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Natural killer cells or NK cells are a type of cytotoxic lymphocyte critical to the innate immune
system. The role NK cells play is analogous to that of cytotoxic T cells in the vertebrate adaptive
immune response. NK cells provide rapid responses to viral-infected cells and respond to tumor
formation, acting at around 3 days after infection. Typically, immune cells detect major
histocompatibility complex (MHC) presented on infected cell surfaces, triggering cytokine
release, causing lysis or apoptosis. NK cells are unique, however, as they have the ability to
recognize stressed cells in the absence of antibodies and MHC, allowing for a much faster
immune reaction. They were named “natural killers” because of the initial notion that they do
not require activation to kill cells that are missing “self” markers of MHC class 1.[1] This role is
especially important because harmful cells that are missing MHC 1 markers cannot be detected
and destroyed by other immune cells, such as T lymphocyte cells. In addition to the knowledge
that natural killer cells are effectors of innate immunity, recent research has uncovered
information on both activating and inhibitory NK cell receptors which play important function
roles including self tolerance and sustaining NK cell activity. NK cells also play a role in adaptive
immune response,[4] numerous experiments have worked to demonstrate their ability to
readily adjust to the immediate environment and formulate antigen-specific immunological
memory, fundamental for responding to secondary infections with the same antigen. The role of
NK cells in both the innate and adaptive immune responses is becoming increasingly important
in research using NK cell activity and potential cancer therapies. However, recently increasing
evidence suggests that NK cells can display several features that are usually attributed to
adaptive immune cells (e.g. T cell responses) such as expansion and contraction of subsets,
increased longevity and a form of immunological memory, characterized by a more potent
response upon secondary challenge with the same antigen.
The term B cell comes from the Bursa of Fabricius
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IMMUNE DISORDERS
CHAPTER 18
Copyright © 2012 John Wiley &
Sons, Inc. All rights reserved.
Memory immune cells that screen intruders as they enter lymph nodes The newly identified
'Follicular Memory T cells' are related to the T helper cells but unlike circulating memory B and
T cells, they position themselves near the entrance of lymph nodes, particularly those that are
potential sites of microbe re-entry. Lymph nodes are purpose-built structures for trapping
microbes and manufacturing the antibodies needed to neutralise them. They contain clearly
demarcated zones, populated by different kinds of immune cells, carrying out specialised tasks.
When a microbe arrives at the lymph node, it is trapped by sentinel immune cells, called
subcapsular sinus macrophages, which have evolved to act as 'the flypaper of the lymph node'.
This sets off a chain reaction that results in the formation of a 'germinal centre', from which
antibody-producing cells are made. A subset of T helper cells, known as Follicular T helper (Tfh)
cells, are critical for the antibody response because they help B cells navigate through these
quality control filters. This process, from the arrival of a microbe to the creation of potent
antibodies, is known as the 'primary antibody response' and is already well studied and
described. "What we saw in the secondary response really surprised us," said Dr Tri Phan. "The
memory cells weren't coming from the blood, as expected. They were already in the lymph
node, and only in the lymph node closest to the original site of infection. "When the memory
cell sees its target on the macrophage, it becomes activated and the cell divides to start making
a new army of Tfh cells. This second generation of Tfh cells is then sent out via the lymphatic
system to other parts of the body to fight the infection.
How a deadly fungus evades the immune system Previously, scientists
thought that Candida albicans spread by changing from a single, round cell to
a long string of cells, or filaments. They thought this shape change allowed
the fungus to move through the bloodstream and let its filaments penetrate
tissues and destroy immune cells. "It's not the shape-change per se that
enables the fungus to kill the immune cell, but what happens along with
it,"Cowen and her lab found that Candida albicans can kill immune cells even
after its cells have died. They let immune cells called macrophages consume
the fungus, and after an hour they removed the fungal cells from the
macrophages. Then they exposed new macrophages to fungal cells that had
been consumed and those that had not, and they compared the results. "The
fungal cells that were never internalized by macrophages couldn't kill the
fresh macrophages, but those that had been inside a macrophage could kill
beautifully," The researchers then used an enzyme called Endo H to snip off
sugars on the glycosylated proteins attached to the dead fungal cells. The
change completely blocked the ability of the fungus to kill -- a strong lead on a
new and needed therapeutic strategy for Candida albicans.
Immunological disorders
• Hypersensitivity-refers to undesirable reactions produced
by the normal immune system, including allergies and
autoimmunity. These reactions may be damaging,
uncomfortable, or occasionally fatal. Hypersensitivity
reactions require a pre-sensitized (immune) state of the
host.
• Immunodeficiency-is a state in which the immune system's
ability to fight infectious disease is compromised or
entirely absent-
Copyright © 2012 John Wiley &
Sons, Inc. All rights reserved.
Overview of Immunological Disorders:
In hypersensitivity, or Allergy, the immune system reacts in an
exaggerated or inappropriate way to a foreign substance. There are four types of
hypersensitivity:
1) immediate hypersensitivity (Type I), or anaphylaxis, results from
a prior exposure to a foreign substance called allergen an antigen that evokes a
hypersensitivity response (e.g., food, pollen, insect stings),
2) cytotoxic hypersensitivity (Type II), is elicited by antigens on
cells, especially red blood cells, that the immune system recognizes as foreign.
3) immune complex hypersensitivity (Type III) is elicited by
antigens in vaccines, on microoganisms or on a persons own cells. Large Ag-Ab
complexes form, precipitate on blood vessel walls, and cause tissue injury within hours.
4) delayed hypersensitivity (Type IV). Is triggered by exposure to
foreign substances from the environment (such as poison ivy), infectious disease agents,
transplanted tissues, and the body’s own tissues and cells. Delayed hypersensitivity T
cells react with the foreign cells or substances, cause in some cases extensive damage.
The type that develops depends on which components of the immune
response are involved and on how quickly the reaction develops.
http://www.youtube.com/watch?v=Cv_zt9eOB-A&feature=related
Immunodeficiency- the immune system responds
inadequately to an antigen, either because of inborn or
acquired defects in B cells or T cells. The weak
response can leave an individual susceptible to
infections, which can be severe.
Primary immuno-deficiencies are genetic or
developmental defects in which the individual lacks T
cells or B cells or has defective ones
Secondary immuno-deficiencies result from
damage to T cells or B cells after they have developed
normally. These disorders can be cause by
malignancies, malnutrition infections such as AIDS, or
drugs that suppress the immune system.
Anaphylaxis
Reagin
Localized vs
Generalized
Allergens
Mechanism of
activation
The allergen triggers the production of IgE rather than IgG
Fig. 18.1 The mechanism of immediate (Type I) hypersensitivity or anaphylactic hypersensitivity
The mechanism of immediate (Type I) hypersensitivity, or anaphylactic
hypersensitivity (See Fig. 18.1).
a) allergen binds to dentrictic cell on mucosa. Allergen fragment
presentation activates TH 2 cells, which activate B cells, Dendritic cells
(another cell(DCs) are immune cells and form part of the mammalian
immune system. Their main function is to process antigen material and
present it on the surface to other cells of the immune system, thus
functioning as antigen presenting cells. They are located mainly on skin
and the inner lining of the nose, lungs stomach and intestines.
b) B cells develop into the plasma cells that secrete IgE antibody,
c) IgE binds by its Fc tail to basophils and mast cells. In a second
or later exposure,
d) allergen binds to sensitized mast cells and basophils, crosslinking IgE molecules,
e) this cross-linking stimulates degranulation of histamine and
other mediators that cause the symptoms of allergies.
Localized anaphylaxis- the
hypersensitive response is
dependent on where the allergen
enters the body.
If allergen is on skin,
wheal (redness, swelling, itching),
If allergen on mucous
membrane of respiratory tract,
inflammation, runny nose and
watery eyes,
If allergen is ingested
mucous membrane of digestive
tract becomes inflamed possible
abdominal pain and diarrhea.
Some ingested allergens, such as
food and drugs, also cause skin
rashes
March 20, 2007
In Testing for Allergies, a Single Shot May Suffice
By LAURIE TARKAN
At the age of 5, Sarah Marcus had her first skin test for allergies. She had 18 needle pricks and screamed from the first to the last. At
8, when she needed to be retested, she was terrified.
“It was horrible to see your child so panicked,” said her mother, Ann Marcus, of Watchung, N.J.
Because Sarah had severe symptoms that did not respond to allergy medicines like antihistamines and decongestants, she began
immunotherapy — regular shots to immunize her body against a host of allergens, among them cats, dust mites and birch pollen. But
that was an ordeal, too.
During a third round of testing in high school, Sarah had a severe reaction and passed out. When a fourth series was needed to
wean her off the shots before college, she refused the needle pricks. At an impasse with the doctor, her mother mentioned that a
friend had gotten a blood test for allergies. Her doctor agreed to give it a try.
“It was one needle prick and then it was all over,” Mrs. Marcus said.
Some people describe the traditional rounds of test pricks as archaic or inhumane; others are unfazed by them. But few patients
are aware that an alternative technique is available: testing the blood for immunoglobulin E, or IgE
against the specific allergen.
Allergists have typically turned to blood testing as a last resort when skin testing cannot be used. Few in the United States use blood
testing routinely, experts say, though it is being used more often to help diagnose food allergies. Yet studies have found that newer
blood tests are as sensitive as skin tests and less subjective.
The blood test is also part of a larger debate about who should be treating allergy sufferers. Blood testing would allow pediatricians
and other primary care doctors to diagnose allergies and treat many patients. But allergists contend that these generalists are not
qualified to assess the laboratory results.
Skin testing produces an answer in about 20 minutes, compared with 48 hours for a blood test. The quick turnaround allows doctors
to offer a diagnosis and immediate advice.
Some experts contend that allergists resist blood testing in part to protect their revenue. “A barrier to
allergy testing in the states has been the economics in our system,” said Dr. Richard G. Roberts,
professor of family medicine at the University of Wisconsin School of Medicine and Public Health. If an
allergist does an in-office skin-prick test, he gets the fees for those tests. If he requests a blood test, the
laboratory gets the fee.
But others say allergists are simply more familiar with skin testing. “They have been trained to do skin testing, they’re comfortable
with it, and they get an answer in 20 minutes,” said Dr. Portnoy.
This table is important- need to know
The drug Singulair- is a leukotriene inhibitor
Generalized anaphylaxis (anaphylactic shock)Respiratory anaphylaxis- the airways become
severely constricted and filled with mucous secretions, and the
allergic individual may die of suffocation- asthma is an example
of respiratory anaphylaxis (histamine, leukotrienes,
prostaglandins).
Anaphylactic shock- blood vessels suddenly
dilate and become more permeable, causing an abrupt and
life-threatening drop in blood pressure- insect bites and stings
are a common source of this type of anaphylactic shock (also
sometimes when desensitizing an individual against an allergen
anaphylactic shock can happen).
Genetic factors in allergy- High levels of IgE in families
appears to predispose individuals to allergies and thereby
has a genetic basis.
Desensitization (hyposensitization) is the only currently
available treatment intended to cure an allergy.
a) normal allergic response
b) denatured allergen is injected under skin- promotes tolerance preventing B cells from maturing into
plasma cells to make IgE antibodies. Exposure to denatured allergen also may activate those B cells that
mature into the plasma cells that make IgG blocking antibody.
c) how the blocking IgG antibody functions
Fig. 18.5 A proposed mechanism of action for desensitization allergy shots (hyposensitization).
Cytotoxic (Type II) Hypersensitivity- In cytotoxic (Type II)
hypersensitivity, specific antibodies react with cell surface
antigens interpreted as foreign by the immune system, leading to
phagocytosis, killer cell activity, or complement-mediated lysis.
The associated anti-A antibodies and anti-B antibodies are usually IgM antibodies, which are
usually produced in the first years of life by sensitization to environmental substances such as
food, bacteria and viruses.
IgM
In the cytotoxic
hypersensitivity the
Antibody is IgM
-Mechanism of cytotoxic (Type II) hypersensitivity.
Mismatched red blood cell antigen usually
is bound to IgM. Complement is activated and results in either subsequent phagocytosis or lysis
or the red blood cells.
Fig. 18.6 The mechanisms of cytotoxic (Type II) hypersensitivity
GALNac
GalNac
Galactose
Gal
GALNac
Gal
Enzyme Discovery Could Greatly Expand Blood Supply
(HealthDay News) -- Scientists say they've found a way to change type A and B donated blood -- which can only be used by
people with those types -- into universally usable type O.
Most people are born with one of four blood types: A, B, A/B or O. At the cellular level, types A and B red blood cells are
characterized by distinct sugar molecules lying on their surfaces, while A/B carries both the A and B surface molecules.
These molecules are "antigens" that can trigger lethal immunological reactions -- for example, if a type B person is
transfused with type A blood.
Luckily, about one-quarter of the population also carries a form of blood without these surface antigens that's called type
O. This means their donated blood can be safely used by any recipient. Type O blood is especially useful in emergency
situations, when doctors don't have time to determine a patient's blood group.
"For this reason, hospitals use a lot more group O blood than they do type A or B," Benjamin said. "When you hear about
'blood shortages' in the press, we are really talking about the fact that we don't have enough type O."
One way to end these shortages would be to find a biochemical means of stripping away the A and B surface antigens from
red blood cells, turning them into O. Molecules called enzymes can do this, but it has been tough to find enzymes that
target only the A and B antigens and leave the rest of the cell alone.
But the new research -- as yet tested only in a lab -- has achieved an efficiency that is many times "better than that prior
work," Benjamin said.
The new effort was led by Dr. Henrik Clausen of Harvard Medical School and the University of Copenhagen. His team
combed through an exhaustive database of bacteria and fungi looking for enzymes highly specific to the A and B surface
antigens. They
found two families of bacterial enzymes called glycosidases that target and
remove the sugar molecules.
"This is big," said Dr. Louis M. Katz, executive vice president of medical affairs at America's
Blood Centers, which oversees 77 regional blood centers serving more than 180 million
people nationwide. "It clearly needs to be pushed forward toward clinical trials."
But Katz cautioned that crucial questions remain. "Do these enzymes change anything else on the red blood cell? We
might now develop immune reactions to enzyme-treated red cells, for example," he said. Miniscule "residual" levels of the
enzyme itself, left behind in the blood, might also cause immune problems, he said.
Finally, Katz said, how much would enzyme-based processing of A and B blood cost? In the research paper, the study
authors said processing could be "efficient and cost-effective." Benjamin said the American Red Cross has been talking
closely with ZymeQuest, and "I do know that they are trying to develop machines that could process multiple units at a
time and get it down to an economic proposition."
But Katz, who also directs the Mississippi Valley Regional Blood Center in Davenport, Iowa, was somewhat more skeptical.
"The real question is whether the resources needed to scale up to this kind of thing would be better put toward better
(blood) donor recruitment," he said. "Right now, five percent of the population donates per year. If we made that seven
percent, the issue of availability
Fig. 18 Cause and effect of hemolytic disease of the newborn erythroblastosis
The antibodies produced by RBC’s (A, B)
are IgM. In contrast the antibodies produced
in erythroblastosis fetalis are IgG.
What does all the above mean regarding the
survival of the fetus due to A, B and O
mixing?
Type III Hypersensitivity (Immune
Complex)
• Mechanisms
• Examples of
Reactions
Copyright © 2012 John Wiley &
Sons, Inc. All rights reserved.
Fig. 18.9 The mechanism of immune complex (Type III) hypersensitivity
Major blood group determinants (A,B and O) are determined by
a single sugar either galactose or N-acetylgalactosamine
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Growth of global antibiotic use for livestock raises concerns about drug resistance A new study
predicts the next 15 years will see a startling increase in worldwide use of antibiotics in livestock, raising
serious concerns about the effect this will have on a growing global health problem - drug-resistant
pathogens or superbugs. Antibiotics are used widely in the farming of food animals to treat disease and
increase productivity. In the US, antibiotic consumption in animals accounts for up to 80% of antibiotic
sales. While studies suggest such practice fuels the spread of drug-resistant pathogens in animals and
humans, the lack of reliable global data makes it hard to both measure the size of the problem and come up
with solutions. n the Proceedings of the National Academy of Sciences, they present their findings in the
form of a global map of antibiotic use in livestock, covering a total of 228 countries. Senior study author Dr.
Ramanan Laxminarayan, a senior research scholar at the Princeton Environmental Institute at Princeton
University, NJ, says:"The invention of antibiotics was a major public health revolution of the 20th century.
Their effectiveness - and the lives of millions of people around the world - are now in danger due to the
increasing global problem of antibiotic resistance, which is being driven by antibiotic consumption."The
researchers estimate "conservatively" that the total global consumption of antibiotics by livestock in
2010 was 63,151 tons, and that by 2030, this figure will be 67% larger overall.
They suggest most of the growth (66%) will be due to increases in the number of animals raised for food driven mostly by rising demand in middle-income countries, and partly (34%) due to a shift toward largescale, intensive or "factory" farming where antibiotics are used routinely.
In Brazil, China, India, Russia and South Africa the increase will be dramatic, mostly because of these two
factors. These five countries will see a 99% increase in antibiotic consumption but only a 13% growth in
their human populations over the same period. "Antibiotic resistance is a dangerous and growing global
public health threat that isn't showing any signs of slowing down. Our findings advance our understanding
of the consequences of the rampant growth of livestock antibiotic use and its effects on human health - a
crucial step towards addressing the problem of resistance."
New way to block dengue transmission using bacteria modeled on computer Researchers
working on a way to block dengue transmission using the insect bacterium Wolbachia to infect
mosquitoes, have also produced a computer model that predicts how effective the method
might be in different scenarios. As many as 400 million people are infected with dengue every
year. The virus - which spreads among humans via Aedes aegypti mosquitoes - causes flu-like
symptoms, including intense headache and joint pains. Wolbachia bacteria reside naturally in
around 60% of insect species and are probably the most prevalent infectious bacteria on Earth.
They live inside the cells of insects - and are passed to the next generation through the host's
eggs. For many years, scientists have been studying Wolbachia, to see if they can use it to
control the mosquitoes that spread human diseases.
So far, this research has found A. aegypti mosquitoes stably infected with strains of Wolbachia
are resistant to dengue virus infection and field trials are currently being done to find out how
effective this is. In this new study, the researchers carried out a "real world" experiment where
they allowed mosquitoes infected with Wolbachia and uninfected mosquitoes to feed on the
blood of Vietnamese dengue patients. hey measured how efficiently the bacterium blocked
dengue virus infection of the mosquito body and saliva, which in turn steps stops them
spreading the virus among humans. The team then developed a computer-based model of
dengue virus transmission and primed it with the results of the experiment to predict how
well the use of Wolbachia might reduce the intensity of dengue transmission in various
scenarios. "We found that Wolbachia could eliminate dengue transmission in locations where
the intensity of transmission is low or moderate. In high transmission settings, Wolbachia would
also cause a significant reduction in transmission.""Our results will enable policy makers in
dengue-affected countries to make informed decisions on Wolbachia when allocating scarce
resources to dengue control."
Immune Complex (Type III) Hypersensitivity- results from the
formation of Ag-Ab complexes. Hypersensitivity occurs when
Ag-Ab complexes persist or are continuously formed.
Mechanism of immune complex disorders
Figure 18-9 the mechanism of immune
complex (Type III) hypersensitivity. Immune complexes are
formed when antigen is introduced into a previously sensitized
individual. When the resulting immune complex is deposited, it
activates complement, producing fever, itching, rash or
hemorrhagic areas, joint pain, and acute inflammation. On a
systemic basis (a protein injected into the blood), this can cause
serum sickness.
Examples of immune complex disorders: serum sickness,
Arthus reaction, rheumatoid arthritis, and systemic lupus
erythematosus, are all examples of immune complex
disorders. Immune complex diseases are also considered
as autoimmune diseases.
Serum sickness- antitoxin sera used to immunize
people passively. For example, diphtheria antitoxin made in
horses and then given to patients. The patient would make
Ab against the horse serum which would form immune
complex (horse serum-Ab). The immune complexes, would
attach to the glomeruli of kidneys. The filtration capacity of
the glomeruli will be impaired causing proteins and blood
cells to be excreted in the urine. Immune complexes are also
deposited in joints and in skin blood vessels.
Cell mediated or delayed type hypersensitivity- typically take 12 or more hours to develop.
These reactions are mediated by TH1 cells (sometimes called a delayed hypersensitivity T [TDH]
cell)-- not by antibodies. On first exposure antigen molecules bind to antigen-presenting cells
that presents antigen fragments to TH1 (inflammatory T) cells. When APCs again present the
same antigen during a second, later exposure, the sensitized TH1 cells release various cytokines,
including (-interferon and migration inhibiting factor (MIF). (-interferon stimulates macrophages
to ingest the antigens).
Fig. 18.12 The mechanism of cell-mediated, or delayed (Type IV), hypersensitivity.
Examples of cell-mediated disorders
Contact dermatitis- occurs in sensitized individuals on second or
subsequent exposure to allergens such as oils from poison ivy, rubber, certain
metals, dyes soaps, cosmetics, some plastics, topical medications, and other
substances.
Tuberculin hypersensitivity tuberculin activates TH1 cells, which in
turn release cytokines that cause large numbers of lymphocytes, monocytes,
and macrophages to infiltrate the dermis. In a tuberculin skin test, purified
protein derivative (PPD) from Mycobacterium tuberculosis is injected
subcutaneously. A positive test is the formation of an induration within 48
hours. The diameter and elevation of the induration, indicate whether further
Tests are needed.
Granulomatous hypersensitivity - the most serious of the cellmediated hypersensitivities and usually occurs when macrophages have
engulfed pathogens but have failed to kill them. TH1 cells sensitized to an
antigen of the pathogen elicit the hypersensitivity reaction, attracting several
cell types to the skin or lung. A granuloma in the skin (leproma) or lung
(tubercle) develops.
Autoimmune Disorders- occur when individuals become
hypersensitive to specific antigens on cells or tissues of their own
bodies despite mechanisms that ordinarily create tolerance to those
self antigens. The antigens elicit an immune response in which
auto-antibodies, antibodies against ones own tissues, are produced.
An autoimmune response can be T-cell-mediated as well as
against antibodies. These disorders are characterized by
cell destruction in various types of hypersensitivity
reactions.
Crohns disease
Arrows point to the more common autoimmune diseases . Multiple sclerosis is not included in
the above table but is certainly considered as an autoimmune disease (encephalomyelitis) as
is Celiac disease.
Example of autoimmune
disordersMyasthenia gravis- This
disorder involves a loss of
acetylcholine receptors from the
neuromuscular junction.
IgG antibodies are produced against the acetylcholine receptors markedly reducing their
numbers.
Fig. 18.15 Myasthenia gravis- example of an autoimmune disease
Rheumatoid arthritis- Joint inflammation is
typical in people suffering from rheumatoid arthritis.
a) Gamma-ray photograph, swollen joints
appear as bright spots
b) mechanism
Inflammation in the
joints
Fig. 18.16 Rheumatoid arthritis-immune complex autoimmune disease
Systemic lupus erythromatosus (SLE) In SLE autoantibodies (IgG, IgM, IgA) are
made primarily against component of DNA but can also be made against blood
cells, neurons, and other tissues. As the normal dying process of cells (skin, intestinal,
kidney) occurs, anti-DNA antibodies attack the remnants of these cells. Immune
complexes are deposited between the dermis and epidermis and in blood vessels,
joints, glomeruli of the kidneys, and the central nervous system. They cause
inflammation and interfere with normal functions at these sites.
Inflammation of blood vessels, heart valves and joints
are common effects
SLE most often harms the heart, joints, skin, lungs, blood vessels, liver, kidneys and
nervous sytem. The course of the disease is unpredictable, with periods of illness
(called flares) alternating with remissions. The disease occurs nine times more often in
women than in men, especially between the ages of 15 and 50, and is more common in
those of non-European descent.
Lupus facial rash in a typical wolf-like
distribution.
Transplantation- is the transfer of tissue, called graft tissue, from
one site to another.
Autograft- one part of the body to another
Isograft- A graft between two
genetically identical individuals (identical twins)
allograft- a graft between two people
who are not genetically identical
xenograft- a transplant between
individuals of different animal species
Transplant rejection- is due to the destruction of the grafted
tissue by the recipient’s immune system. This process, which depends
on T cells, also accounts for rejection of most organ transplants in
humans. Transplants recognized as nonself are rejected.
Graft versus host disease involves a situation in which transplantation
introduces tissues containing immunocompetent cells that launch a
cell-mediated response against the recipients tissues.
Histocompatability antigens- All human cells have a
set of self antigens called histocompatibility antigens.
The genes producing these molecules are called the
major histocompatibility complex (MHC). Only
identical twins have exactly the same MHC molecules.
The MHC molecules on human cells are called human
leukocyte antigens (HLA’s). It is a subset of the HLA
antigens that is use for tissue typing (leukocytes are
used as the cell source).
Diseases in green are autoimmune diseases
purple lines = above the normal risk
Not to memorize: This slide shows the
correlation between HLA type and chances
of getting a specific autoimmune diseaseswhich is the point of the slide, i.e., there is
such a correlation.
Figure 18-19 Correlations between specific HLAs and increased risk of developing certain
disease. Many of these are autoimmune conditions.
A combination of both cell-mediated
and humoral immune reactions is
responsible for transplant rejection.
TH1 (inflammatory T) cells activate
macrophages, which produce
inflammatory mediators. TH2 cells trigger
both Tc and B cell activation. B cell
activation leads to the production of
plasma cells that synthesize antibodies,
including anti-HLA-DR. Inflammatory
mediators, Tc cell-mediated toxicity,
and antibodies, along with
complement, bring about transplant
rejection
Fig. 18.20 Transplant rejection
Immunosuppression- The minimizing of immune reactions is called
immunosuppression.
Radiation (X-rays) of lymphoid tissue suppresses the
immune system as do cytotoxic drugs, such as azothioprine, and
methotrexate. Radiation and cytotoxic drugs can kill T cell responses
to infections and also affects B cells.
In contrast, the fungus derived peptide cyclosporine A (CsA)
suppresses but does not kill, T cells and it does not affect B cells.
Tacrolimus (also FK-506)-It has similar
immunosuppressive properties to cyclosporin, but is much more potent
in equal volumes. Also like cyclosporin it has a wide range of adverse
interactions, including that with grapefruit which increases plasmatacrolimus concentration. Several of the newer class of antifungals,
especially of the azole class (fluconazole, posaconazole) also increase
drug levels by competing for degradative enzymes.
Immunosuppression with tacrolimus was associated with a
significantly lower rate of acute rejection compared with
cyclosporin-based immunosuppression (30.7% vs 46.4%) in one
The success of allergic desensitization is mainly dependent on
the ability to produce IgG with a denatured allergin
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How immune cells facilitate the spread of breast cancerThe body's immune system fights
disease, infections and even cancer, acting like foot soldiers to protect against invaders and
dissenters. But it turns out the immune system has traitors amongst their ranks. Dr. Karin de
Visser and her team at the Netherlands Cancer Institute discovered that certain immune cells
are persuaded by breast tumors to facilitate the spread of cancer cells. Their findings are
published in advance online in the journal Nature. A few years ago, it was reported that breast
cancer patients with a high number of immune cells called neutrophils in their blood are at
increased risk of developing metastases. Immune cells are supposed to protect our body. So why
are high neutrophil levels linked to worse outcome in women with breast cancer? The tumor
sends out signaling molecules that through a number of steps cause the immune system to
produce lots of neutrophils. This normally happens as part of an inflammatory reaction, but the
neutrophils that are activated by the tumor behave differently. It turns out they are able to
block the actions of other immune cells, called T cells. The first author of the paper in Nature,
postdoctoral researcher Seth Coffelt, showed the importance of the IL17-neutrophil pathway by
inhibiting this pathway in a mouse model that mimics human breast cancer metastasis. When
neutrophils were inhibited, the animals developed much less metastases than animals from
the control group, in which the IL17-neutrophil route was not inhibited. Anti-IL17 drugs are
currently being tested in clinical trials as a treatment for inflammatory diseases, like psoriasis
and rheumatism. Last month, the first anti-IL17 based therapy for psoriasis patients was
approved by the U.S. Federal Drug Administration (FDA). "It would be very interesting to
investigate whether these already existing drugs are beneficial for breast cancer patients. It may
be possible to turn these traitors of the immune system back towards the good side and prevent
their ability to promote breast cancer metastasis," De Visser says.
C. difficile doubles hospital readmission rates, lengths of stay Patients with Clostridium difficile
infection (CDI) are twice as likely to be readmitted to the hospital as patients without the deadly
diarrheal infection, according to a study published in the American Journal of Infection Control,
the official publication of the Association for Professionals in Infection Control and Epidemiology
(APIC). Researchers from the Detroit Medical Center (DMC), a seven-hospital system in
southeastern Michigan, conducted a large study to understand the epidemiology of CDI
readmissions, analyzing 51,353 all-cause discharges between January 1 and December 31, 2012.
There were 615 patients (1 percent) who were discharged with a CDI diagnosis, including 318
where CDI was present on admission, and 297 who were diagnosed during their hospital stay.
The study indicated that 30.1 percent of CDI patients were readmitted after 30 days versus
14.4 percent of all-cause discharges. The length of stay (LOS) upon readmission was also
significantly higher among CDI patients, adding 4.4 days for community-onset CDI cases and 6.4
days for hospital-onset CDI over non-CDI readmissions. "We found that CDI readmissions for any
reason had almost a one week longer average LOS than all-cause readmissions," said Teena
Chopra, MD, MPH, a leading CDI expert from DMC's Division of Infectious Diseases who led the
study. "This suggests that CDI readmissions place a burden on the health system by requiring
patients to stay in the hospital longer, leading to less patient bed turnover and higher hospital
costs." Patients who take antibiotics are most at risk for developing CDI. More than half of all
hospitalized patients will get an antibiotic at some point during their hospital stay, but studies
have shown that 30 to 50 percent of antibiotics prescribed in hospitals are unnecessary or
incorrect, according to the Centers for Disease Control and Prevention (CDC).
Drug-induced thrombocytopenic purpura
Fig. 18. 21 Drug reactions based on Type II hypersensitivity.
Immunodeficiency diseases- arise from an absence of active
lymphocytes or phagocytes.., the presence of defective lymphocytes or
phagocytes, or the destruction of lymphocytes. Such diseases lead to
impaired and inadequate immunity.
Primary immunodeficiency disease are caused by genetic
defects in embryological development, such as failure of the thymus
gland or Peyer’s patches to develop normally. The result is a lack of
T cells or B cells or defective B or T cells.
Secondary immunodeficiency disease can be caused by ii)
infectious agents, such as those responsible for leprosy, tuberculosis,
measles and AIDS, 2) malignancies such as Hodgkin’s disease or
multiple myeloma or 3) immunosuppressant's, such as
chemotherapeutic drugs, certain antibiotics, and radiation.
Fig. 18.22 Kinds of immunodeficiencies
Fig. 18.23 A nude mouse (lacks a thymus in addition to
being hairless).
David the boy in the bubble
Severe combined
immunodeficiency (SCID) - both
B and T cells are absent.
The most effective treatment for SCID is a stem
cell
transplant. This is when stem cells — cells found primarily in
the bone marrow from which all types of blood cells develop — are
introduced into the body in the hopes that the new cells will rebuild
the immune system.
To provide the best chances for success, a transplant is usually done
using the bone marrow of a sibling. However, a parent's marrow
might also be acceptable. Some children do not have family
members who are suitable donors — in such cases, doctors may use
stem cells from an unrelated donor. The likelihood of a good
outcome also is higher if the transplant is done early, within the
first few months of life, if possible.
Another treatment approach currently being studied is gene
therapy. This involves removing cells from a child with SCID
1971-1984
and inserting healthy genes into them, then transplanting them
back into the child. When they find their way to the bone marrow,
they can start to produce healthy immune cells. Gene therapy has
been successful for some patients with certain types of SCID, but a
few children treated with it developed complications, so it has not
yet become routine treatment. New trials of gene therapy are
ongoing.
David the boy in the bubble had SCID-severe combined immunodeficiency disease
The most common treatment for SCID is bone marrow transplantation,
which requires matched donors (a sibling is generally best).[6] David
Vetter, the original "bubble boy", had one of the first transplantations,
and finally died because of an unscreened virus, Epstein-Barr virus (tests
were not available at the time), in his newly transplanted bone marrow
from his sister. Today, transplants done in the first three months of
life have a high success rate.
Trial treatments of SCID have been gene therapy's only success; since
1999, trials of gene therapy has restored the immune systems of at least 17 children
with two forms (ADA-SCID and X-SCID) of the disorder. These trials were stopped
when it was discovered that two of ten patients in one trial had developed leukemia
resulting from the insertion of the gene-carrying retrovirus near an oncogene. In 2007,
four of the ten patients have developed leukemias. Work is now focusing on correcting
the gene without triggering an oncogene. No leukemia cases have yet been seen in trials
of ADA-SCID, which does not involve the gamma c gene that may be oncogenic when
expressed by a retrovirus.
HIV specifically targets and damages TH cells, macrophages,
dendritic cells and langerhans cells. All these immune cells
bear on their surface antigen called the CD4 marker, to which
HIV binds. Infection by HIV is indicated by the presence of
anti-HIV antibodies.
After a person is infected with HIV there is a cycle of destruction of
virus infected immune cells (e.g., TH cells) and destruction of the
virus.
Eventually the viruses uses up the “stem” cells for the TH
which in turn results in non-stimulation of B cells to form plasma
cells and the immune system is largely non-functional. Without
activated TH cells and macrophages, the immune system cannot
detect infectious microbes.
A normal TH count is 800-1200 per µl of blood.
If the count remains above 400, 8 percent of those infected
will develop AIDS within 18 months. With a count of 200, 33
percent progress to AIDS; if the count is below 100, 58 percent
will develop AIDS within 18 months