Microbiology- a clinical approach by Anthony
Strelkauskas et al. 2010
Chapter 17: Failures of the immune response
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Chapters 14, 15, 16, 17 (up to HIV)
Multiple Choice, T/F; 25 questions, 50 points
Lecture, Chapter Questions
Please bring Scantron, No. 2 pencil
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Host defense can be either inhibited or lost.
◦ When either happens, we don’t have the protection
needed to survive the fight against microorganisms, be it
primary pathogens or opportunists.
◦ Recurrent infections develop leading to premature death.
The immune system can also turn on the host and
cause damage.
◦ This happens in autoimmune diseases and
hypersensitivities.
(inherited)
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There are several reasons why host defense does
not function properly or is absent:
Immune defenses are normal but pathogen
outsmarts the host
Too little immune response
◦ Acquired immune deficiencies
 HIV
◦ Inherited (genetic, primary) immune deficiencies
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Too much immune response
◦ Against self: autoimmune diseases
◦ Against a harmless antigen (allergen): hypersensitivity
reactions
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Subversion of host defenses by pathogens
allows the spread of the pathogen and develop
disease.
Pathogens use a variety of strategies for
avoiding destruction.
◦ Antigenic variation: Influenza virus, Trypanosoma
◦ Latency: Herpes virus, Varizella-zoster virus
◦ Resistance to host defenses: Mycobacterium
tuberculosis
◦ Suppression of the immune response: Haemophilus
influenzae and Neisseria gonorrhoeae secreting IgA
proteases
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“Pneumocystis pneumonia is almost exclusively
limited to immunosuppression patients …The
occurrence of this disease in these five
previously healthy individuals is unusual…. The
fact that these patients are homosexuals
suggests an association between some aspects
of a homosexual lifestyle or disease acquired
through sexual contact.” ~1981
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By 1992, AIDS was the major cause of death in
individuals 25-44 years of age in the US.
The World Health Organization (WHO)
estimates that 20 million people have died of
AIDS.
More than 40 million are currently infected.
◦ 0.6% of 15 – 49 year olds in the US
◦ 25.9% of 15 – 49 year olds in Swaziland
(http://apps.who.int/ghodata/?vid=360)
Changes in the incidence rate of HIV infection, 2001 to 2009, selected countries
Increasing > 25%
Decreasing > 25%
Stable
No data
http://www.unaids.org/documents/20101123_globalreport_em.pdf;
page 17
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Infection by HIV is rising more rapidly in
Eastern Europe and central Asia.
One-third of persons infected with AIDS are
between the ages of 15 and 24.
HIV-1 is seen throughout the world.
HIV-2 is mostly seen in Africa.
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In 1982-83, a retrovirus was isolated
from the blood of individuals by
groups in Paris, France, and Maryland,
US, lead by Luc Montagnier and
Robert Gallo, respectively.
◦ The virus, subsequently named human
immunodeficiency virus - type I (HIV-1),
was demonstrated to be the cause of
AIDS.
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Retrovirus: RNA virus that reverse
transcribes RNA (copies its genome
into DNA)
Enveloped virus with protein spikes
◦ gp 120
◦ gp 41
2 copies of RNA
Reverse transcriptase
Integrase
Protease
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HIV uses two glycoproteins for attachment –
gp120 and gp41.
They bind receptors on helper (CD 4) T cells,
dendritic cells, and macrophages.
For infection to be successful, co-receptors
are required.
◦ Chemokine receptors
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Mutations in these two receptors, among
others, block infection.
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Transmission is primarily through sexual
contact and infected blood.
The efficiency of transfer is based on the
concentration of viral particles.
The highest viral loads are found in peripheral
blood monocytes, blood plasma, and
cerebrospinal fluid.
Semen and genital secretions are also sources
of infection.
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In the US,
transmission is
highest among
homosexuals.
World wide,
transmission is
highest among
heterosexuals.
Sexual activity is still
the leading method
of transmission.
Intravenous drug
abuse is the 2nd most
common form of
transmission.
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The virus can be transmitted across the
placental barrier and via breast milk.
HIV can enter into the lamina propria:
◦ Through direct access via needle stick injury or blood
transfusion.
◦ When the mucosal epithelial cell layer is broken.
The extrusion of the virus from infected cells
can be observed in tissue cultures.
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© Dominika Rudnicka;
Nathalie Sol-Foulon; Olivier Schwartz/ Institut Pasteur
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Cells of the mucosal immune system are prime
targets for initial infection.
◦ Dendritic cells (DC) bind to the HIV-1 envelope
proteins with high affinity.
◦ DC migrate then to the lymph nodes and hold the
virus until susceptible T cells come along and are
infected.
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Reverse transcription of HIV results in the copying
of viral RNA to DNA.
◦ Reverse transcriptase has no proofreading ability.
 Many mutations occur.
 This accounts for the virus’s ability to escape drug therapy and
rapidly develop resistance.
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Retroviruses can use viral enzyme integrase to
integrate viral DNA into the host cell’s
chromosome.
T cell activation induces transcription of provirus
Viral RNA is transcribed, proteins synthesized and
assembled at the cytoplasmic membrane.
Virus exits via budding.
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HIV infection has three phases:
◦ Acute phase
 non specific, lymphadenopathy and flu like symptoms,
high viremia
◦ Asymptomatic phase
 gradual decline in CD4+ TH cells
 Viremia is predictor of how fast the disease progresses
 Virus population becomes more heterogenous
◦ Symptomatic phase
 CD4 + TH cell counts drop below 200/mL blood
 AIDS develops, opportunistic infections, cancer
 Viral replication increases
Cancer
Kaposi sarcoma
Precancerous: hariy leukplakia
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Approximately 10% of HIV infections progress
to AIDS in the first three years.
More than 80% show signs of clinical disease
within 10 years.
The remaining 20% are free of disease for long
periods – more than 20 years in some cases.
A small percentage never move past the
asymptomatic phase.
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HIV replicates best in activated T cells.
◦ The greater number of opportunistic infections, the
greater the number of T cells activated.
◦ The more T cells activated, the larger the quantity of
virus particles produced.
◦ The more virus particles, the more infected cells and
so on.
Currently, viral load is determined by PCR
(polymerase chain reaction, molecular genetic
techniques).
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The rate of HIV replication is astonishingly
high.
1010 virions can be released in a single cycle of
infection per infected cell per day.
The estimated genetic diversity of HIV
produced in a single infected person is greater
than all the diversity seen in a worldwide
epidemic of influenza.
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Antibody response usually occurs during the first few
months of infection.
◦ It can be as quick as a few days after infection.
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Antibodies are produced in response to the infection
but are unable to clear it.
IgG is the dominant form of antibody in any HIV
infection and is involved in:
◦ Neutralizing the virus
◦ Blocking viral receptors
◦ Promoting complement-mediated reactions.
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Antibody response is important in HIV diagnostic.
◦ ELISA and Western immunoblotting
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All infected individuals have a cellular adaptive
response to AIDS.
◦ Cytotoxic T cells are programmed to recognize all
HIV-1 proteins.
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The response does not control and defeat the
infection and the reason for this is not known.
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Antibody detection
◦ Serum samples (ELISA for
screening, Western immunblot
for confirmation)
◦ Most recent development:
OraQuick test detects the
presence of HIV in saliva
collected using a mouth swab.
The test is designed to return
a result within 20 to 40
minutes
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Virus detection by PCR
Culture of the virus
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Lymphoid organs
◦ Lymphadenopathy  destruction of lymphoid tissue
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Nervous system
◦ Sub-acute encephalitis and dementia
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Gastrointestinal tract
◦ Diarrhea and food malabsorption
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Other tissues
◦ Heart, lungs, kidneys, and joints can be affected
A.
B.
C.
D.
E.
Reverse transcription of
HIV by integrase results in
the copying of viral RNA to
DNA.
Viral DNA is then
incorporated into the host
cell’s chromosomal DNA.
Viral RNA is transcribed,
proteins synthesized and
assembled at the
cytoplasmic membrane.
Virus exits via budding.
All steps are correct.
A.
B.
C.
D.
E.
2000 cells/mL
20 cells/mL
20000 cells/mL
200 cells/mL
None of the above.
A.
B.
C.
D.
E.
CD4 molecule
Chemokine coreceptor
MHC II molecule
gp41
None of the above.
Too little immune response
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In primary immunodeficiency disease, the
immune system does not function properly.
Parts of the immune response are defective
because of mutations.
Primary immunodeficiency diseases present as
recurrent overwhelming infections in young
children.
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The type of recurrent infection indicates the
type of primary immunodeficiency.
Recurrent infections by pyogenic bacteria
indicate:
◦ Defects in antibody production
◦ Defects in the complement system
◦ Defects in phagocytosis
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Recurrent fungal or viral infections suggest
that the defect is in reactions mediated by T
cells.
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B cells make antibodies.
B cell defects result in lack of antibodies and
severe and repeated infection with encapsulated
bacteria.
◦ Without capsule-binding, the antibody opsonization
defense is lost
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Example: X-linked agammaglobulinemia
◦ X-chromosome linked mutation
◦ B cell development arrested
◦ Only males are affected: no circulating B cells, no
antibodies
◦ Can be treated with immunoglobulin injections
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T cells, in particular TH cells, are the generals
of our immune defense.
◦ Stimulate macrophages
◦ Act on B cells to make antibodies other than IgM in
particular IgG, an opsonin
◦ Control virus infections and tumors
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Defects in T cell function can result in severe
combined immunodeficiency syndrome (SCID).
◦ X linked forms
◦ Autosomal forms
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Defects in the complement system can lead to an
increase in the occurrence of infectious diseases.
◦ Pyogenic infections with defects at C3 or factors above C3
◦ Neisseria infections with defects of C5 – C9
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Defects in phagocytic cells can cause severe
immunodeficiency.
◦ Total absence of neutrophils is lethal.
◦ Defects in oxidative burst: chronic granulomatous disease
◦ Defects in ability to exit from blood stream: leukocyte
adhesion deficiency
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Dysfunctional
neutrophils
Infection with S. aureus
◦ Cannot produce oxidative
burst
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Monocytes and
macrophages are
recruited and activated
by T cells
◦ Granuloma like structures
are formed
◦ Recurrent an severe
infections with
opportunistic pathogens
and also primary pathogens
http://www.springerimages.com/Images/MedicineA
ndPublicHealth/2-AID1101-08-032
Too much immune response
against self
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Normally, tolerance prevents the development
of autoimmune diseases.
◦ Developing lymphocytes are tested for self
reactivity and those lymphocytes that are self
reactive are removed by apoptosis or permanently
inactivated.
◦ Lymphocytes are primarily activated by sudden
increases in antigen concentrations.
◦ Lymphocytes require co-stimulatory signals to
become fully activated, the right antigen is not
enough
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Autoimmune diseases are the consequence of
a failure of tolerance.
The immune system reacts against self
components.
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It is impossible to rid the host of the self
antigen.
Once self reaction has been initiated it is
perpetuated.
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The autoimmune response destroys host tissues.
Tissue destruction frees up more self antigens.
This causes production of more autoantibody.
Which destroys more tissue.
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Some people are genetically predisposed to
autoimmune disease.
◦ Defect in the lymphocyte screening program
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Drugs and toxins can cause autoimmunity.
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Infection can result in an autoimmune
reaction.
◦ They can react with self antigens to form
derivatives perceived as foreign or nonself.
◦ Inflammation leads to tissue destruction and
provides co-stimulatory signals.
◦ Previously protected sites (brain, eyes, testis,
ovaries) become exposed to lymphocytes and selfreactive lymphocytes can become activated.
◦ Cross reactive antibodies can be generated
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Autoimmune diseases vary in:
◦ Severity
◦ Effector mechanisms
 Autoantibodies
 Self reactive cytotoxic T cells
◦ The tissue affected
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Autoimmune diseases are divided into two
types:
◦ Organ-specific – reaction against self is confined to
certain organs
 Type 1 insulin-dependent diabetes
◦ Systemic autoimmunity – affects multiple organs
 Systemic lupus erythematosus
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Insulin Dependent
Diabetes Mellitus
(IDDM)
Early, sudden onset
(adolescence)
Initially mediated
by autoantibodies
against b-cell
antigen
Later phases include
cytotoxic T-cell
response
Immunohistochemistry
Insulin = brown
Glucagon = black
Normal
IDDM
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Auto-antibodies against nuclear
components (DNA, histones, etc)
Immune complexes activate
complement
Complexes transported via on
phagocytes or on erythrocytes to
spleen/liver for sequestration
Excess complexes are deposited
in small blood vessels
Local inflammation in skin, joints
and kidneys, multi-organ damage
May lead to activation of self
reactive T lymphocytes
Too much immune response
against harmless antigen
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An allergic reaction is a form of immune
response.
◦ “Too much against a harmless antigen”
◦ It is not usually life-threatening.
◦ It can produce serious tissue injury, even death.
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Allergic responses are the result of a person
becoming hypersensitized.
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There are four main types of hypersensitivity
reaction:
◦ Type I hypersensitivity (allergic rhinitis,
conjunctivitis, asthma)
◦ Type II hypersensitivity (drug allergies,
thrombocytopenic purpura)
◦ Type III hypersensitivity (serum sickness)
◦ Type IV hypersensitivity (tuberculin test -TH cell
mediated; poison ivy contact dermatitis- CTL
mediated)
Antibody
Cell
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Type I (“Allergy”)
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Type II (drug allergies, thrombocytopenic
purpura)
 Soluble antigen: IgE: Mastcells
 Immediate-type
 Atopy: Exaggerated tendency to mount an IgE response
 Cell associated antigen: IgG: phagocytes, NK cells
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Type III (serum sickness)
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Type IV (tuberculin test, poison ivy contact
dermatitis)
 Soluble antigen  Antigen-Antibody complexes
 T-cell mediated
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Occurs when the immunoglobulin IgE responds
to antigens called allergens.
◦ Most human allergies are caused by inhaling small,
water-soluble proteins carried on pollen grains or
dust-mite feces.
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Occurs when the immunoglobulin IgE responds to
antigens called allergens.
◦ Most human allergies are caused by inhaling small, watersoluble proteins carried on pollen grains or dust-mite
feces.
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Allergens trigger activation of IgE-binding cells.
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Upon allergen binding these cells degranulate and
release huge amounts of bioactive molecules
◦ Mast cells
◦ Basophils
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Histamine
Enzymes
Leukotrienes
IL4
Chemokines
Clinical effects vary according to the site of mast cell
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Eosinophils have two functions in allergic
reactions:
◦ Release highly toxic granules and free radicals.
 They normally kill microorganisms.
 They cause significant tissue damage in allergic
reactions.
◦ Produce chemical mediators, prostaglandins,
leukotrienes, and cytokines.
 This enhances and amplifies the allergic reaction.
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Immediate reaction
◦ Histamine mediated
◦ Smooth muscle contraction
◦ Vascular endothelial cell leakage
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Late phase reaction (8 – 12 h)
◦ Chemokine, cytokine,
leukotriene, and enzyme
mediated
◦ Sustained edema
◦ Cell influx
◦ Tissue remodeling
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Exaggerated tendency to mount an IgE
response to environmental allergens
Individuals affected are called atopic.
◦ They have higher levels of eosinophils.
◦ They are more susceptible to allergic diseases.
◦ Susceptibility may be genetic.
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Allergen can be deposited directly into the blood or
rapidly absorbed causing systemic anaphylaxis.
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Widespread increase in vascular permeability
Catastrophic loss of blood pressure
Airway constriction
Swelling of the epiglottis
The reaction is known as anaphylactic shock and is
potentially fatal.
◦ It requires immediate injection of epinephrine.
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Both environmental and inherited
factors are important
Environment:
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Susceptibility genes for asthma
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◦ Exposure to infectious agents in early
childhood drives a TH1 response
◦ Too hygienic environment with too
little infectious agents drive a TH2
response
◦ Diet
◦ IL4, IL4 receptor
◦ High affinity IgE receptor
◦ MHC II
Allergies!!
Less allergies!!
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Drug associated
Drug (e.g., penicillin)
binds to platelets
Big enough to be seen by
immune system
Antibodies made and
bind to drug-platelet
complex
Macrophages take up
complex or complement
becomes activated and
attacks membrane of
platelets
Platelet numbers
decrease
Spontaneous bleeding
occurs
Cell infiltrate!!
Lipid soluble allergen
is absorbed through
skin and crosses cell
membranes
 Allergen modifies self
peptides
 Presentation of
modified self peptide
via MHC I to CTL
 Destruction of
modified cell
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The immune system can break down and in some cases
fail. It can also turn against the host.
There are three ways the adaptive immune response
can fail: viral infection (HIV) leading to AIDS,
subversion of the immune response by pathogens, and
genetic immunodeficiency.
Autoimmune disease occurs when the adaptive
immune response attacks the host.
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HIV is a latent virus that carries the enzyme reverse
transcriptase. This enzyme allows the viral RNA to be
converted to DNA, which can integrate into a host
cell chromosome.
There are three strategies that are used to subvert
or defeat the host defense: antigenic variation,
resistance to host defense, and suppression of the
immune response.
Resistance to host defense can involve several
mechanisms, including the inhibition of phagocytosis.
Primary immunodeficiency involves genetic
abnormalities.
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Tolerance to self antigens prevents the development
of autoimmune disease.
Specialized regulatory T cells (T reg cells) control
the development of an autoimmune response.
Autoimmunity can be organ-specific or systemic.
An allergic response is a type of immune response
against antigens that are referred to as allergens.
There are four types of hypersensitivity response.