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
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 one’s own body is called autoimmunity.
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
Bacteria
Viruses
Physical
barriers
Innate response
Mucous membranes
Acquired response
Cellular response
Cilia
Cytokines
Antimicrobial secretions
Macrophages
Macrophages
present antigens
T cells
Cytokines
Humoral response
B cells
Memory B cells
Cytotoxic T cells
Plasma cells
Antibodies
Inflammatory response
A non-specific response triggered by
- injury
- penetration of bacteria
-skin, respiratory, digestive, urinary or reproductive
tract
Two main players
- histamine
- complement
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
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
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
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.
Antibodies
- antibodies are proteins that bind to antigens
- antigens - a protein or other molecule that causes antibody
production
antibody 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).
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 (cellmediated immunity).
Antibody-mediated and cell-mediated immune systems work
together.
Humoral response -Antibody-directed Immunity
Three basic steps
- detect the antigen
- activate helper T cells
- make the antibodies
Antigens activate B cells directly and indirectly
HOWEVER - indirect is the major pathway.
Antigen-presenting macrophage activates helper T cell
Role of helper T cells in the humoral response
- Recognize antigens presented by macrophages
- Stimulate B cells to produce antibodies
Antibodies
- several different classes
- known as immunoglobulins, IgG, IgM, IgE, etc
Antibody structure
• Antibodies minimally consist of four proteins
• Two long proteins = heavy chains
• Two shorter proteins = light chains
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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.
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
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
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
cells when antigen is reintroduced
T
Cytotoxic T cells can destroy cancer cells
Join T cell
surface receptors
to bind antigen
Cell transport is
disrupted and
cell dies
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
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
ABO blood group
The I gene encodes enzymes that attach cell surface
molecules on the sugar chains of red blood cells.
A allele
B allele
O allele
attaches antigen A
attaches antigen B
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.
Type O is the universal donor.
Type AB is the universal recipient.
Rh factor
Rh factor or rhesus factor is another blood group affecting
cell surface molecules.
Phenotypes:
Rh+
Rh-
- produces Rh factor on RBC
- 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
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.
Antigen Presenting Cells
Cells which bind antigens with HLA glycoproteins are called
antigen presenting cells.
Two types of antigen presenting cells are:
Macrophages
Lymphocytes
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.
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)
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
xenotransplants
- animal –human transplant
- transgenic pigs
therapeutic cloning
Xenografts
HLA and disease
There is a relationship between certain HLA antigens and specific
diseases
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.
•=> HLA-B27 is a significant factor but not the sole factor in ankylosing
spondylitis.
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
Autoimmune Diseases
When the immune system attacks the tissues of an
individual’s 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.
Autoimmune
disorder
Target of Antibodies
Symptoms
Glomerulonephritis
Lower back pain
Graves disease
Restlessness, weight loss, irritability, Thyroid gland antigen
increased heart rate and blood
pressure
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
Kidney cell antigen that
resembles Streptococcus
antigen
Colon cells
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.
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 don’t 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
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
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
result - increased susceptibility to infection and certain forms of
cancer - early death
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.
HIV envelope proteins gp41 and gp120 bind to
CD4 and CCR5 receptors on the helper T cell.
Final note on AIDS:
its not that the immune system can’t fight the HIV
infection, it just can’t 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
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.
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.
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
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.
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.