow working
are Leukemia, Anemia (along with some forms of
anemia, for example Aplastic Anemia),
Hemophilia, etc. Allogenic transplants are only
available to a minority of patients because 70
lack a suitablity of a sibling donor. Survival
rates for transplantation is as high as 90 from
a single experienced institution performing the
procedure. For people who are not candidates,
immunosuppression drugs are used. One of the
most common immunosuppression drug is ATG
(antithymocyte globulin), which consists of horse
protein. But this can have toxic effects, this
could lead to serum sickness after 11 days after
treatment.
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Biopsy specimen of bone marrow. Magnetic
resonance imaging scan of the spine shows uniform
replacement of bone marrow with fat. Long-term
bone marrow culture-initiating cell number as a
surrogate of stem cell number. Horizontal bars
indicate mean values.
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Bone Marrow Transplants cont.
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The Genomic View of Immunity The Pathogens
Perspective

• There are 2 subdivisions of this particular
  subject

Crowd Disease
and
Bioweapons
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