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17.4: Disruptions in the Immune System - Biology

17.4: Disruptions in the Immune System - Biology



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A functioning immune system is essential for survival, but even the sophisticated cellular and molecular defenses of the mammalian immune response can be defeated by pathogens at virtually every step. In the competition between immune protection and pathogen evasion, pathogens have the advantage of more rapid evolution because of their shorter generation time, large population sizes and often higher mutation rates. Thus pathogens have evolved a diverse array of immune escape mechanisms. For instance, Streptococcus pneumoniae (the bacterium that causes pneumonia and meningitis) surrounds itself with a capsule that inhibits phagocytes from engulfing it and displaying antigens to the adaptive immune system. Staphylococcus aureus (the bacterium that can cause skin infections, abscesses, and meningitis) synthesizes a toxin called leukocidin that kills phagocytes after they engulf the bacterium. Other pathogens can also hinder the adaptive immune system. HIV infects TH cells using their CD4 surface molecules, gradually depleting the number of TH cells in the body (Figure (PageIndex{1})); this inhibits the adaptive immune system’s capacity to generate sufficient responses to infection or tumors. As a result, HIV-infected individuals often suffer from infections that would not cause illness in people with healthy immune systems but which can cause devastating illness to immune-compromised individuals.

Inappropriate responses of immune cells and molecules themselves can also disrupt the proper functioning of the entire system, leading to host-cell damage that can become fatal.

Immunodeficiency

Immunodeficiency is a failure, insufficiency, or delay in the response of the immune system, which may be acquired or inherited. Immunodeficiency can allow pathogens or tumor cells to gain a foothold and replicate or proliferate to high enough levels so that the immune system becomes overwhelmed. Immunodeficiency can be acquired as a result of infection with certain pathogens that attack the cells of the immune system itself (such as HIV), chemical exposure (including certain medical treatments such as chemotherapy), malnutrition, or extreme stress. For instance, radiation exposure can destroy populations of lymphocytes and elevate an individual’s susceptibility to infections and cancer. Rarely, primary immunodeficiencies that are present from birth may also occur. For example, severe combined immunodeficiency disease (SCID) is a condition in which children are born without functioning B or T cells.

Hypersensitivities

A maladaptive immune response toward harmless foreign substances or self-antigens that occur after tissue sensitization is termed a hypersensitivity. Types of hypersensitivities include immediate, delayed, and autoimmune. A large proportion of the human population is affected by one or more types of hypersensitivity.

Allergies

The immune reaction that results from immediate hypersensitivities in which an antibody-mediated immune response occurs within minutes of exposure to a usually harmless antigen is called an allergy. In the United States, 20 percent of the population exhibits symptoms of allergy or asthma, whereas 55 percent test positive against one or more allergens. On initial exposure to a potential allergen, an allergic individual synthesizes antibodies through the typical process of APCs presenting processed antigen to TH cells that stimulate B cells to produce the antibodies. The antibody molecules interact with mast cells embedded in connective tissues. This process primes, or sensitizes, the tissue. On subsequent exposure to the same allergen, antibody molecules on mast cells bind the antigen and stimulate the mast cell to release histamine and other inflammatory chemicals; these chemical mediators then recruit eosinophils (a type of white blood cell), which also appear to be adapted to responding to parasitic worms (Figure (PageIndex{2})). Eosinophils release factors that enhance the inflammatory response and the secretions of mast cells. The effects of an allergic reaction range from mild symptoms like sneezing and itchy, watery eyes to more severe or even life-threatening reactions involving intensely itchy welts or hives, airway constriction with severe respiratory distress, and plummeting blood pressure caused by dilating blood vessels and fluid loss from the circulatory system. This extreme reaction, typically in response to an allergen introduced to the circulatory system, is known as anaphylactic shock. Antihistamines are an insufficient counter to anaphylactic shock and if not treated with epinephrine to counter the blood pressure and breathing effects, this condition can be fatal.

Delayed hypersensitivity is a cell-mediated immune response that takes approximately one to two days after secondary exposure for a maximal reaction. This type of hypersensitivity involves the TH1 cytokine-mediated inflammatory response and may cause local tissue lesions or contact dermatitis (rash or skin irritation). Delayed hypersensitivity occurs in some individuals in response to contact with certain types of jewelry or cosmetics. Delayed hypersensitivity facilitates the immune response to poison ivy and is also the reason why the skin test for tuberculosis results in a small region of inflammation on individuals who were previously exposed to Mycobacterium tuberculosis, the organism that causes tuberculosis.

CONCEPT IN ACTION

Try your hand at diagnosing an allergic reaction by selecting one of the interactive case studies at the World Allergy Organization website.

Autoimmunity

Autoimmunity is a type of hypersensitivity to self-antigens that affects approximately five percent of the population. Most types of autoimmunity involve the humoral immune response. An antibody that inappropriately marks self-components as foreign is termed an autoantibody. In patients with myasthenia gravis, an autoimmune disease, muscle-cell receptors that induce contraction in response to acetylcholine are targeted by antibodies. The result is muscle weakness that may include marked difficultly with fine or gross motor functions. In systemic lupus erythematosus, a diffuse autoantibody response to the individual’s own DNA and proteins results in various systemic diseases (Figure (PageIndex{3})). Systemic lupus erythematosus may affect the heart, joints, lungs, skin, kidneys, central nervous system, or other tissues, causing tissue damage through antibody binding, complement recruitment, lysis, and inflammation.

Autoimmunity can develop with time and its causes may be rooted in molecular mimicry, a situation in which one molecule is similar enough in shape to another molecule that it binds the same immune receptors. Antibodies and T-cell receptors may bind self-antigens that are structurally similar to pathogen antigens. As an example, infection with Streptococcus pyogenes (the bacterium that causes strep throat) may generate antibodies or T cells that react with heart muscle, which has a similar structure to the surface of S. pyogenes. These antibodies can damage heart muscle with autoimmune attacks, leading to rheumatic fever. Insulin-dependent (Type 1) diabetes mellitus arises from a destructive inflammatory TH1 response against insulin-producing cells of the pancreas. Patients with this autoimmunity must be treated with regular insulin injections.

Summary

Immune disruptions may involve insufficient immune responses or inappropriate immune responses. Immunodeficiency increases an individual's susceptibility to infections and cancers. Hypersensitivities are misdirected responses either to harmless foreign particles, as in the case of allergies, or to the individual’s own tissues, as in the case of autoimmunity. Reactions to self-components may be the result of molecular mimicry.

Glossary

allergy
an immune reaction that results from immediate hypersensitivities in which an antibody-mediated immune response occurs within minutes of exposure to a harmless antigen
autoantibody
an antibody that incorrectly marks “self” components as foreign and stimulates the immune response
autoimmunity
a type of hypersensitivity to self-antigens
hypersensitivity
a spectrum of inappropriate immune responses toward harmless foreign particles or self-antigens; occurs after tissue sensitization and includes immediate-type (allergy), delayed-type, and autoimmunity
immunodeficiency
a failure, insufficiency, or delay at any level of the immune system, which may be acquired or inherited

Disruption Of Immune-system Pathway Key Step In Cancer Progression, Study Shows

Human immune cells communicate constantly with one another as they coordinate to fight off infection and other threats. Now researchers at Stanford University's School of Medicine have shown that muffling a key voice in this conversational patter is an early step in the progression of human cancers. Silencing an inter-cell signaling mechanism called the interferon pathway may be one way newly developing cancers gain the upper hand. It may also explain the immune dysfunctions seen in many cancer patients and why cancer immunotherapies are often ineffective.

"Over half of cancer patients mount an immune response against their own cancer," said hematologist Peter P. Lee, MD, associate professor of hematology. "So, why does it so often fail? Our research indicates that cancers interfere with a critically important immune signaling pathway. There's a possibility that correcting this defect may one day become part of a useful treatment for many types of cancer." Lee is the senior author of the research, which will be published in the advance online version of Proceedings of the National Academy of Sciences on May 18.

Clues that the interferon pathway is important in fighting off cancers come from mouse models in which the pathway has been artificially disrupted. These animals develop spontaneous tumors at higher rates than normal animals with functional interferon signaling &mdash showing that the immune system quashes many cancers in their infancy. Some viruses are also known to inhibit the interferon pathway.

"It's a very dynamic interaction," said Lee. "If the immune system is successful in stopping a developing cancer, we never know about it because no disease develops. If the cancer cell population overcomes the immune system, you get cancer." In other words, physicians and patients see only the immune system's defeats. This adds an additional hurdle to overcome for new cancer treatments called immunotherapies that are meant to work by stimulating the patient's immune system to attack tumor cells.

Lee and his colleagues had previously shown that the interferon signaling pathway was compromised in melanoma patients. In the current study, the researchers investigated whether patients with two other types of cancer &mdash breast and gastrointestinal &mdash also showed the same defect. They isolated immune cells called lymphocytes in blood samples from patients with three types of cancers (32 breast cancer patients, 12 melanoma patients and 11 gastrointestinal cancer patients) as well as from 28 age-matched healthy patients.

They then compared the response of three classes of lymphocytes &mdash B cells, T cells and NK cells &mdash to exposure to interferons. They found that lymphocytes from breast cancer patients, as well as melanoma and gastrointestinal cancer patients, expressed significantly lower levels of interferon-responsive signaling molecules than did lymphocytes from healthy patients.

"They have a clear defect in the interferon signaling pathway," said Lee. When the researchers looked more closely at the lymphocytes from breast cancer patients, they found that the defect was equally severe in samples from people with early- and late-stage cancers &mdash indicating that the problem must arise soon after the cancer begins to develop &mdash and that it was present regardless of whether the patient had ever been treated with chemotherapy. Finally, the researchers showed that the immune cells from the breast cancer patients responded less efficiently to external activation signals.

"It's now looking like the interferon pathway may harbor a general immune defect in many types of cancers," said Lee. He and his colleagues are working to pinpoint what exactly is going haywire in the pathway and why. They are also investigating whether the problems are likely to block the effectiveness of some of the newer immunotherapies that rely on the presence of a functional immune system.

"Whatever functional defect these immune cells have likely impacts the effectiveness of both active immunotherapy, like cancer vaccines, and passive immunotherapy, like cellular therapies," said Lee. "If these forces are still at play in vivo, the patient's immune response to these types of treatments will be blunted."

Other Stanford researchers who contributed to the work include postdoctoral scholars Rebecca Critchley-Thorne, PhD Ning Yan, PhD Andrea Miyahira, PhD research assistant Diana Simons associate professor of surgery Frederick Dirbas, MD associate professor of surgery Denise Johnson, MD associate professor of dermatology Susan Swetter, MD professor of medicine Robert Carlson, MD associate professor of medicine George Fisher, MD assistant professor of radiation oncology Albert Koong, MD and professor of statistics Susan Holmes, PhD. The research was funded by a Department of Defense Era of Hope Scholar Award.


Immunodeficiency

Failures, insufficiencies, or delays at any level of the immune response can allow pathogens or tumor cells to gain a foothold and replicate or proliferate to high enough levels that the immune system becomes overwhelmed. Immunodeficiency is the failure, insufficiency, or delay in the response of the immune system, which may be acquired or inherited. Immunodeficiency can be acquired as a result of infection with certain pathogens (such as HIV), chemical exposure (including certain medical treatments), malnutrition, or possibly by extreme stress. For instance, radiation exposure can destroy populations of lymphocytes and elevate an individual’s susceptibility to infections and cancer. Dozens of genetic disorders result in immunodeficiencies, including Severe Combined Immunodeficiency (SCID), Bare lymphocyte syndrome, and MHC II deficiencies. Rarely, primary immunodeficiencies that are present from birth may occur. Neutropenia is one form in which the immune system produces a below-average number of neutrophils, the body’s most abundant phagocytes. As a result, bacterial infections may go unrestricted in the blood, causing serious complications.


Disruptions in the Immune System

A functioning immune system is essential for survival, but even the sophisticated cellular and molecular defenses of the mammalian immune response can be defeated by pathogens at virtually every step. In the competition between immune protection and pathogen evasion, pathogens have the advantage of more rapid evolution because of their shorter generation time and other characteristics. For instance, Streptococcus pneumoniae (bacterium that cause pneumonia and meningitis) surrounds itself with a capsule that inhibits phagocytes from engulfing it and displaying antigens to the adaptive immune system. Staphylococcus aureus (bacterium that can cause skin infections, abscesses, and meningitis) synthesizes a toxin called leukocidin that kills phagocytes after they engulf the bacterium. Other pathogens can also hinder the adaptive immune system. HIV infects TH cells via their CD4 surface molecules, gradually depleting the number of TH cells in the body this inhibits the adaptive immune system’s capacity to generate sufficient responses to infection or tumors. As a result, HIV-infected individuals often suffer from infections that would not cause illness in people with healthy immune systems but which can cause devastating illness to immune-compromised individuals. Maladaptive responses of immune cells and molecules themselves can also disrupt the proper functioning of the entire system, leading to host cell damage that could become fatal.


Immunodeficiency

Immunodeficiency is a failure, insufficiency, or delay in the response of the immune system, which may be acquired or inherited. Immunodeficiency can allow pathogens or tumor cells to gain a foothold and replicate or proliferate to high enough levels so that the immune system becomes overwhelmed. Immunodeficiency can be acquired as a result of infection with certain pathogens that attack the cells of the immune system itself (such as HIV), chemical exposure (including certain medical treatments such as chemotherapy), malnutrition, or extreme stress. For instance, radiation exposure can destroy populations of lymphocytes and elevate an individual’s susceptibility to infections and cancer. Rarely, primary immunodeficiencies that are present from birth may also occur. For example, severe combined immunodeficiency disease (SCID) is a condition in which children are born without functioning B or T cells.


Immunodeficiency

Immunodeficiency is a failure, insufficiency, or delay in the response of the immune system, which may be acquired or inherited. Immunodeficiency can allow pathogens or tumor cells to gain a foothold and replicate or proliferate to high enough levels so that the immune system becomes overwhelmed. Immunodeficiency can be acquired as a result of infection with certain pathogens that attack the cells of the immune system itself (such as HIV), chemical exposure (including certain medical treatments such as chemotherapy), malnutrition, or extreme stress. For instance, radiation exposure can destroy populations of lymphocytes and elevate an individual’s susceptibility to infections and cancer. Rarely, primary immunodeficiencies that are present from birth may also occur. For example, severe combined immunodeficiency disease (SCID) is a condition in which children are born without functioning B or T cells.


The immune reaction that results from immediate hypersensitivities in which an antibody-mediated immune response occurs within minutes of exposure to a harmless antigen is called an allergy . In the United States, 20 percent of the population exhibits symptoms of allergy or asthma, whereas 55 percent test positive against one or more allergens. Upon initial exposure to a potential allergen, an allergic individual synthesizes antibodies of the IgE class via the typical process of APCs presenting processed antigen to TH cells that stimulate B cells to produce IgE. This class of antibodies also mediates the immune response to parasitic worms. The constant domain of the IgE molecules interact with mast cells embedded in connective tissues. This process primes, or sensitizes, the tissue. Upon subsequent exposure to the same allergen, IgE molecules on mast cells bind the antigen via their variable domains and stimulate the mast cell to release the modified amino acids histamine and serotonin these chemical mediators then recruit eosinophils which mediate allergic responses. [link] shows an example of an allergic response to ragweed pollen. The effects of an allergic reaction range from mild symptoms like sneezing and itchy, watery eyes to more severe or even life-threatening reactions involving intensely itchy welts or hives, airway contraction with severe respiratory distress, and plummeting blood pressure. This extreme reaction is known as anaphylactic shock. If not treated with epinephrine to counter the blood pressure and breathing effects, this condition can be fatal.


Delayed hypersensitivity is a cell-mediated immune response that takes approximately one to two days after secondary exposure for a maximal reaction to be observed. This type of hypersensitivity involves the TH1 cytokine-mediated inflammatory response and may manifest as local tissue lesions or contact dermatitis (rash or skin irritation). Delayed hypersensitivity occurs in some individuals in response to contact with certain types of jewelry or cosmetics. Delayed hypersensitivity facilitates the immune response to poison ivy and is also the reason why the skin test for tuberculosis results in a small region of inflammation on individuals who were previously exposed to Mycobacterium tuberculosis. That is also why cortisone is used to treat such responses: it will inhibit cytokine production.


Phagocytosis is an important feature of innate immunity that is performed by cells classified as phagocytes. In the process of phagocytosis, phagocytes engulf and digest pathogens or other harmful particles. Phagocytes generally patrol the body searching for pathogens, but they can also be called to specific locations by the release of cytokine s when inflammation occurs. Some phagocytes reside permanently in certain tissues.

As shown in Figure 17.4.6, when a pathogen such as a bacterium is encountered by a phagocyte, the phagocyte extends a portion of its plasma membrane, wrapping the membrane around the pathogen until it is enveloped. Once inside the phagocyte, the pathogen becomes enclosed within an intracellular vesicle called a phagosome. The phagosome then fuses with another vesicle called a lysosome , forming a phagolysosome. Digestive enzymes and acids from the lysosome kill and digest the pathogen in the phagolysosome. The final step of phagocytosis is excretion of soluble debris from the destroyed pathogen through exocytosis .

Figure 17.4.6 Phagocytosis is a multi-step process in which a pathogen is engulfed and digested by immune cells called phagocytes.

Types of leukocytes that kill pathogens by phagocytosis include neutrophils, macrophages, and dendritic cells. You can see illustrations of these and other leukocytes involved in innate immune responses in Figure 17.4.7.

Figure 17.4.7 Types of leukocytes evolved in innate immune responses are illustrated here.


Immune system disruption

Erin keeps a photo of herself playing soccer in the living room of her tidy cottage near San Francisco Bay. It captures her image frozen in time and space, hurtling like a comet between two opponents, her white-blond ponytail fanned out like flames.

Extras:

Illustration by Jeffrey Decoster

“She was a midfielder with boundless energy, lightning fast,” recalls the coach of her Big Ten college soccer team.

Erin, in her early 30s, always assumed that soccer would be at the center of her life. As a little girl, her favorite toy was a soccer ball, a present from a cousin living in Rome. At age 4, she drew a picture of herself competing in the Olympics. In high school, she was invited to try out for the national team’s talent pool. After college, she played for the Detroit Jaguars, a semi-professional team.

But her dream of playing competitive soccer abruptly ended after a trip to Mexico in 2007.

“I was doing social work at an orphanage when I got sick,” says Erin (who asked that her real name not be used). “I passed out and was hospitalized with a high fever, low blood pressure and swollen lymph nodes. After that, I was never the same.”

Thus began her seven-year journey battling a devastating illness with no known cause or cure. She was bedridden for all but four hours a day. She could stand only for 20 minutes without fainting. But the worst symptom was the brain fog.

“It was like my thoughts were stuck in molasses,” says Erin.

No one could figure out what was wrong or how to fix it. She was labeled with chronic fatigue syndrome. Despair set in as the door to her old life slowly closed.

Interrogating the immune system

That same year a door opened on the other end of San Francisco Bay, in a windowless basement of a clinical research building at Stanford University. Here Mark Davis, PhD, an immunologist with a computer hacker’s mindset, was launching a center that aimed to break open the black box called the human immune system. This dynamic network of biological sensors, cells, secretions and genes is like a sixth sense, able to detect microbial friend from foe in the food we eat, the things we touch and the air we breathe. The most intelligent facets of the immune system are still a mystery. How does it differentiate between the cells that are part of you and the interlopers? What are the steps involved in launching an army of white blood cells to attack a microbial invader? How does the system dial down the resulting tissue-damaging inflammation? How do our traitorous cells — the cancers — make themselves invisible to our immune system?

Davis, director of Stanford’s Institute for Immunology, Transplantation and Infection, is in the right place at the right time for this quest, swimming in the primordial soup of creative disruption, Silicon Valley. At long Stanford cafeteria tables frequented by geneticists, bioengineers, math geniuses, computer programmers, surgeons and cancer biologists, ideas just happen. And sometimes, visionary entrepreneurs throw money at these ideas. Such is the case with Davis’ Human Immune Monitoring Center, which before long had enough funding to acquire a CyTOF, a time-of-flight mass spectrometer for high-speed acquisition of multiparametric single-cell data. (If someone asks you if you want one of these instruments, just say yes.)

The CyTOF enables researchers to detect 40 different components within a single cell at the rate of 1,000 cells per second. It not only measures static levels of proteins, useful in identifying different types of immune cells, but it also detects minute changes in signaling proteins within cells in response to various stimuli. Using this device, a staggering amount of data is generated. And armed with big-data analytical methods developed during the Human Genome Project, Davis’ multidisciplinary team is trying to bring order and meaning to the output.

When it’s all done, the team hopes to create a map of what a healthy person’s immune system should look like and a flow chart depicting how immune-system signaling pathways work.

The ultimate goal of Davis’ “Human Immunome Project” is to develop better tools to answer immunological questions no one can answer now. One of the first: What is wrong with the immune systems of patients like Erin, and how can we help them get better?

Mark Davis is leading a massive analysis of the immune system.

Two years into her illness, Erin was broken. On any given day, she would cycle through a laundry list of symptoms: brain fog, dizziness, light sensitivity, a sore throat, nausea, swollen lymph nodes, crushing fatigue, a racing heart, ear ringing, drenching sweats and fainting.

During this time, she had lost some of her most active and athletic friends, who grew impatient with the waxing and waning symptoms that prevented her from the leaving the house on most days.

“I had times where I’d shut the blinds, lie down and hope for a better day,” says Erin. “Literally, my escape was through my dreams. I just couldn’t stand to be in my body.”

Her life revolved around doctors’ appointments. One physician ruled out infectious diseases. Neurologists examined her for seizure disorders and brain tumors. A rheumatologist evaluated her for systemic lupus erythematosus and other inflammatory diseases. An endocrinologist agreed that the origin of her fatigue was not the thyroid, the adrenals or any other gland. A cardiologist assured her it was not her heart.

None of them could settle on a definitive diagnosis, so the physicians tagged her with the insurance code for chronic fatigue syndrome, a controversial diagnosis for a set of symptoms also sometimes labeled as CFIDS — for chronic fatigue and immune dysfunction syndrome — and ME — for myalgic encephalomyelitis. The dominant moniker today is ME/CFS.

No one knows what causes ME/CFS. Some think that an infectious agent or overactive immune system triggers it. Others blame genetic flaws, environmental factors or a combination of any of the above.

Roughly 17 million people worldwide (1 million to 4 million in the United States) have ME/CFS. It strikes people of all ages and racial, ethnic and socioeconomic groups. It is diagnosed two to four times more often in women than men.

It’s a syndrome that gets little respect in the medical community because, with no tangible cause and an ever-changing constellation of symptoms, patients often get labeled as hypochondriacs, malingerers or seekers of addictive pain medications. The primary diagnostic criterion for this condition is infuriatingly vague — “six or more consecutive months of severe fatigue” — virtually unchanged since 1994.

As Erin went from specialist to specialist, well-meaning doctors grew frustrated with their inability to help her. One day Erin blacked out while driving, almost hitting a streetlight. After another fainting accident, an emergency room physician told her, “On hot days, women faint.”

“I felt objectified, like a slab of meat,” says Erin.

Finally, in 2009 Erin was diagnosed with postural orthostatic tachycardia syndrome — which accounted for her fainting spells. For treatment, her cardiologist sent her to Stanford Hospital’s cardiology clinic to see one of the nation’s few POTS specialists, cardiac electrophysiologist Karen Friday, MD.

POTS, which often accompanies ME/CFS, is a fainting disorder associated with an abnormal increase in heart rate and low blood pressure. The mechanism is unknown, but some people develop it after contracting viral or bacterial infections like mononucleosis, pneumonia or Lyme disease. Friday prescribed fludrocortisone to manage Erin’s low blood pressure, but to explore the possibility of an underlying microbial trigger, she sent Erin to see Stanford professor of infectious diseases José Montoya, MD.

Montoya, 54, dapper in his white coat and tie and smiling widely, greeted Erin with a bear hug and told her in his thick Colombian accent, “I want to make your life beautiful again.”

“Dr. Montoya was a shining beacon of hope,” says Erin.

Montoya’s ethos to reduce patient suffering was shaped by a hardworking, single mother and the iron-fisted priests at his Catholic school in Cali, Colombia. He was accepted into medical school at age 18, after receiving the third-highest qualifying exam score in his native country that year. After medical school he went on to Tulane University School of Medicine for his residency, then joined the infectious disease division at Stanford. At Stanford he became a world-recognized authority on infections affecting heart transplant recipients and on toxoplasmosis, a common parasitic disease.

Montoya conducted a detailed medical history and physical exam on Erin, then ordered a battery of tests for viruses, bacteria and fungi. His wide-net diagnostic approach paid off he found two blood-borne microbes — Human Herpesvirus-4 and the coxsackie virus — known to cause chronic disease and POTS.

Though Montoya wasn’t sure if these viruses were at the root of Erin’s illness or merely collateral infections, he started her on a high dose of the antiviral drug famciclovir. Erin was relieved to finally have a physician who wasn’t going to punt her case to another specialist.

“I wanted to live my life again,” says Erin.

Montoya is one of only a handful of clinician-researchers who accept ME/CFS patients, and he currently has a waiting list of about 150.

Back in 2005, while attending a conference on toxoplasmosis in Paris, Montoya told his mentor that he wanted to research ME/CFS. His mentor scoffed at the idea, pointing to a homeless person lying in a Parisian gutter.

“That’s going to be you if you go into chronic fatigue research,” the mentor told him.

The hard truth is that most medical research labs rely in large part on U.S. government funding, and the ME/CFS research budget is insufficient to support a typical university research lab.

The National Institutes of Health, the largest funder of medical research in the United States, allocated only $5 million for ME/CFS research in 2013. (To put this in context, the annual NIH research budget for multiple sclerosis, with 400,000 sufferers, is $112 million.) The reasons behind this underfunding are complicated.

One factor is that the NIH funding process favors well-defined diseases that fit neatly into medical specialties like cardiology, cancer and neurology. Most of these medical societies have organized lobbying efforts, sometimes backed by pharmaceutical or medical technology companies. Another factor is that collectively ME/CFS patients are too sick to organize, raise money and lobby for research dollars. And then there is the stigma associated with the condition some NIH grant reviewers are reluctant to fund research because they believe that ME/CFS is a psychosomatic, “all in the head,” disorder. (To remedy this, the NIH recently created a special emphasis panel so that researchers familiar with the condition review grant applications.)

But none of this deterred Montoya, who was driven to do something for the suffering patients queuing up for appointments.

Opportunity knocked in 2008 when a wealthy donor met with Montoya to talk about the ME/CFS problem. He asked if a $5 million donation for research could make a difference.

Montoya could hardly believe the sum, replying, “Yes, give me five years.”

With the freedom of private funding, Montoya was able to take a multifaceted and rigorous approach to analyzing ME/CFS. Traditionally, NIH funding is awarded through medical specialty groups that tend to favor research that tests one narrow hypothesis about a disease. For example, a researcher might get funded to screen blood samples for one virus, or treat patients with one drug. This approach takes a long time, and researchers typically aren’t able to share and build on discoveries for years.

Montoya’s game plan was to use a big-picture, big-data strategy to find out what was wrong with patients like Erin. His first step in launching the Stanford Initiative on Infection-Associated Chronic Diseases was to convince a dozen or so academic investigators to venture out of their comfort zones to research a wildly unpopular disease using technologies yet to be developed.

Montoya convinced experts in immunology, rheumatology, genetics, bioengineering, anesthesiology, neuroradiology, cardiology, psychiatry, infectious diseases and bioinformatics to all work together. The team members would be searching blood samples for infectious microbes, inflammation-related molecules and genetic flaws. They’d do brain scans and physical exams. They’d survey study subjects for fatigue levels and medical histories. Then they’d compare all this data with that of healthy people to see what was different. Next, he launched a Bay Area recruitment campaign for 200 patients who met the Centers for Disease Control’s definition for chronic fatigue syndrome, including Erin, and 400 age- and sex-matched healthy volunteers, all of whom agreed to donate eight tubes of blood and be poked, scanned and surveyed over the next decade.

The most complex part of the ME/CFS initiative was the exploration into what was happening with the immune system of these patients. For this role, he needed an expert who didn’t care about the ME/CFS stigma or how things have been done in the past. So he called on Mark Davis.

There will be blood

Davis, in well-worn jeans and running shoes, leans back in his chair, surrounded by pillar-piles of scientific papers. At first glance one might assume that he is — in California-speak — a mellow dude.

But looks can be deceiving, because Davis, who discovered how T cells help a body fight off infections, is all about the fight.

As if to prove this point, Davis reaches into a random stack of paper and pulls out a black-and-white photo of a collegiate fencing match.

“This is me,” he says, pointing to a man in white flying off the ground, plunging the tip of a silver foil directly between the eyes of a masked opponent. “I like to poke people.”

He then reaches into another stack of paper and pulls out the Dec. 19, 2008, issue of Immunity. It is a poke-in-the-eye to fellow immunologists, an essay titled, “A Prescription for Human Immunology.”

In this oft-quoted paper, he describes immunology as a field known for its “impenetrable jargon, byzantine complexity and acrimonious disputes.”

He also chides many of his colleagues for spending too much time on mouse studies and not enough on human studies. For immunological studies, mice are fast and easy. They can be bred with specific diseases, such as diabetes or Parkinson’s, and then dissected to evaluate the effectiveness of experimental treatments. There are relatively few regulatory, financial and ethical hurdles to working with mice. He emphasizes that lab mice live in isolated, disease-free, temperature-controlled environments, far different from the crowded, germ-ridden urban habitats of your typical Homo sapiens. (Most humans are infected with six different herpes viruses, and who knows what else.) The other problem with “mouse models” is that their common ancestors are genetically separated from Homo sapiens by some 65 million years.

Erin, a social worker and therapist, is an ME/CFS study participant.

“Inbred mice have not, in most cases, been a reliable guide for developing treatments for human immunological diseases,” says Davis.

Instead, he would like to shift the focus of immunology research back to where it can do the most good — to humans and their blood. And along the way, he’d like to slay a few sacred cows of medicine.

First off, Davis believes it’s time to rethink the CBC or complete blood count, the most commonly ordered medical test on the planet. The CBC, which has changed little since it was put into mainstream use in the ’50s, provides physicians with relative numbers of a patient’s red, white and platelet blood cells. This test isn’t really “complete” and it doesn’t begin to capture the nuances of a working immune system.

As researchers gain a better understanding of this system, he’d like to develop a new set of metrics for immune system health that communicates more of a continuum of health rather than a black-and-white declaration. If the immune system is underactive, a person is open to infections, mutations and premature aging. If it is overactive, a person may suffer from allergies, autoimmune disease and excessive inflammation. Davis wants to redefine health as an immune system in balance, then develop better reporting tools to help clinicians determine if a patient is fighting a virus, a bacteria, an allergy or environmental toxins.

Davis’ field of dreams for this effort is Stanford’s Human Immune Monitoring Center. Launched in 2007, today the center consists of dozens of instruments that provide standardized, state-of-the-art immune system analysis at the RNA, protein and cellular levels. Its gene-sequencing instrumentation is located in a nearby building and shared with the Stanford Functional Genomics Facility. For researchers both inside and outside of the university, the center’s 15-person staff provides a one-stop shop for these services. At the start of a project, the center’s director, Holden Maecker, PhD, meets with investigators to help plan studies and determine needs, such as what samples to take, how to store those samples and which tests will best answer their scientific questions. There is also assistance on results archiving, reporting and data mining.

“We have about 60 different projects under way at the center right now,” says Maecker. These include searches for immune biomarkers for aging, Alzheimer’s, autoimmune disease, cancer, chronic pain, rejection in organ transplantation and viral infections.

“I believe this is the only facility of its kind anywhere,” says Davis.

Montoya’s chronic illness initiative is the largest project in the HIMC at this time, and the complexity of the task ahead is daunting. The staff is looking for meaningful patterns in the many components of the 600 blood samples, including dozens of cytokines, 35 cell-surface proteins, 15 or so types of blood cells, and more than 47,000 genes and regulatory nucleic acids. The challenge is not only to quantify the normal ranges for these components, but also to understand relationships between the components and reverse-engineer the cascade of biochemical reactions that drive immune system processes. He anticipates it will take about a year to run all 600 samples through the processes.

“It’s like dumping a hundred different puzzles on the floor and trying to find two pieces that fit,” says Davis.

The workhorses for these tasks are the center’s two CyTOFs. Stanford has seven of these $630,000 instruments, more than any other academic medical center, thanks to Garry Nolan, PhD, a Stanford professor of microbiology and immunology. Nolan purchased the first commercially available CyTOF, and as an early adopter developed protocols for using it in cancer biology, immunology and cell biology. He now holds equity in Fluidigm, a company that manufactures the machines.

Infectious disease expert José Montoya is looking for causes of chronic fatigue.

His enthusiasm for the technology and his willingness to share what he’s learned has catalyzed an active Stanford community of CyTOF experts.

“With seven CyTOFs on campus, Stanford continues to innovate and lead the way in ‘deep-profiling’ studies of the immune system,” says Nolan

Through this work, the Stanford team hopes to gain a better understanding of the complex, inner workings of the immune system. This will ultimately give physicians and their patients the tools to answer the fundamental question, “How is my immune system doing today?”

Putting the pieces together

This past March, four years after the launch of the ME/CFS initiative, Montoya held an all-day symposium to present early findings on what’s happening within the hearts, blood, brains and genomes of ME/CFS patients. The lecture hall was packed with researchers from Australia, Canada, the United Kingdom and the United States, as well as patients, all eager for any news on a research agenda that had been stalled for decades.

At the end of the day, the biggest news was the identification of a number of biological markers that indicate ME/CFS patients may be suffering from out-of-control inflammation.

First up was a neuroinflammation researcher, Jarred Younger, PhD, who worked with the HIMC to measure daily fluctuations of 74 blood markers and cytokines. For this study, published in the Journal of Translational Medicine (http://www.translational-medicine.com/content/11/1/93), volunteers gave blood once a day for 25 days, and reported their fatigue levels on a hand-held computer twice a day. (Younger moved to the University of Alabama in Birmingham in August.) Through complex statistical analysis, the team found 12 cytokines that were consistently elevated on days that ME/CFS patients felt the most fatigued. One of these cytokines, leptin, activates microglial cells, the brain’s first line of defense against infections. When microglial cells are primed, they start pumping out signaling chemicals that generate the flulike symptoms commonly reported by ME/CFS patients — fatigue, headaches and brain fog.

Amit Kaushal, a medical resident with a PhD in bioinformatics, did the first pass on genomic analysis. For his part of the investigation, he scanned the blood of 200 ME/CFS patients and 400 healthy subjects for 47,000 gene elements, then ran this data through the Nextbio Disease Atlas, a publically accessible database that catalogs gene markers associated with specific diseases. After analysis, he found genetic markers in the blood of ME/CFS patients similar to those in patients with well-defined chronic inflammatory diseases.

The quarterback for the search for infectious microbes is W. Ian Lipkin, MD, a renowned microbe hunter and the director of the Center for Infection and Immunity at Columbia University’s Mailman School of Public Health. He is using high-throughput sequencing platforms that enable rapid identification and molecular characterization of known and novel disease agents.

“We decided to go in without any preconceived notions about what we’d find,” says Lipkin. “Our approach is comprehensive, rigorous and quite deep.”

In the first analysis, his team found no significant differences in the types of infectious organisms present in the blood of people with ME/CFS or their matched normal controls. In the next phase he’ll search inside the blood cells and analyze the gastrointestinal microbiome for the presence of bacteria or viruses that may trigger the immunological disturbances that are so disabling in ME/CFS. The objective of this work is to identify the agents responsible for initiating and perpetuating disease. This could lead to vaccines, drugs or probiotic interventions.

While not all of these results have been published or independently confirmed, the researchers were excited about finding measurable, physical differences between ME/CFS patients and healthy controls. (Stanford assistant professor of radiology Michael Zeineh, MD, has identified structural brain abnormalities in the ME/CFS patients — findings are slated for publication in the coming months.) More pieces of the puzzle are coming together, providing other ME/CFS researchers with ideas to build on. For ME/CFS patients it was validation — their symptoms are real, with measurable biological markers.

Eight months after seeing Montoya, Erin’s recovery from ME/CFS started with fleeting windows of cognitive clarity. She was on high-dose antivirals and POTS medications for about five years, and her recovery was infuriatingly slow and inconsistent. It was like wiping off a mirror in a steamy bathroom. She saw her former self briefly, then the image fogged over again.

Montoya doesn’t know why these drugs worked for Erin, but he knew from treating other patients that beating back viral infections sometimes helps get an immune system back into balance.

Erin also believes that the antiviral and POTS drugs were instrumental in her recovery, but other factors — family support, meditation and Montoya’s coaching — were also important.

One of Montoya’s key messages to ME/CFS patients is this: If you have one good day, don’t try to make up for lost time by overexerting yourself.

“Don’t burn out your engine,” says Montoya, because the resulting crash can reset the recovery process by months.

And at appointments he would remind Erin, “Take in all the love that is all around you and use it to heal.”

During her illness, Erin’s mother became her advocate, managing her medical issues and driving her to appointments. Her father added her to his health insurance policy so she could afford the visits to medical specialists. And her sister, who is her best friend and housemate, was her wingman.

“My sister was my voice of hope,” says Erin. “She’d tell me, ‘OK, you took five steps forward and two back today, but maybe tomorrow you’ll take six steps forward and only one back.’”

It’s been seven years since Erin fell into the abyss of a mysterious illness. This girl interrupted, now a woman, is picking up the pieces of her life and starting to live again.

Today, she works as a social worker and therapist. She plays soccer in a local league. She’s also started dating again. It gives her hope that researchers are finally focused on ME/CFS and that others may be able to benefit from the treatment that has given her life back.

As she packs for a camping trip, she reflects on how this illness has changed her.

“It’s made me a person of more depth and compassion,” says Erin. “Before, I’d been so active, I didn’t have the opportunity to sit with myself in this way and take a deeper inward journey. Adventure had been the focus of my life. As I sit with clients who are coming in with devastating situations, with unknown futures, I’m able to share with them hope and the power of self-fulfilling prophesies. I help them find those things inside, spiritually, that will help them meet the adversities in their lives.”

At this point her voice becomes soft, almost a whisper, as she says, “I’ll always miss playing soccer at a competitive level, but I’ve gained so much. It’s helped me reinterpret what success looks like. It’s not everything you achieve and how many games you win. It’s the process of getting there. This is my biggest achievement — recovering from this illness.”

In soccer, a “hat trick” is where a player scores three goals in a row. Montoya achieved his first goal, the launch of the first major ME/CFS research initiative, with a little funding luck and the recruitment of a top-notch research team. With the assistance of Davis and his immune system hackers, he’s close to reaching his second goal: the identification of biomarkers and causes, which will enable physicians to provide a definitive diagnosis and treatment options to patients suffering from this debilitating condition.

The third goal of his hoped-for hat trick will be a whole new way to look at the human immune system. It’s a game changer. It will provide researchers with a new playbook of research strategies to help them discover the causes of other confounding conditions, from Lyme disease to multiple sclerosis to fibromyalgia. It will provide clinicians with a better set of metrics for assessing patients’ health. And then the patients lying in dark rooms with forgotten diseases, whose numbers could fill hundreds of soccer stadiums, will have reasons to stand up and cheer.


Abstract

Throughout the past century, we have seen the emergence of a large number of multifactorial diseases, including inflammatory, autoimmune, metabolic, neoplastic and neurodegenerative diseases, many of which have been recently associated with intestinal dysbiosis — that is, compositional and functional alterations of the gut microbiome. In linking the pathogenesis of common diseases to dysbiosis, the microbiome field is challenged to decipher the mechanisms involved in the de novo generation and the persistence of dysbiotic microbiome configurations, and to differentiate causal host–microbiome associations from secondary microbial changes that accompany disease course. In this Review, we categorize dysbiosis in conceptual terms and provide an overview of immunological associations the causes and consequences of bacterial dysbiosis, and their involvement in the molecular aetiology of common diseases and implications for the rational design of new therapeutic approaches. A molecular- level understanding of the origins of dysbiosis, its endogenous and environmental regulatory processes, and its downstream effects may enable us to develop microbiome-targeting therapies for a multitude of common immune-mediated diseases.


Watch the video: Introduction To Immune System (August 2022).