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.

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.

Fig. 18.1 The mechanism of immediate (Type I) hypersensitivity or anaphylactic hypersensitivity

The allergen triggers the production of IgE rather than IgG

Anaphylaxis

Reagin

Localized vs

Generalized

Allergens

Mechanism of activation

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, cross-

linking 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, 2007In Testing for Allergies, a Single Shot May Suffice

By LAURIE TARKANAt 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.

Fig. 18.5 A proposed mechanism of action for desensitization allergy shots (hyposensitization).

a) normal allergic responseb) 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

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.

Fig. 18.6 The mechanisms of cytotoxic (Type II) hypersensitivity

-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.

In the cytotoxic hypersensitivity theAntibody is IgM

IgM

GalNac

Galactose

GALNac

Gal GalGALNac

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 fetalis.

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 large-scale, 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 disordersFigure 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.

Fig. 18.12 The mechanism of cell-mediated, or delayed (Type IV), hypersensitivity.

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).

Examples of cell-mediated disordersContact 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 cell-mediated 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.

Fig. 18.15 Myasthenia gravis- example of an autoimmune disease

IgG antibodies are produced against the acetylcholine receptors markedly reducing their numbers.

Example of autoimmune disorders-

Myasthenia gravis- This disorder involves a loss of acetylcholine receptors from the neuromuscular junction.

Fig. 18.16 Rheumatoid arthritis-immune complex autoimmune disease

Inflammation in thejoints

Rheumatoid arthritis- Joint inflammation is typical in people suffering from rheumatoid arthritis.

a) Gamma-ray photograph, swollen joints appear as bright spots

b) mechanism

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 anotherIsograft- A graft between two

genetically identical individuals (identical twins)allograft- a graft between two people

who are not genetically identicalxenograft- a transplant between

individuals of different animal speciesTransplant 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).

Figure 18-19 Correlations between specific HLAs and increased risk of developing certain disease. Many of these are autoimmune conditions.

purple lines = above the normal risk

Not to memorize: This slide shows the correlation between HLA type and chances of getting a specific autoimmune diseases-which is the point of the slide, i.e., there is such a correlation.

Diseases in green are autoimmune diseases

Fig. 18.20 Transplant rejection

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

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 plasma-tacrolimus 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 study.

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).

Fig. 18. 21 Drug reactions based on Type II hypersensitivity.

Drug-induced thrombocytopenic purpura

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 had SCID-severe combined immunodeficiency disease

David the boy in the bubbleSevere 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 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.

1971-1984

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