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20.1: Case Study: Your Defense System

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• Page ID 16844

• Suzanne Wakim & Mandeep Grewal
• Butte College

Case Study: Defending Your Defenses

Twenty-six-year-old Wei isn’t feeling well. Wei uses he/him/his pronouns. He is more tired than usual, dragging through his workdays despite going to bed earlier and napping on the weekends. He doesn't have much of an appetite and has started losing weight. When he presses on the side of his neck, like the doctor is doing in Figure \(\PageIndex{1}\), he notices an unusual lump.

Wei goes to his doctor, who performs a physical exam and determines that the lump is a swollen lymph node. Lymph nodes are part of the immune system, and they will often become enlarged when the body is fighting off an infection. Dr. Bouazizi thinks that the swollen lymph node and fatigue could be signs of a viral or bacterial infection, or indicate a type of cancer called lymphoma. However, an infection is a more likely cause, particularly in a young person like Wei. Dr. Bouazizi prescribes an antibiotic in case Wei has a bacterial infection and advises him to return in a few weeks if his lymph node does not shrink or if he is not feeling better.

Wei returns a few weeks later. He is not feeling better and his lymph node is still enlarged. Dr. Bouazizi is concerned and orders a biopsy of the enlarged lymph node. A lymph node biopsy for suspected lymphoma often involves the surgical removal of all or part of a lymph node, to determine whether the tissue contains cancerous cells.

The initial results of the biopsy indicate that Wei does have lymphoma. Although lymphoma is more common in older people, young adults and even children can get this disease. There are many types of lymphoma, with the two main types being Hodgkin and non-Hodgkin lymphoma. Non-Hodgkin lymphoma (NHL), in turn, has many subtypes depending on factors such as which cell types are affected. For instance, some subtypes of NHL affect immune system cells called B cells, while others affect different immune system cells called T cells.

Dr. Bouazizi explains to Wei that it is important to determine which type of lymphoma he has, in order to choose the best course of treatment. Wei’s biopsied tissue will be further examined and tested to see which cell types are affected and which specific cell-surface proteins, called antigens, are present. This should help in identifying his specific type of lymphoma.

As you read this chapter, you will learn about the functions of the immune system, and the specific roles that its cells and organs—such as B and T cells and lymph nodes— play in defending the body. At the end of this chapter, you will learn what type of lymphoma Wei has and what some of his treatment options are, including treatments that make use of the biochemistry of the immune system to fight cancer with the immune system itself.

Chapter Overview: Immune System

In this chapter, you will learn about the immune system—the system that defends the body against infections and other causes of disease such as cancerous cells. Specifically, you will learn about:

• How the immune system identifies normal cells of the body as “self” and pathogens and damaged cells as “non-self.”
• The two major subsystems of the general immune system: the innate immune system, which provides a quick but non-specific response; and the adaptive immune system, which is slower but provides a specific response that often results in long-lasting immunity.
• The specialized immune system that protects the brain and spinal cord called the neuroimmune system.
• The organs, cells, and responses of the innate immune system, which include physical barriers such as skin and mucus, chemical and biological barriers, inflammation, activation of the complement system of molecules, and non-specific cellular responses such as phagocytosis.
• The lymphatic system—which includes white blood cells called lymphocytes; lymphatic vessels that transport a fluid called lymph; and organs such as the spleen, tonsils, and lymph nodes—and its important role in the adaptive immune system.
• Specific cells of the immune system and their functions, including B cells, T cells, plasma cells, and natural killer cells.
• How the adaptive immune system can generate specific and often long-lasting immunity against pathogens through the production of antibodies.
• How vaccines work to generate immunity.
• How cells in the immune system detect and kill cancerous cells.
• Some strategies that pathogens employ to evade the immune system.
• Disorders of the immune system, including allergies, autoimmune diseases (such as diabetes and multiple sclerosis), and immunodeficiency resulting from conditions such as HIV infection.

As you read the chapter, think about the following questions:

• What are the functions of lymph nodes?
• What are B and T cells and how do they relate to lymph nodes?
• What are cell-surface antigens? How do they relate to the immune system and to cancer?

Attributions

• Palpating lymph nodes by BodyParts3D/Anatomography (NIH), public domain via Wikimedia Commons
• Text adapted from Human Biology by CK-12 licensed CC BY-NC 3.

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17.7 Case Study Conclusion: Defending Your Defenses

Created by CK-12 Foundation/Adapted by Christine Miller

Case Study Conclusion: Defending Your Defenses

These people are participating in a bike ride to raise funds for leukemia and lymphoma research (Figure 17.7.1). Leukemia and lymphoma are blood cancers. In 2020,  approximately 6,900 Canadians will be diagnosed with leukemia and 3,000 will die from this cancer. Lymphoma is the most common type of blood cancer. As a lymphoma patient, Hakeem, who you learned about in the beginning of this chapter, may eventually benefit from research funded by a bike ride like this one.

What type of blood cell is affected in lymphoma ? As the name implies, lymphoma is a cancer that affects lymphocytes, which are a type of leukocyte. As you have learned in this chapter, there are different types of lymphocytes, including the B and T cells of the adaptive immune system . Different types of lymphoma affect different types of lymphocytes in different ways. It is important to correctly identify the type of lymphoma, so that patients can be treated appropriately.

You may recall that one of Hakeem’s symptoms was a swollen lymph node , and he was diagnosed with lymphoma after a biopsy of that lymph node. Swollen lymph nodes are a common symptom of lymphoma. As you have learned, lymph nodes are distributed throughout the body along lymphatic vessels, as part of the lymphatic system . The lymph nodes filter lymph and store lymphocytes. Therefore, they play an important role in fighting infections. Because of this, they will often swell in response to an infection. In Hakeem’s case, the swelling and other symptoms did not improve after several weeks and a course of antibiotics, which caused Dr. Hayes to suspect lymphoma instead. The biopsy showed that Hakeem did indeed have cancerous lymphocytes in his lymph nodes.

But which type of lymphocytes were affected? Lymphoma most commonly affects B or T lymphocytes. The two major types of lymphoma are called Hodgkin (HL) or non-Hodgkin lymphoma (NHL). NHL is more common than HL. In 2020, the Canadian Cancer Society estimates 10,400 Canadians will be diagnosed with non-Hodgkin lymphoma, whereas 1,000 will be diagnosed with Hodgkin lymphoma. While HL is one distinct type of lymphoma, NHL has about 60 different subtypes, depending on which specific cells are affected and how.

Hakeem was diagnosed with a type of NHL called diffuse large B-cell lymphoma (DLBCL) — the most common type of NHL. This type of lymphoma affects B cell s and causes them to appear large under the microscope. In addition to Hakeem’s symptoms of fatigue, swollen lymph nodes, loss of appetite, and weight loss, common symptoms of this type of lymphoma include fever and night sweats. It is an aggressive and fast-growing type of lymphoma that is fatal if not treated. The good news is that with early detection and proper treatment, about 70% of patients with DLBCL can be cured.

How do physicians determine the specific type of lymphoma? Tissue obtained from a biopsy can be examined under a microscope to observe physical changes (such as abnormal cell size or shape) that are characteristic of a particular subtype of lymphoma. Additionally, tests can be performed on the tissue to determine which cell-surface antigens are present. Recall that antigens are molecules that bind to specific antibodies. Antibodies can be produced in the laboratory and labeled with compounds that can be identified by their colour under a microscope. When these antibodies are applied to a tissue sample, this colour will appear wherever the antigen is present, because it binds to the antibody. This technique was used in the photomicrograph in Figure 17.7.2 to identify the presence of a cell-surface antigen (shown as reddish-brown) in a sample of skin cells. This technique, called immunohistochemistry, is also commonly used to identify antigens in tissue samples from lymphoma patients.

Why would identifying cell-surface antigens be important in diagnosing and treating lymphoma? As you have learned, the immune system uses antigens present on the surface of cells or pathogens to distinguish between self and non-self, and to launch adaptive immune responses. Cells that become cancerous often change their cell-surface antigens. This is one way that the immune system can identify and destroy them. Also, different cell types in the body can sometimes be identified by the presence of specific cell-surface antigens. Knowing the types of cell-surface antigens present in a tissue sample can help physicians identify which cells are cancerous, and possibly the specific subtype of cancer. Knowing this information can be helpful in choosing more tailored and effective treatments.

One treatment for NHL is, in fact, the use of medications made from antibodies that bind to cell-surface antigens present on cells affected by the specific subtype of NHL. This is called immunotherapy . These drugs can directly bind to and kill the cancerous cells. For patients with DLBCL like Hakeem, immunotherapy is often used in conjunction with chemotherapy and radiation as a course of treatment. Although Hakeem has a difficult road ahead, he and his medical team are optimistic that — given the high success rate when DLBCL is caught and treated early — he may be cured. More research into how the immune system functions may lead to even better treatments for lymphoma — and other types of cancers — in the future.

Chapter 17 Summary

In this chapter, you learned about the immune system. Specifically, you learned that:

• Any agent that can cause disease is called a pathogen . Most human pathogens are microorganisms , such as bacteria and viruses . The immune system is the body system that defends the human host from pathogens and cancerous  cells.
• The innate immune system is a subset of the immune system that provides very quick, but non-specific responses to pathogens. It includes multiple types of barriers to pathogens, leukocytes that phagocytize pathogens, and several other general responses.
• The adaptive immune system is a subset of the immune system that provides specific responses tailored to particular pathogens. It takes longer to put into effect, but it may lead to immunity to the pathogens.
• Both innate and adaptive immune responses depend on the ability of the immune system to distinguish between self and non-self molecules. Most body cells have major histocompatibility complex (MHC) proteins that identify them as self. Pathogens, infected cells, and tumor cells have non-self proteins called antigens that the immune system recognizes as foreign.
• Antigens  are proteins that bind to specific receptors on immune system cells and elicit an adaptive immune response. Some immune cells ( B cells ) respond to foreign antigens by producing antibodies that bind with antigens and target pathogens for destruction.
• An important role of the immune system is tumor surveillance. Killer T cells  of the adaptive immune system find and destroy tumor cells, which they can identify from their abnormal antigens.
• The neuroimmune system that protects the central nervous system is thought to be distinct from the peripheral immune system that protects the rest of the human body. The blood-brain and blood-spinal cord barriers are one type of protection of the neuroimmune system. Neuroglia also play a role in this system, for example, by carrying out phagocytosis .
• The lymphatic system is a human organ system that is a vital part of the adaptive immune system. It consists of several organs and a system of vessels that transport or filter the fluid called lymph . The main immune function of the lymphatic system is to produce, mature, harbor, and circulate white blood cells called lymphocytes, which are the main cells in the adaptive immune system, and are circulated in lymph.
• The return of lymph to the bloodstream is one of the functions of the lymphatic system. Lymph flows from tissue spaces, where it leaks out of blood vessels, to major veins in the upper chest. It is then returned to the cardiovascular system . Lymph is similar in composition to blood plasma . Its main cellular components are lymphocytes.
• Lymphatic vessels called lacteals  are found in villi that line the small intestine . Lacteals absorb fatty acids from the digestion of lipids in the digestive system . The fatty acids are then transported through the network of lymphatic vessels to the bloodstream.
• Lymphocytes, which include B cells  and T cells , are the subset of leukocytes involved in adaptive immune responses . They may create a lasting memory of and immunity to specific pathogens.
• All lymphocytes are produced in bone marrow and then go through a process of maturation, in which they “learn” to distinguish self from non-self. B cells mature in the bone marrow, and T cells mature in the thymus . Both the bone marrow and thymus are considered primary lymphatic organs .
• Secondary lymphatic organs include the tonsils, spleen, and lymph nodes. There are four pairs of tonsils  that encircle the throat. The spleen filters blood, as well as lymph. There are hundreds of lymph nodes  located in clusters along the lymphatic vessels. All of these secondary organs filter lymph and store lymphocytes, so they are sites where pathogens encounter and activate lymphocytes and initiate adaptive immune responses.
• Unlike the adaptive immune system, the innate immune system does not confer immunity. The innate immune system includes surface barriers, inflammation, the complement system, and a variety of cellular responses.
• The body’s first line of defense consists of three different types of barriers that keep most pathogens out of body tissues. The types of barriers are mechanical, chemical, and biological barriers.
• Mechanical barriers  — which include the skin , mucous membranes , and fluids (such as tears and urine ) — physically block pathogens from entering the body.
• Chemical barriers — such as enzymes in sweat , saliva , and semen  — kill pathogens on body surfaces.
• Biological barriers are harmless bacteria that use up food and space so pathogenic bacteria cannot colonize the body.
• If pathogens breach the protective barriers, inflammation occurs. This creates a physical barrier against the spread of infection and repairs tissue damage. Inflammation is triggered by chemicals (such as cytokines  and histamines ), and it causes swelling, redness, and warmth.
• The complement system is a complex biochemical mechanism that helps antibodies kill pathogens. Once activated, the complement system consists of more than two dozen proteins that lead to disruption of the cell membrane of pathogens and bursting of the cells.
• Cellular responses of the innate immune system involve various types of leukocytes (white blood cells). For example, neutrophils , macrophages , and dendritic cells  phagocytize pathogens. Basophils  and mast cells  release chemicals that trigger inflammation. Natural killer cells  destroy cancerous or virus-infected cells, and eosinophils  kill parasites.
• Many pathogens have evolved mechanisms that help them evade the innate immune system. For example, some pathogens form a protective capsule around themselves, and some mimic host cells so the immune system does not recognize them as foreign.
• The main cells of the adaptive immune system are lymphocytes . There are two major types of lymphocytes: T cells and B cells. Both types must be activated by foreign antigens to become functioning immune cells.
• Most activated T cells become either killer T cells  or helper T cells . Killer T cells destroy cells that are infected with pathogens or are cancerous. Helper T cells manage immune responses by releasing cytokines that control other types of leukocytes.
• Activated B cells form plasma cell s that secrete antibodies, which bind to specific antigens on pathogens or infected cells. The antibody-antigen complexes generally lead to the destruction of the cells, for example, by attracting phagocytes or triggering the complement system.
• After an adaptive immune response occurs, long-lasting memory B cells and memory T cells may remain to confer immunity to the specific pathogen that caused the adaptive immune response. These memory cells are ready to activate an immediate response if they are exposed to the same antigen again in the future.
• Immunity may be active or passive.
•   Active immunity occurs when the immune system has been presented with antigens that elicit an adaptive immune response. This may occur naturally as the result of an infection, or artificially as the result of immunization. Active immunity may last for years or even for life.
• Passive immunity occurs without an adaptive immune response by the transfer of antibodies or activated T cells. This may occur naturally between a mother and her fetus or her nursing infant, or it may occur artificially by injection. Passive immunity lasts only as long as the antibodies or activated T cells remain alive in the body, generally just weeks or months.
• Many pathogens have evolved mechanisms to evade the adaptive immune system. For example, human immunodeficiency virus ( HIV ) evades the adaptive immune system by frequently changing its antigens and by forming its outer envelope from the host’s cell membrane.
• An allergy is a disorder in which the immune system makes an inflammatory response to a harmless antigen. Any antigen that causes allergies is called an allergen . Common allergens include pollen, dust mites, mold, specific foods (such as peanuts), insect stings, and certain medications (such as aspirin).
• The prevalence of allergies has been increasing for decades, especially in developed countries, where they are much more common than in developing countries. The hygiene hypothesis posits that this has occurred because humans evolved to cope with more pathogens than we now typically face in our relatively sterile environments in developed countries. As a result, the immune system “keeps busy” by attacking harmless antigens.
• Allergies occur when B cells are first activated to produce large amounts of antibodies to an otherwise harmless allergen, and the antibodies attach to mast cells. On subsequent exposures to the allergen, the mast cells immediately release cytokines and histamines that cause inflammation.
• Mild allergy symptoms are frequently treated with antihistamines that counter histamines and reduce allergy symptoms. A severe systemic allergic reaction, called anaphylaxis , is a medical emergency that is usually treated with injections of epinephrine. Immunotherapy for allergies involves injecting increasing amounts of allergens to desensitize the immune system to them.
• Autoimmune diseases  occur when the immune system fails to recognize the body’s own molecules as self and attacks them, causing damage to tissues and organs. A family history of autoimmunity and female gender are risk factors for autoimmune diseases.
• In some autoimmune diseases, such as type I diabetes, the immune system attacks and damages specific body cells. In other autoimmune diseases, such as systemic lupus erythematosus, many different tissues and organs may be attacked and injured. Autoimmune diseases generally cannot be cured, but their symptoms can often be managed with drugs or other treatments.
• Immunodeficiency occurs when the immune system is not working properly, generally because one or more of its components are inactive. As a result, the immune system is unable to fight off pathogens or cancers that a normal immune system would be able to resist.
• Primary immunodeficiency is present at birth and caused by rare genetic diseases. An example is severe combined immunodeficiency. Secondary immunodeficiency occurs because of some event or exposure experienced after birth. Possible causes include substance abuse, obesity, and malnutrition, among others.
• The most common cause of immunodeficiency in the world today is human immunodeficiency virus (HIV), which infects and destroys helper T cells. HIV is transmitted through mucous membranes or body fluids. The virus may eventually lead to such low levels of helper T cells that opportunistic infections occur. When this happens, the patient is diagnosed with acquired immunodeficiency syndrome (AIDS). Medications can control the multiplication of HIV in the human body, but it can’t eliminate the virus completely.

Up to this point, this book has covered body systems that carry out processes within individuals, such as the digestive, muscular, and immune systems. Read the next chapter to learn about the body system that allows humans to produce new individuals — the reproductive system.

Chapter 17 Review

• Compare and contrast a pathogen and an allergen.
• Describe three ways in which pathogens can enter the body.
• The complement system involves the activation of several proteins to kill pathogens. Why do you think this is considered part of the innate immune system, instead of the adaptive immune system?
• Why are innate immune responses generally faster than adaptive immune responses?
• Explain how an autoimmune disease could be triggered by a pathogen.
• What is an opportunistic infection? Name two diseases or conditions that could result in opportunistic infections. Explain your answer.
• Which cell type in the immune system can be considered an “antibody factory?”
• Besides foreign pathogens, what is one thing that the immune system protects the body against?
• What cell type in the immune system is infected and killed by HIV?
• Name two types of cells that produce cytokines in the immune system. What are two functions of cytokines in the immune system?
• Many pathogens evade the immune system by altering their outer surface in some way. Based on what you know about the functioning of the immune system, why is this often a successful approach?
• What is “missing self?” How does this condition arise?

17.7 Explore More

What is leukemia? – Danilo Allegra and Dania Puggioni, TED-Ed, 2015.

Attributions

Figure 17.7.1

Cycling to Beat Blood Cancer by Blood Cancer UK (Formerly Bloodwise) on Flickr is used under a CC BY-NC-ND 2.0 (https://creativecommons.org/licenses/by-nc-nd/2.0/) license.

Figure 17.7.2

antigen stain by Ed Uthman from Houston, TX, USA on Wikimedia Commons is used under a CC BY 2.0 (https://creativecommons.org/licenses/by/2.0) license.

Hodgkin lymphoma statistics [online article]. (2020). Canadian Cancer Society. https://www.cancer.ca:443/en/cancer-information/cancer-type/hodgkin-lymphoma/statistics/?region=on

Non-Hodgkin lymphoma statistics [online article]. (2020). Canadian Cancer Society. https://www.cancer.ca:443/en/cancer-information/cancer-type/non-hodgkin-lymphoma/statistics/?region=on

TED-Ed. (2015, April 30). What is leukemia? – Danilo Allegra and Dania Puggioni. YouTube. https://www.youtube.com/watch?v=Z3B-AaqjyjE&feature=youtu.be

A cancer that begins in infection-fighting cells of the immune system, called lymphocytes.

A subset of the immune system that makes tailored attacks against specific pathogens or tumor cells such as the production of antibodies that match specific antigens.

One of many small structures located along lymphatic vessels where pathogens are filtered from lymph and destroyed by lymphocytes.

A body system consisting of a network of tissues and organs that help rid the body of toxins, waste and other unwanted materials. The primary function of the lymphatic system is to transport lymph, a fluid containing infection-fighting white blood cells, throughout the body.

A fluid that leaks out of capillaries into spaces between cells and circulates in the vessels of the lymphatic system.

A type of white blood cell and, specifically, a type of lymphocyte.

Many B cells mature into what are called plasma cells that produce antibodies (proteins) necessary to fight off infections while other B cells mature into memory B cells.

An antibody, also known as an immunoglobulin, is a large, Y-shaped protein produced mainly by plasma cells that is used by the immune system to neutralize pathogens such as pathogenic bacteria and viruses.

A treatment for an allergy in which a patient is gradually desensitized to an allergen through periodic injections with increasing amounts of the allergen; or treatment for cancer that attempts to stimulate the immune system to destroy cancer cells.

The treatment of disease by the use of chemical substances, especially the treatment of cancer by cytotoxic (cell-killing) and other drugs.

A microorganism which causes disease.

An organisms that is so small it is invisible to the human eye.

Any member of a large group of unicellular microorganisms which have cell walls but lack organelles and an organized nucleus, including some which can cause disease.

A tiny, nonliving particle that contains nucleic acids but lacks other characteristics of living cells and may cause human disease.

A group of diseases involving abnormal cell growth with the potential to invade or spread to other parts of the body.

A subset of the immune system that makes generic attacks such as inflammation against invading pathogens.

The state of being immune from or insusceptible to a particular disease or the like. the condition that permits either natural or acquired resistance to disease. the ability of a cell to react immunologically in the presence of an antigen.

A set of molecules normally found on most human cells that provide a way for the immune system to recognize body cells as self.

Molecules on the surface of cells or viruses that the immune system identifies as either self (produced by your own body) or non-self (not produced by your own body).

A T lymphocyte (a type of white blood cell), also known as a cytoxic T cell) that kills cancer cells, cells that are infected (particularly with viruses), or cells that are damaged in other ways.

A part of the immune system that protects the central nervous system.

One of two main divisions of the nervous system that includes the brain and spinal cord.

The part of the immune system that protects all of the body except for the central nervous system (which is protected by the neuroimmune system).

The process by which a cell uses its plasma membrane to engulf a large particle, giving rise to an internal compartment called the phagosome.

Refers to the body system consisting of the heart, blood vessels and the blood. Blood contains oxygen and other nutrients which your body needs to survive. The body takes these essential nutrients from the blood.

A straw-yellow fluid part of blood that contains many dissolved substances and blood cells.

A lymphatic capillary that absorbs dietary fats in the villi of the small intestine.

A microscopic, finger-like projections in a mucous membrane that form a large surface area for absorption.

A long, narrow, tube-like organ of the digestive system where most chemical digestion of food and virtually all absorption of nutrients take place.

A body system including a series of hollow organs joined in a long, twisting tube from the mouth to the anus. The hollow organs that make up the GI tract are the mouth, esophagus, stomach, small intestine, large intestine, and anus. The liver, pancreas, and gallbladder are the solid organs of the digestive system.

A type of lymphocyte that kills infected or cancerous cells (killer T cell) or helps regulate the immune response (helper T cell).

A soft connective tissue in spongy bone that produces blood cells.

An organ of the lymphatic system where lymphocytes called T cells mature.

Any organ where lymphocytes are formed and mature. They provide an environment for stem cells to divide and mature into B- and T- cells: There are two primary lymphatic organs: the red bone marrow and the thymus gland.

A set of organs which includes lymph nodes and the spleen) maintain mature naive lymphocytes and initiate an adaptive immune response.

A secondary organ of the lymphatic system where blood and lymph are filtered.

A physical barrier which pathogens cannot cross, protecting the body. These barriers include: The outer layer of the skin and mucous membranes.

The major organ of the integumentary system that covers and protects the body and helps maintain homeostasis, for example, by regulating body temperature.

Epithelial tissue that lines inner body surfaces and body openings and produces mucus.

A liquid waste product of the body that is formed by the kidneys and excreted by the other organs of the urinary system.

Salty fluid secreted into ducts by sweat glands in the dermis that excretes wastes and helps cool the body; also called perspiration.

A fluid secreted by salivary glands that keeps the mouth moist and contains the digestive enzymes amylase and lipase.

Fluid containing sperm and glandular secretions, which nourishes sperm and carries them through the urethra and out of the body.

The response of the innate immune system that establishes a physical barrier against the spread of infection and repairs tissue damage while causing redness, swelling, and warmth.

A chemical released by injured, infected, or immune cells that triggers inflammation or other immune responses.

A compound which is released by cells in response to injury and in allergic and inflammatory reactions, causing contraction of smooth muscle and dilation of capillaries.

An innate immune response that consists of a cascade of proteins that complement the killing of pathogens by antibodies.

The semipermeable membrane surrounding the cytoplasm of a cell.

A type of immune cell that is one of the first cell types to travel to the site of an infection. Neutrophils help fight infection by ingesting microorganisms and releasing enzymes that kill the microorganisms. A neutrophil is a type of white blood cell, a type of granulocyte, and a type of phagocyte.

A large phagocytic cell found in stationary form in the tissues or as a mobile white blood cell, especially at sites of infection.

A special type of immune cell that is found in tissues, such as the skin, and boosts immune responses by showing antigens on its surface to other cells of the immune system. A dendritic cell is a type of phagocyte and a type of antigen-presenting cell (APC).

A type of immune cell that has granules (small particles) with enzymes that are released during allergic reactions and asthma. A basophil is a type of white blood cell and a type of granulocyte.

A type of white blood cell  found in connective tissues all through the body, especially under the skin, near blood vessels and lymph vessels, in nerves, and in the lungs and intestines. Mast cells play an important role in how the immune system responds to certain pathogens by releasing chemicals such as histamines and cytokines during allergic reactions and certain immune responses.

A type of immune cell that has granules (small particles) with enzymes that can kill tumor cells or cells infected with a virus. A natural killer cell is a type of white blood cell.

A type of immune cell that has granules (small particles) with enzymes that are released during infections, allergic reactions, and asthma. An eosinophil is a type of white blood cell and a type of granulocyte.

A type of leukocyte produced by the lymphatic system that is a key cell in the adaptive immune response to a specific pathogen or tumor cell.

A type of immune cell that stimulates killer T cells, macrophages, and B cells to make immune responses. A helper T cell is a type of white blood cell and a type of lymphocyte.

A fully differentiated B cell that produces a single type of antibody.

A lymphocyte (B or T cell) that retains a “memory” of a specific pathogen after an infection is over and thus provides immunity to the pathogen.

The ability to resist a specific pathogen that results when an adaptive immune response to the pathogen produces memory lymphocytes for that pathogen.

Short-term immunity to a particular pathogen that results when antibodies or activated T cells are transferred to a person who has never been exposed to the pathogen.

Either of two species of Lentivirus that infect humans. Over time, they cause acquired immunodeficiency syndrome, a condition in which progressive failure of the immune system allows life-threatening opportunistic infections and cancers to thrive.

A damaging immune response by the body to a substance, especially pollen, fur, a particular food, or dust, to which it has become hypersensitive.

Any substance, typically an antigen, that causes an allergy.

An acute, potentially life-threatening hypersensitivity reaction, involving the release of mediators from mast cells, basophils and recruited inflammatory cells. Anaphylaxis is defined by a number of signs and symptoms, alone or in combination, which occur within minutes, or up to a few hours, after exposure to a provoking agent. It can be mild, moderate to severe, or severe. Most cases are mild but any anaphylaxis has the potential to become life-threatening.

A type of disease, such as Type 1 Diabetes, in which the immune system attacks the body’s own cells as though they were pathogens.

A group of more than 400 rare, chronic disorders in which part of the body’s immune system is missing or functions improperly. While not contagious, these diseases are caused by hereditary or genetic defects, and, although some disorders present at birth or in early childhood, the disorders can affect anyone, regardless of age or gender.

Occurs when the immune system is compromised due to an environmental factor. Examples of these outside forces include HIV, chemotherapy, severe burns or malnutrition.

The late stage of HIV infection that occurs when the body's immune system is badly damaged because of the virus.

Human Biology Copyright © 2020 by Christine Miller is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License , except where otherwise noted.

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High school biology

Course: high school biology   >   unit 8.

• Types of immune responses: Innate and adaptive, humoral vs. cell-mediated
• Role of phagocytes in innate or nonspecific immunity
• Self vs. non-self immunity
• Intro to viruses
• Viral replication: lytic vs lysogenic

The immune system review

• The immune system

Infectious disease

Nonspecific defense: the innate immune system, first line of defense, second line of defense, specific defense: the adaptive immune system, humoral immunity, cell-mediated immunity, viral structure, steps of viral infection.

• Attachment. Virus binds to receptor on cell surface.
• Entry. Virus enters cell by endocytosis. In the cytoplasm, the capsid comes apart, releasing the RNA genome.
• Replication and gene expression. The RNA genome is copied (this would be done by a viral enzyme, not shown) and translated into viral proteins using a host ribosome. The viral proteins produced include capsid proteins.
• Assembly. Capsid proteins and RNA genomes come together to make new viral particles.
• Release. The cell lyses (bursts), releasing the viral particles, which can then infect other host cells.
• The virus recognizes and binds to a host cell via a receptor molecule on the cell surface.
• The virus or its genetic material enters the cell.
• The viral genome is copied and its genes are expressed to make viral proteins.
• New viral particles are assembled from the genome copies and viral proteins.
• Completed viral particles exit the cell and can infect other cells.

Common mistakes and misconceptions

• Incorrect : All bacteria are pathogens.
• Correct : Most bacteria are actually harmless and, in fact, we would not survive without them! Bacteria help us digest food, produce vitamins, and act as fermenting agents in certain food preparations. Some bacteria also fill niches that would otherwise be open for pathogenic bacteria. For example, the use of antibiotics can wipe out gastrointestinal (GI) flora. This allows competing pathogenic bacteria to fill the empty niche, which can result in diarrhea and GI upset.
• Incorrect : We should stop vaccinating people for diseases which are now rare due to vaccines.
• Correct : Some diseases have been nearly eliminated through the use of vaccines. However, this does not mean that we should stop vaccinating against these diseases. Most of these diseases still do exist in the human population, and without the continued use of vaccines, people are at risk of getting and spreading the disease.
• Incorrect : Vaccines always provide permanent immunity to a disease.
• Correct : For some diseases, a single vaccine is sufficient, but for many diseases you must get vaccinated more than once to be protected. For example, the flu vaccine becomes less effective over time because of how rapidly the flu virus mutates. Therefore, the flu shot’s formulation changes each year to protect against specific viruses that are predicted to be prominent each year.

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Chapter 1: Overview of the Human Immune System

Learning Objectives

By the end of this chapter you will be able to:

• Define Immunology
• Describe the functions of the immune system
• The innate and adaptive responses
• The three lines of immunological defense
• Explain the role of the lymphatic tissues in both returning fluid to the circulatory system and in monitoring for infection
• Define hematopoiesis and name the two major lineages of immune cells
• Explain how the immune system exists in a balance between immune response and immune tolerance
• Describe how an imbalance in immune homeostasis lead to immunological disorders

JD is 45 years old and is considered a heavy smoker, having consumed an average 30 cigarettes per day for 20 years. JD was diagnosed with chronic obstructive pulmonary disease (COPD) and presents with respiratory symptoms, reduced exercise tolerance, and frequent respiratory infections. Frequent infection resulted in chronic bronchitis, a condition where the airway epithelial tissue has eroded and become inflamed. Sputum analysis of coughed up phlegm  identified large numbers of immune cells called neutrophils within the airway space. A blood test revealed elevated antibody levels but also identified antibodies that specifically attach to collagen and elastin, proteins on the surface of human airway epithelial cells.

• What examples of immune defense impairment are described in this case study?
• Why does the respiratory airway produce mucus when mucus plugs could obstruct the airway and impair normal breathing?
• Why is it concerning that JD is producing antibodies against human tissues?

Answers to these questions are at the end of the chapter .

1.1 The Immune System and its Functions

We exist in a world of microorganisms that are invisible to the human eye but impact our health in remarkable ways. Most microorganisms are harmless to a healthy person. However some, classified as pathogens , have evolved alongside us for million of years to adapt ways of overcoming our defenses, evading our immune system and causing debilitating or even life threatening infection.

What is Immunology?

Immunology is the study of immune barriers and responses that form the immune system to protect us from infection by microorganisms. Immunology also involves the study of dysfunction that may occur in the immune response as well as medical methodologies that aim to use or modulate components of our immune system to promote health.

Since pathogens are diverse and have independently developed many ways to infect the human body, the immune system has adapted a layered approach that uses a series of strategies to prevent infection.

Some of these strategies include:

Surface Barriers: These barriers may include physical barriers, like the skin and secreted mucus , or chemical barriers, like sebum (oil), enzymes, salty or acidic body fluids and antimicrobial substances. Even the harmless microbes that inhabit our body surface and form the microbiome create a protective barrier from infection.

Immune Sensing and Communication: Most immune cells as well as epithelial cells, which line the surface of the body, have special receptor proteins on the cell surface that allow them to recognize characteristic patterns associated with infection. Some patterns, called pathogen associated molecular patterns ( PAMPs ) include molecules that are typically found on the surface of pathogens but are not normally in the human body. Other patterns, called damage associated molecular patterns (DAMPs) indicate cell damage that might be resulting from infection or may place a person at greater risk for infection. On sensing PAMPs and/or DAMPs, immune cells communicate the risk of infection to other cells by secreting cytokines.

Fever Grading

• Normal temperature: 36.5-37.5
• Mild low-grade fever: 37.7-38.3
• Moderate fever: 38.8-39.4
• High fever: >40

Inflammation and Fever: Large numbers of immune cells are found in the bloodstream. When a pathogen is found in the body tissues, the affected cells secrete cytokines to temporarily remodel the local blood vessel through inflammation. Specifically,  during inflammation, blood vessels swell and become leaky, allowing more immune cells to flow into the affected tissue and combat the infection. Cytokines released into the bloodstream can spread the inflammation to other parts of the body. Some of these cytokines will also migrate to the brain and increase the body temperature to induce a fever. Higher body temperatures will slow down the growth of bacteria and viruses as the environment become unfavourable for growth.

Phagocytosis: Many immune cells will sense PAMPs or DAMPs and, upon detecting these foreign patterns, consume the target through the process of phagocytosis. During phagocytosis, the surface of the immune cell wraps around the foreign material to create a bubble inside the cell, called a phagosome. Within the phagosome, the foreign cell or substance is degraded with the aid of acid and digestive enzymes.

Adaptive Response: The adaptive immune response is highly specific to the offending pathogen. Typical responses may induce cells that directly engage and eliminate pathogens and infected cells as well as indirect elimination using antibodies. Adaptive responses typically require a period of time to initiate, following exposure to the pathogen or a vaccine antigen. However, after the initial adaptive response, immunological memory may be established to ensure a rapid and effective response on each subsequent future exposure.

1.2 Features of the Immune System

The immune response is most easily imagined at the level of a single tissue, but in reality the immune response spans the entire body and consists of integrated and cooperating tissues and organs. Central components of the immune system include the lymphatic system , which drains fluid form tissues and monitors this fluid for infection, and the hematopoietic cells that produce immune cells and regulates the balance between immune response and immune tolerance .

Lymphatic System

The human heart pumps blood through the body under high pressure. This causes blood fluid to leak into tissues, where it is then described as interstitial fluid . While most of the interstitial fluid is reabsorbed into the bloodstream, approximately 3L of fluid accumulates in the tissues and is absorbed by lymphatic vessels. The fluid is then filtered within lymph nodes and other lymphastic tissues before returning to the bloodstream.

The lymphatic tissues are a major site for the production and storage of immune cells, as well as monitoring for evidence of infection in the interstitial fluid.

Hematopoietic Cells

After birth, most of our immune cells are produced through the process of hematopoiesis that primarily occurs in the red bone marrow. In children, this process occurs in long bones. Hematopoiesis is mostly restricted to the cranial and pelvic bones in adults.

Hematopoiesis starts with a hematopoietic stem cell, which is called a pluripotent cell because it can produce red blood cells ( erythrocytes ), platelets ( thrombocytes ) and white blood cells ( leukocytes ). Leukocytes are the primary immune cells and they become specialized to form two specific stem cell populations, myeloid stem cells and lymphoid stem cells .

Myeloid Cells: Stem cells in these lineages produce red blood cells and platelets, as well as white blood cells that perform phagocytosis and mediate inflammation.

Lymphoid Cells: Stem cells in these lineages form the lymphocytes (T-cells and B-cells) and natural killer (NK) cells, which are largely associated with the development of immunity.

More details on hematopoiesis are available in Chapter 2 .

1.3 Classification of immune defenses

Innate and adaptive immune systems.

The immune system is often divided into two branches: (1) The innate immune system and (2) the adaptive immune system. The innate immune system is not specific to any particular pathogen and is largely developed at birth. The adaptive immune system involves responses that are develop after exposure to a pathogen and generate a stronger and more tailored response upon future exposures. This enhanced subsequent response involves a phenomenon called immunological memory and is responsible of the state that we usually refer to as “ immunity ” following infection or vaccine immunization.

Table 1.1 – Features of Innate and Adaptive Immune systems

The three lines of defense

The immune system is also frequently described as having three lines of defense , where some immunological defenses are ubiquitous , meaning they are always present, while others are induced only when the immune response is triggered by infection or another source.

The first line of defense involves surface barriers, listed above. Skin, sebum, mucus and other barriers are formed before infection and are ubiquitously present. However, these barriers may be fortified during infection. For example, a respiratory infection may result in enhanced mucus secretion that is coughed out as phlegm.

The second line of defense involves cells and chemicals that are ubiquitously  present but may also be rapidly induced during infection. The ubiquitous components make up the primary defense during the first four hours of infection. The induced response becomes more prominent after the first few hours. An example of this transition is seen in immune cells. Tissues often have resident immune cells that are already present and patrol for infectious agents. However, following infection these resident cells will become exhausted and a large number of new immune cells will be recruited from the bloodstream.

The third line of defense coincides with the adaptive immune response. If an infection becomes serious enough that it cannot be overcome by the innate defense mechanisms, specialized immune cells (e.g. monocytes, macrophages, dendritic cells) will interact with T-cells to trigger a stronger and more tailored response against the pathogen. The third line of defense involves enhanced stimulation of immune cells and production of antibodies or both. Helper T-cells secrete cytokines to induce and coordinate the adaptive immune response. B-cells secrete antibodies that mark a foreign cell or agent for immune destruction. Cytotoxic T-cells perform surveillance of all cells and eliminate cells that are infected or become tumor cells that might cause cancer.

Table 1.2 – Three Lines of Immune Defense

Immune Response and Immune Tolerance

The immune system needs to balance two opposing challenges, which are associated with inducing a rapid and effective response to infection while simultaneously minimize the immune response to human tissues and the harmless microbes of our microbiome.

A rapid immune response can be achieved through pre-formed immune components in their inactive forms. Examples of pre-formed components include leukocytes stored within lymph nodes and immune proteins that circulate in an inactive form. Infected cells and immune cells also release chemicals called cytokines that can rapidly accumulate in the tissues or bloodstream. Cytokines are potent inducers of the immune response.

In direct opposition to the immune response is the process of immune tolerance or immune homeostasis. Immune tolerance involves the suppression of the immune response. Immune tolerance is critical in suppressing immune cells following the resolution of an infection, preventing immune responses against human cells and tissues, and suppressing immune responses against harmless commensal microbes of the human microbiome. Immune tolerance is achieved by directly killing lymphocytes that react to human tissues during their development. In addition, specialized cells called regulatory T-cells detect and suppress the local immune responses to commensal microbes and ones own cells and tissue. Immune tolerance involves immune checkpoints where immune cells are inactivated through physical binding   and the secretion of immunosuppressive cytokines, such as interleukin 10 (IL-10).

Disorders of the Immune System

The immune system is complex and multifaceted. Any disruption to the immune barriers and immune responses resulting in immunodeficiency increases the risk for infection. For example, broken skin resulting from trauma or a burn injury can contribute to infection. Malnutrition that affects immune cell production can impair a person’s ability to mount a productive immune response. An individuals immune response fluctuates based on various factors including genetics, age, chronic stress and the environment.

An overactive immune response ( hypersensitivity ) can also contribute to immune disorders. Immune response to harmless substances in our environment results in allergies, while immune responses to harmless microbes on the body surface create inflammatory conditions. In some cases, human tissues may be inadvertently or even specifically targeted by the immune system, resulting in an autoimmune condition. Finally, an inability to control the intensity of the immune response during an infection or to resolve the immune response after infection can contribute to persistent and potentially lethal impairment of health.

• Forming barriers to infection along the body surface
• Sensing an infection and communicating between cells and tissues to develop a response
• Inducing inflammation and fever as responses to infection in order to recruit cells to the site of infection and impair the growth and dispersal of microbes
• Engaging cells that consume foreign particles and microbes by phagocytosis
• Inducing an adaptive immune response that produces a pathogen-specific response as well as a long-term immunological memory
• The lymphatic system drains fluid from the tissues
• Lymph nodes and lymphatic tissues filter and monitor lymphatic fluid
• Immune cells of the myeloid and lymphoid cell lineages are produced by hematopoiesis in the bone marrow
• The immune response aims to rapidly eliminate pathogens from the body
• Immune tolerance aims to prevent immune responses to self tissues and harmless microbes within the microbiome
• This balance is established by killing self-reactive lymphocytes during development as well as having cytokine signals that indicate whether an immune response should be enhanced or suppressed
• Under-activity of the immune response is called immunodeficiency and can result in more frequent or more severe infection
• Over-activity of the immune response is called hypersensitivity, resulting in persistent inflammation or autoimmune disease

Chapter Review

Case study review.

A slimy substance secreted by mucous membranes. They serve to moisten, lubricate and protect the gastrointestinal, respiratory and genitourinary tracts of the body.

Pathogen associated molecular patterns (PAMPs) are the general features that our innate immune system uses to identify foreign agents, like bacteria and viruses. PAMPs are different from "antigens", which are molecules that are specifically identified by cells and antibodies of the adaptive immune system.

Basic Concepts in Applied Immunology Copyright © 2023 by Simon Duffy and Supipi Duffy is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License , except where otherwise noted.

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Case Western Reserve University researchers study how the immune system responds to COVID-19

School of medicine awarded $2.6m; receives two of 13 grants nationally.

New research funded by the National Cancer Institute (NCI) aims to boost understanding of how the immune system responds to COVID-19, from the start of infection to recovery. Two projects totaling over $2.6 million are led by Case Western Reserve University and Cleveland Clinic researchers as part of the NCI’s Serological Sciences Network (SeroNet) , which awarded just 13 grants nationally. The network aims to combat the pandemic by improving the ability to test for infection, especially among diverse populations, and speed the development of treatments and vaccines. 

“Case Western Reserve is a leader in emerging infections, immune response and clinical cancer investigation,” said Stan Gerson, MD , interim dean of the School of Medicine and director of the Case Comprehensive Cancer Center and director of the National Center for Regenerative Medicine. “This funding from the National Cancer Institute allows us to pivot existing knowledge and resources to accelerate our understanding of COVID-19 infections to optimize our protections and response to this clinically devastating infection.” 

From the time a person is exposed to SARS-CoV-2, the virus that causes COVID-19, the immune system is hard at work performing early immunological events. Doctors and researchers have been unable to fully understand the immune response to CoV2 and why certain people show symptoms and others remain asymptomatic.

A team of investigators including Adam Burgener, PhD , Mark Cameron, PhD , David Canaday, MD, Jeff Jacobson, MD, Jon Karn, PhD , Christopher L. King, MD, PhD , and Curtis Tatsuoka, PhD at Case Western Reserve School of Medicine, acknowledges that a major gap exists in understanding antibody resistance to CoV2 and the series of immunological events that take place after exposure.

The team is focused on discerning how the earliest innate immune responses to CoV2 either positively or negatively affect development of humoral immunity. Their research involves following household contacts of clinical cases of CoV2 to determine innate and adaptive immune events associated with this early viral exposure over a 28-day period. They will track how this impacts the durability of immunity to CoV2 over several years.

“By characterizing the early immune response prior to onset of symptoms we hope to identify features that will predict symptomatic versus asymptomatic cases, disease severity and long-term immunity,” said King, who is helping to coordinate the team’s effort.

Recovery from COVID-19 can put extreme pressure on the immune system, especially for patients with pre-existing complications. Certain individuals, including those with impaired immune function and those with heart disease, appear to be at a higher risk for contracting COVID-19.

David Zidar, MD, an associate professor at the School of Medicine and an interventional cardiologist at Louis Stokes Cleveland VA Medical Center, and Timothy A. Chan, MD, PhD , director of the Center for Immunotherapy and Precision Immuno-Oncology at Cleveland Clinic and co-director of the National Center for Regenerative Medicine at Case Western Reserve, are investigating differences in immunologic function and risk factors for heart disease, and how these relate to COVID-19. They will also compare which patients develop heart involvement in response to COVID-19 versus those who do not, identifying ways the virus may directly or indirectly attack distant organs such as the heart.

The team’s research could have an impact for all COVID-19 patients with pre-existing conditions, not just those with heart disease.

“We are trying to understand the intrinsic mechanisms that explain why some develop life-threatening disease whereas others are minimally affected,” said Zidar. “We hope to develop strategies to identify and prevent severe illness from developing in those with COVID.”

                                                           ###

This research is supported by National Institutes of Health, National Cancer Institute grant awards U01CA260539 and U01CA260513.

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• Published: 18 April 2024

Single-cell immune repertoire analysis

• Sergio E. Irac   ORCID: orcid.org/0000-0001-5622-1409 1   na1 ,
• Megan Sioe Fei Soon 2   na1 ,
• Nicholas Borcherding 3 , 4 &
• Zewen Kelvin Tuong   ORCID: orcid.org/0000-0002-6735-6808 2 , 5  

Nature Methods ( 2024 ) Cite this article

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Single-cell T cell and B cell antigen receptor-sequencing data analysis can potentially perform in-depth assessments of adaptive immune cells that inform on understanding immune cell development to tracking clonal expansion in disease and therapy. However, it has been extremely challenging to analyze and interpret T cells and B cells and their adaptive immune receptor repertoires at the single-cell level due to not only the complexity of the data but also the underlying biology. In this Review, we delve into the computational breakthroughs that have transformed the analysis of single-cell T cell and B cell antigen receptor-sequencing data.

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Acknowledgements

We thank G. Sturm for the useful discussions and D. Maresco-Pennisi and C. Lee for helping to proofread the document. We acknowledge Children’s Hospital Foundation’s philanthropic contributions awarded to the Ian Frazer Centre for Children’s Immunotherapy Research.

Author information

These authors contributed equally: Sergio E. Irac, Megan Sioe Fei Soon.

Authors and Affiliations

Cancer Immunoregulation and Immunotherapy, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia

Sergio E. Irac

Ian Frazer Centre for Children’s Immunotherapy Research, Child Health Research Centre, Faculty of Medicine, The University of Queensland, Brisbane, Queensland, Australia

Megan Sioe Fei Soon & Zewen Kelvin Tuong

Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, USA

Nicholas Borcherding

Omniscope, Palo Alto, CA, USA

Frazer Institute, Faculty of Medicine, The University of Queensland, Brisbane, QLD, Australia

Zewen Kelvin Tuong

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S.E.I., N.B. and Z.K.T. wrote the original draft. S.E.I. and Z.K.T. synthesized the literature and designed the review structure. M.S.F.S., N.B. and Z.K.T. critically reviewed, revised and edited the manuscript. M.S.F.S. made and synthesized the figures and tables. Z.K.T. conceptualized the review, outlined the structure, provided overall direction and supervised the writing.

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Correspondence to Zewen Kelvin Tuong .

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N.B. is Head of Computational Biology at Omniscope and has consulted for Starling Biosciences and Santa Ana Bio. Z.K.T. has consulted for Synteny Biotechnology in the last 3 years. All other authors declare no competing interests.

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Irac, S.E., Soon, M.S.F., Borcherding, N. et al. Single-cell immune repertoire analysis. Nat Methods (2024). https://doi.org/10.1038/s41592-024-02243-4

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The impact of stress on body function: A review

Habib yaribeygi.

1 Neurosciences Research Center, Baqiyatallah University of Medical Sciences, Tehran, Iran

Yunes Panahi

2 Clinical Pharmacy Department, Faculty of Pharmacy, Baqiyatallah University of Medical Sciences, Tehran, Iran

Hedayat Sahraei

Thomas p. johnston.

3 Division of Pharmaceutical Sciences, School of Pharmacy, University of Missouri-Kansas City, Kansas City, Missouri, USA

Amirhossein Sahebkar

4 Biotechnology Research Center, Mashhad University of Medical Sciences, Mashhad, Iran

Any intrinsic or extrinsic stimulus that evokes a biological response is known as stress. The compensatory responses to these stresses are known as stress responses. Based on the type, timing and severity of the applied stimulus, stress can exert various actions on the body ranging from alterations in homeostasis to life-threatening effects and death. In many cases, the pathophysiological complications of disease arise from stress and the subjects exposed to stress, e.g. those that work or live in stressful environments, have a higher likelihood of many disorders. Stress can be either a triggering or aggravating factor for many diseases and pathological conditions. In this study, we have reviewed some of the major effects of stress on the primary physiological systems of humans.

Abbreviations

ACTH: Adrenocorticotropic hormone

CNS: Central nervous system

CRH: Corticotropin releasing hormone

GI: Gastrointestinal

LTP: Long-term potentiation

NMDA : N-methyl-D-aspartate

VTA: Ventral tegmental area

Stress and the Brain Function Complications

For a long time, researchers suggested that hormones have receptors just in the peripheral tissues and do not gain access to the central nervous system (CNS) (Lupien and Lepage, 2001[ 63 ]). However, observations have demonstrated the effect of anti-inflammatory drugs (which are considered synthetic hormones) on behavioral and cognitive disorders and the phenomenon called “Steroid psychosis” (Clark et al., 1952[ 16 ]). In the early sixties, neuropeptides were recognized as compounds devoid of effects on the peripheral endocrine system. However, it was determined that hormones are able to elicit biological effects on different parts of the CNS and play an important role in behavior and cognition (De Kloet, 2000[ 22 ]). In 1968, McEven suggested for the first time that the brain of rodents is capable of responding to glucocorticoid (as one of the operators in the stress cascade). This hypothesis that stress can cause functional changes in the CNS was then accepted (McEwen et al., 1968[ 74 ]). From that time on, two types of corticotropic receptors (glucocorticosteroids and mineralocorticoids) were recognized (de Kloet et al., 1999[ 23 ]). It was determined that the affinity of glucocorticosteroid receptors to cortisol and corticosterone was about one tenth of that of mineralocorticoids (de Kloet et al., 1999[ 23 ]). The hippocampus area has both types of receptors, while other points of the brain have only glucocorticosteroid receptors (de Kloet et al., 1999[ 23 ]).

The effects of stress on the nervous system have been investigated for 50 years (Thierry et al., 1968[ 115 ]). Some studies have shown that stress has many effects on the human nervous system and can cause structural changes in different parts of the brain (Lupien et al., 2009[ 65 ]). Chronic stress can lead to atrophy of the brain mass and decrease its weight (Sarahian et al., 2014[ 100 ]). These structural changes bring about differences in the response to stress, cognition and memory (Lupien et al., 2009[ 65 ]). Of course, the amount and intensity of the changes are different according to the stress level and the duration of stress (Lupien et al., 2009[ 65 ]). However, it is now obvious that stress can cause structural changes in the brain with long-term effects on the nervous system (Reznikov et al., 2007[ 89 ]). Thus, it is highly essential to investigate the effects of stress on different aspects of the nervous system (Table 1 (Tab. 1) ; References in Table 1: Lupien et al., 2001[ 63 ]; Woolley et al., 1990[ 122 ]; Sapolsky et al., 1990[ 99 ]; Gould et al., 1998[ 35 ]; Bremner, 1999[ 10 ]; Seeman et al., 1997[ 108 ]; Luine et al., 1994[ 62 ]; Li et al., 2008[ 60 ]; Scholey et al., 2014[ 101 ]; Borcel et al., 2008[ 9 ]; Lupien et al., 2002[ 66 ]).

Stress and Memory

Memory is one of the important functional aspects of the CNS and it is categorized as sensory, short term, and long-term. Short term memory is dependent on the function of the frontal and parietal lobes, while long-term memory depends on the function of large areas of the brain (Wood et al., 2000[ 121 ]). However, total function of memory and the conversion of short term memory to long-term memory are dependent on the hippocampus; an area of the brain that has the highest density of glucocorticosteroid receptors and also represents the highest level of response to stress (Scoville and Milner, 1957[ 107 ]; Asalgoo et al., 2015[ 1 ]). Therefore, during the past several decades, the relationship between the hippocampus and stress have been hotly debated (Asalgoo et al., 2015[ 1 ]; Lupien and Lepage, 2001[ 63 ]). In 1968, it was proven that there were cortisol receptors in the hippocampus of rats (McEwen et al., 1968[ 74 ]). Later, in 1982, by using specific agonists of glucocorticosteroid and mineralocorticoid receptors, the existence of these two receptors in the brain and hippocampus area of rats was proven (Veldhuis et al., 1982[ 119 ]). It should also be noted that the amygdala is very important to assessing the emotional experiences of memory (Roozendaal et al., 2009[ 91 ]).

The results of past studies have demonstrated the effect of stress on the process of memory (Ghodrat et al., 2014[ 32 ]). Various studies have shown that stress can cause functional and structural changes in the hippocampus section of the brain (McEwen, 1999[ 72 ]). These structural changes include atrophy and neurogenesis disorders (Lupien and Lepage, 2001[ 63 ]). Also, chronic stress and, consequently, an increase in plasma cortisol, leads to a reduction in the number of dendritic branches (Woolley et al., 1990[ 122 ]) and the number of neurons (Sapolsky et al., 1990[ 99 ]), as well as structural changes in synaptic terminals (Sapolsky et al., 1990[ 99 ]) and decreased neurogenesis in the hippocampus tissue (Gould et al., 1998[ 35 ]). Glucocorticosteroids can induce these changes by either effecting the cellular metabolism of neurons (Lawrence and Sapolsky, 1994[ 58 ]), or increasing the sensitivity of hippocampus cells to stimulatory amino acids (Sapolsky and Pulsinelli, 1985[ 98 ]) and/or increasing the level of extracellular glutamate (Sapolsky and Pulsinelli, 1985[ 98 ]).

High concentrations of stress hormones can cause declarative memory disorders (Lupien and Lepage, 2001[ 63 ]). Animal studies have shown that stress can cause a reversible reduction in spatial memory as a result of atrophy of the hippocampus (Luine et al., 1994[ 62 ]). In fact, high plasma concentrations of glucocorticosteroids for extended periods of time can cause atrophy of the hippocampus leading to memory disorders (Issa et al., 1990[ 45 ]). Additionally, people with either Cushing's syndrome (with an increased secretion of glucocorticosteroids), or people who receive high dosages of exogenous synthetic anti-inflammatory drugs, are observed to have atrophy of the hippocampus and associated memory disorders (Ling et al., 1981[ 61 ]). MRI images taken from the brains of people with post-traumatic stress disorder (PTSD) have demonstrated a reduction in the volume of the hippocampus along with neurophysiologic effects such as a weak verbal memory (Bremner, 1999[ 10 ]). Several human studies have suggested that even common therapeutic doses of glucocorticosteroids and dexamethasone can cause problems with explicit memory (Keenan et al., 1995[ 49 ]; Kirschbaum et al., 1996[ 53 ]). Thus, there is an inverse relationship between the level of cortisol and memory (Ling et al., 1981[ 61 ]), such that increasing levels of plasma cortisol following prolonged stress leads to a reduction in memory (Kirschbaum et al., 1996[ 53 ]), which improves when the level of plasma cortisol decreases (Seeman et al., 1997[ 108 ]).

Stress also has negative effects on learning. Results from hippocampus-dependent loading data demonstrate that subjects are not as familiar with a new environment after having been exposed to a new environment (Bremner, 1999[ 10 ]). Moreover, adrenal steroids lead to alteration in long-term potentiation (LTP), which is an important process in memory formation (Bliss and Lømo, 1973[ 7 ]).

Two factors are involved in the memory process during stress. The first is noradrenaline, which creates emotional aspects of memories in the basolateral amygdala area (Joëls et al., 2011[ 47 ]). Secondly, this process is facilitated by corticosteroids. However, if the release of corticosteroids occurs a few hours earlier, it causes inhibition of the amygdala and corresponding behaviors (Joëls et al., 2011[ 47 ]). Thus, there is a mutual balance between these two hormones for creating a response in the memory process (Joëls et al., 2011[ 47 ]).

Stress does not always affect memory. Sometimes, under special conditions, stress can actually improve memory (McEwen and Lupien, 2002[ 71 ]). These conditions include non-familiarity, non-predictability, and life-threatening aspects of imposed stimulation. Under these specific conditions, stress can temporarily improve the function of the brain and, therefore, memory. In fact, it has been suggested that stress can sharpen memory in some situations (Schwabe et al., 2010[ 105 ]). For example, it has been shown that having to take a written examination can improve memory for a short period of time in examination participants. Interestingly, this condition is associated with a decrease in the level of cortisol in the saliva (Vedhara et al., 2000[ 118 ]). Other studies have shown that impending stress before learning occurs can also lead to either an increase in the power of memory (Domes et al., 2002[ 27 ]; Schwabe et al., 2008[ 102 ]), or decrease in the capacity for memory (Diamond et al., 2006[ 26 ]; Kirschbaum et al., 1996[ 53 ]). This paradox results from the type of imposed stress and either the degree of emotional connection to the stressful event (Payne et al., 2007[ 83 ]; Diamond et al., 2007[ 25 ]), or the period of time between the imposing stress and the process of learning (Diamond et al., 2007[ 25 ]).

The process of strengthening memory is usually reinforced after stress (Schwabe et al., 2012[ 103 ]). Various studies on animal and human models have shown that administration of either glucocorticosteroids, or stress shortly after learning has occurred facilitates memory (Schwabe et al., 2012[ 103 ]). Also, it has been shown that glucocorticosteroids (not mineralocorticoids) are necessary to improve learning and memory (Lupien et al., 2002[ 66 ]). However, the retrieval of events in memory after exposure to stress will be decreased (Schwabe et al., 2012[ 103 ]), which may result from the competition of updated data for storage in memory in a stressful state (de Kloet et al., 1999[ 23 ]). Some investigations have shown that either exposure to stress, or injection of glucocorticosteroids before a test to assess retention, decreases the power of memory in humans and rodents (Schwabe and Wolf, 2009[ 104 ]).

In summary, it has been concluded that the effect of stress on memory is highly dependent on the time of exposure to the stressful stimulus and, in terms of the timing of the imposed stress, memory can be either better or worse (Schwabe et al., 2012[ 103 ]). Moreover, recent studies have shown that using a specific-timed schedule of exposure to stress not only affects hippocampus-dependent memory, but also striatum-dependent memory, which highlights the role of timing of the imposed stressful stimulus (Schwabe et al., 2010[ 105 ]).

Stress, Cognition and Learning

Cognition is another important feature of brain function. Cognition means reception and perception of perceived stimuli and its interpretation, which includes learning, decision making, attention, and judgment (Sandi, 2013[ 95 ]). Stress has many effects on cognition that depend on its intensity, duration, origin, and magnitude (Sandi, 2013[ 95 ]). Similar to memory, cognition is mainly formed in the hippocampus, amygdala, and temporal lobe (McEwen and Sapolsky, 1995[ 73 ]). The net effect of stress on cognition is a reduction in cognition and thus, it is said that any behavioral steps undertaken to reduce stress leads to increase in cognition (Scholey et al., 2014[ 101 ]). In fact, stress activates some physiological systems, such as the autonomic nervous system, central neurotransmitter and neuropeptide system, and the hypothalamus-pituitary-adrenal axis, which have direct effects on neural circuits in the brain involved with data processing (Sandi, 2013[ 95 ]). Activation of stress results in the production and release of glucocorticosteroids. Because of the lipophilic properties of glucocorticosteroids, they can diffuse through the blood-brain barrier and exert long-term effects on processing and cognition (Sandi, 2013[ 95 ]).

It appears that being exposed to stress can cause pathophysiologic changes in the brain, and these changes can be manifested as behavioral, cognitive, and mood disorders (Li et al., 2008[ 60 ]). In fact, studies have shown that chronic stress can cause complications such as increased IL-6 and plasma cortisol, but decreased amounts of cAMP responsive element binding protein and brain-derived neurotrophic factor (BDNF), which is very similar to what is observed in people with depression and mood disorders that exhibit a wide range of cognitive problems (Song et al., 2006[ 114 ]). Additionally, the increased concentrations of inflammatory factors, like interleukins and TNF-α (which play an important role in creating cognitive disorders), proves a physiologic relationship between stress and mood-based cognitive disorders (Solerte et al., 2000[ 113 ]; Marsland et al., 2006[ 68 ]; Li et al., 2008[ 60 ]). Studies on animals suggest that cognitive disorders resulting from stress are created due to neuroendocrine and neuroamine factors and neurodegenerative processes (Li et al., 2008[ 60 ]). However, it should be noted that depression may not always be due to the over activation of the physiological-based stress response (Osanloo et al., 2016[ 81 ]).

Cognitive disorders following exposure to stress have been reported in past studies (Lupien and McEwen, 1997[ 64 ]). Stress has effects on cognition both acutely (through catecholamines) and chronically (through glucocorticosteroids) (McEwen and Sapolsky, 1995[ 73 ]). Acute effects are mainly caused by beta-adrenergic effects, while chronic effects are induced in a long-term manner by changes in gene expression mediated by steroids (McEwen and Sapolsky, 1995[ 73 ]). In general, many mechanisms modulate the effects of stress on cognition (McEwen and Sapolsky, 1995[ 73 ]; Mendl, 1999[ 75 ]). For instance, adrenal steroids affect the function of the hippocampus during cognition and memory retrieval in a biphasic manner (McEwen and Sapolsky, 1995[ 73 ]). In chronic stress, these steroids can destroy neurons with other stimulatory neurotransmitters (Sandi, 2013[ 95 ]). Exposure to stress can also cause disorders in hippocampus-related cognition; specifically, spatial memory (Borcel et al., 2008[ 9 ]; Sandi et al., 2003[ 96 ]). Additionally, stress can halt or decrease the genesis of neurons in the dentate gyrus area of the hippocampus (this area is one of the limited brain areas in which neurogenesis occurs in adults) (Gould and Tanapat, 1999[ 34 ]; Köhler et al., 2010[ 54 ]). Although age is a factor known to affect cognition, studies on animals have demonstrated that young rats exposed to high doses of adrenal steroids show the same level of decline in their cognition as older adult animals with normal plasma concentrations of glucocorticoids (Landfield et al., 1978[ 57 ]). Also, a decrease in the secretion of glucocorticosteroids causes preservation of spatial memory in adults and has also been shown to have neuroprotective effects (Montaron et al., 2006[ 78 ]). Other studies have shown that stress (or the injection of adrenal steroids) results in varied effects on cognition. For instance, injection of hydrocortisone at the time of its maximum plasma concentration (in the afternoon) leads to a decrease in reaction time and improves cognition and memory (Lupien et al., 2002[ 66 ]).

In summary, the adverse effects of stress on cognition are diverse and depend on the type, timing, intensity, and duration (Sandi, 2013[ 95 ]). Generally, it is believed that mild stress facilitates an improvement in cognitive function, especially in the case of virtual or verbal memory. However, if the intensity of stress passes beyond a predetermined threshold (which is different in each individual), it causes cognitive disorders, especially in memory and judgment. The disruption to memory and judgment is due to the effects of stress on the hippocampus and prefrontal cortex (Sandi, 2013[ 95 ]). Of course, it must be realized that factors like age and gender may also play a role in some cognitive disorders (Sandi, 2013[ 95 ]). Importantly, it should be emphasized that different people may exhibit varied responses in cognition when exposed to the very same stressful stimulus (Hatef et al., 2015[ 39 ]).

Stress and Immune System Functions

The relationship between stress and the immune system has been considered for decades (Khansari et al., 1990[ 50 ]; Dantzer and Kelley, 1989[ 21 ]). The prevailing attitude between the association of stress and immune system response has been that people under stress are more likely to have an impaired immune system and, as a result, suffer from more frequent illness (Khansari et al., 1990[ 50 ]). Also, old anecdotes describing resistance of some people to severe disease using the power of the mind and their thought processes, has promoted this attitude (Khansari et al., 1990[ 50 ]). In about 200 AC, Aelius Galenus (Galen of Pergamon) declared that melancholic women (who have high levels of stress and, thus, impaired immune function) are more likely to have cancer than women who were more positive and exposed to less stress (Reiche et al., 2004[ 88 ]). This may be the first recorded case about the relationship between the immune system and stress. In an old study in the early 1920's, researchers found that the activity of phagocytes in tuberculosis decreased when emotional stress was induced. In fact, it was also suggested that living with stress increases the risk of tuberculosis by suppressing the immune system (Ishigami, 1919[ 44 ]). Following this study, other researchers suggested that the probability of disease appearance increases following a sudden, major, and extremely stressful life style change (Holmes and Rahe, 1967[ 41 ]; Calabrese et al., 1987[ 12 ]).

Over the past several decades, there have been many studies investigating the role of stress on immune system function (Dantzer and Kelley, 1989[ 21 ]; Segerstrom and Miller, 2004[ 109 ]). These studies have shown that stress mediators can pass through the blood-brain barrier and exert their effects on the immune system (Khansari et al., 1990[ 50 ]). Thus, the effect of stress on the immune system is now an accepted relationship or association.

Stress can affect the function of the immune system by modulating processes in the CNS and neuroendocrine system (Khansari et al., 1990[ 50 ]; Kiecolt-Glaser and Glaser, 1991[ 51 ]). Following stress, some neuroendocrine and neural responses result in the release of corticotropin-releasing hormone (CRH), adrenocorticotropic hormone (ACTH), and other stress mediators (Carrasco and Van de Kar, 2003[ 13 ]). However, evidence suggests that the lymphatic system, which is a part of the immune system, also plays a role in releasing these mediators (Khansari et al., 1990[ 50 ]). For instance, thymus peptides, such as thymopentine, thymopoietin, and thymosin fraction-5, cause an increase in ACTH production (Goya et al., 1993[ 36 ]). Additionally, the existence of CRH in thymus has been proven (Redei, 1992[ 87 ]). It has also been proven that interleukin-1 released from phagocytes has a role in ACTH secretion (Berkenbosch et al., 1987[ 4 ]). On the other hand, natural or synthetic glucocorticosteroids (which are the final stress operators) are known as anti-inflammatory drugs and immune suppressants and their role in the inhibition of lymphocytes and macrophages has been demonstrated as well (Elenkov et al., 1999[ 28 ]; Reiche et al., 2004[ 88 ]). Moreover, their role in inhibiting the production of cytokines and other immune mediators and decreasing their effect on target cells during exposure to stress has also been determined (Reiche et al., 2004[ 88 ]).

In addition to adrenal steroids, other hormones are affected during stress. For example, the secretion of growth hormone will be halted during severe stress. A study showed that long-term administration of CRH into the brain ventricles leads to a cessation in the release of growth hormone (Rivier and Vale, 1985[ 90 ]). Stress also causes the release of opioid peptides to be changed during the time period over which the person is exposed to stress (McCarthy et al., 2001[ 70 ]). In fact, stress modifies the secretion of hormones that play a critical role in the function of the immune system (Khansari et al., 1990[ 50 ]). To date, it has been shown that various receptors for a variety of hormones involved in immune system function are adversely affected by stress. For example, ACTH, vasoactive intestinal peptide (VIP), substance P, growth hormone, prolactin, and steroids all have receptors in various tissues of the immune system and can modulate its function (De la Fuente et al., 1996[ 24 ]; Gala, 1991[ 30 ]; Mantyh, 1991[ 67 ]). In addition, active immune cells are also able to secrete several hormones; thus, some researchers believe that these hormones, as mediators of immune system, play a significant role in balancing its function (Blalock et al., 1985[ 6 ]).

Severe stress can lead to malignancy by suppressing the immune system (Reiche et al., 2004[ 88 ]). In fact, stress can decrease the activity of cytotoxic T lymphocytes and natural killer cells and lead to growth of malignant cells, genetic instability, and tumor expansion (Reiche et al., 2004[ 88 ]). Studies have shown that the plasma concentration of norepinephrine, which increases after the induction stress, has an inverse relationship with the immune function of phagocytes and lymphocytes (Reiche et al., 2004[ 88 ]). Lastly, catecholamines and opioids that are released following stress have immune-suppressing properties (Reiche et al., 2004[ 88 ]).

Stress and the Function of the Cardiovascular System

The existence of a positive association between stress and cardiovascular disease has been verified (Rozanski et al., 1999[ 93 ]). Stress, whether acute or chronic, has a deleterious effect on the function of the cardiovascular system (Rozanski et al., 1999[ 93 ]; Kario et al., 2003[ 48 ]; Herd, 1991[ 40 ]). The effects of stress on the cardiovascular system are not only stimulatory, but also inhibitory in nature (Engler and Engler, 1995[ 29 ]). It can be postulated that stress causes autonomic nervous system activation and indirectly affects the function of the cardiovascular system (Lazarus et al., 1963[ 59 ]; Vrijkotte et al., 2000[ 120 ]). If these effects occur upon activation of the sympathetic nervous system, then it mainly results in an increase in heart rate, strength of contraction, vasodilation in the arteries of skeletal muscles, a narrowing of the veins, contraction of the arteries in the spleen and kidneys, and decreased sodium excretion by the kidneys (Herd, 1991[ 40 ]). Sometimes, stress activates the parasympathetic nervous system (Pagani et al., 1991[ 82 ]). Specifically, if it leads to stimulation of the limbic system, it results in a decrease, or even a total stopping of the heart-beat, decreased contractility, reduction in the guidance of impulses by the heart stimulus-transmission network, peripheral vasodilatation, and a decline in blood pressure (Cohen et al., 2000[ 17 ]). Finally, stress can modulate vascular endothelial cell function and increase the risk of thrombosis and ischemia, as well as increase platelet aggregation (Rozanski et al., 1999[ 93 ]).

The initial effect of stress on heart function is usually on the heart rate (Vrijkotte et al., 2000[ 120 ]). Depending upon the direction of the shift in the sympatho-vagal response, the heart beat will either increase or decrease (Hall et al., 2004[ 38 ]). The next significant effect of stress on cardiovascular function is blood pressure (Laitinen et al., 1999[ 56 ]). Stress can stimulate the autonomic sympathetic nervous system to increase vasoconstriction, which can mediate an increase in blood pressure, an increase in blood lipids, disorders in blood clotting, vascular changes, atherogenesis; all, of which, can cause cardiac arrhythmias and subsequent myocardial infarction (Rozanski et al., 1999[ 93 ]; Vrijkotte et al., 2000[ 120 ]; Sgoifo et al., 1998[ 111 ]). These effects from stress are observed clinically with atherosclerosis and leads to an increase in coronary vasoconstriction (Rozanski et al., 1999[ 93 ]). Of course, there are individual differences in terms of the level of autonomic-based responses due to stress, which depends on the personal characteristics of a given individual (Rozanski et al., 1999[ 93 ]). Thus, training programs for stress management are aimed at reducing the consequences of stress and death resulting from heart disease (Engler and Engler, 1995[ 29 ]). In addition, there are gender-dependent differences in the cardiovascular response to stress and, accordingly, it has been estimated that women begin to exhibit heart disease ten years later that men, which has been attributed to the protective effects of the estrogen hormone (Rozanski et al., 1999[ 93 ]).

Studies have shown that psychological stress can cause alpha-adrenergic stimulation and, consequently, increase heart rate and oxygen demand (Rozanski et al., 1998[ 92 ], 1999[ 93 ]; Jiang et al., 1996[ 46 ]). As a result, coronary vasoconstriction is enhanced, which may increase the risk of myocardial infarction (Yeung et al., 1991[ 124 ]; Boltwood et al., 1993[ 8 ]; Dakak et al., 1995[ 20 ]). Several studies have demonstrated that psychological stress decreases the microcirculation in the coronary arteries by an endothelium-dependent mechanism and increases the risk of myocardial infarction (Dakak et al., 1995[ 20 ]). On the other hand, mental stress indirectly leads to potential engagement in risky behaviors for the heart, such as smoking, and directly leads to stimulation of the neuroendocrine system as part of the autonomic nervous system (Hornstein, 2004[ 43 ]). It has been suggested that severe mental stress can result in sudden death (Pignalberi et al., 2002[ 84 ]). Generally, stress-mediated risky behaviors that impact cardiovascular health can be summarized into five categories: an increase in the stimulation of the sympathetic nervous system, initiation and progression of myocardial ischemia, development of cardiac arrhythmias, stimulation of platelet aggregation, and endothelial dysfunction (Wu, 2001[ 123 ]).

Stress and Gastrointestinal Complications

The effects of stress on nutrition and the gastrointestinal (GI) system can be summarized with two aspects of GI function.

First, stress can affect appetite (Bagheri Nikoo et al., 2014[ 2 ]; Halataei et al., 2011[ 37 ]; Ranjbaran et al., 2013[ 86 ]). This effect is related to involvement of either the ventral tegmental area (VTA), or the amygdala via N-methyl-D-aspartate (NMDA) glutamate receptors (Nasihatkon et al., 2014[ 80 ]; Sadeghi et al., 2015[ 94 ]). However, it should also be noted that nutrition patterns have effects on the response to stress (Ghanbari et al., 2015[ 31 ]), and this suggests a bilateral interaction between nutrition and stress.

Second, stress adversely affects the normal function of GI tract. There are many studies concerning the effect of stress on the function of the GI system (Söderholm and Perdue, 2001[ 112 ]; Collins, 2001[ 18 ]). For instance, studies have shown that stress affects the absorption process, intestinal permeability, mucus and stomach acid secretion, function of ion channels, and GI inflammation (Collins, 2001[ 18 ]; Nabavizadeh et al., 2011[ 79 ]). Stress also increases the response of the GI system to inflammation and may reactivate previous inflammation and accelerate the inflammation process by secretion of mediators such as substance P (Collins, 2001[ 18 ]). As a result, there is an increase in the permeability of cells and recruitment of T lymphocytes. Lymphocyte aggregation leads to the production of inflammatory markers, activates key pathways in the hypothalamus, and results in negative feedback due to CRH secretion, which ultimately results in the appearance of GI inflammatory diseases (Collins, 2001[ 18 ]). This process can reactivate previous silent colitis (Million et al., 1999[ 76 ]; Qiu et al., 1999[ 85 ]). Mast cells play a crucial role in stress-induced effects on the GI system, because they cause neurotransmitters and other chemical factors to be released that affect the function of the GI system (Konturek et al., 2011[ 55 ]).

Stress can also alter the functional physiology of the intestine (Kiliaan et al., 1998[ 52 ]). Many inflammatory diseases, such as Crohn's disease and other ulcerative-based diseases of the GI tract, are associated with stress (Hommes et al., 2002[ 42 ]). It has been suggested that even childhood stress can lead to these diseases in adulthood (Schwartz and Schwartz, 1983[ 106 ]). Irritable bowel syndrome, which is a disease with an inflammatory origin, is highly related to stress (Gonsalkorale et al., 2003[ 33 ]). Studies on various animals suggest the existence of inflammatory GI diseases following induction of severe stress (Qiu et al., 1999[ 85 ]; Collins et al., 1996[ 19 ]). Additionally, pharmacological interventions, in an attempt to decrease the response of CRH to stress, have been shown to result in an increase in GI diseases in rats (Million et al., 1999[ 76 ]).

Altering the permeability of the mucosal membrane by perturbing the functions of mucosal mast cells may be another way that stress causes its effects on the GI system, since this is a normal process by which harmful and toxic substances are removed from the intestinal lumen (Söderholm and Perdue, 2001[ 112 ]). Also, stress can both decrease the removal of water from the lumen, as well as induce sodium and chloride secretion into the lumen. This most likely occurs by increasing the activity of the parasympathetic nervous system (Barclay and Turnberg, 1987[ 3 ]). Moreover, physical stress, such as trauma or surgery, can increase luminal permeability (Söderholm and Perdue, 2001[ 112 ]) (Table 2 (Tab. 2) ; References in Table 2: Halataei et al., 2011[ 37 ]; Ranjbaran et al., 2013[ 86 ]; Mönnikes et al., 2001[ 77 ]; Collins, 2001[ 18 ]; Nabavizadeh et al., 2011[ 79 ]; Barclay and Turnberg, 1987[ 3 ]; Million et al., 1999[ 76 ]; Gonsalkorale et al., 2003[ 33 ]).

Stress also affects movement of the GI tract. In this way, it prevents stomach emptying and accelerates colonic motility (Mönnikes et al., 2001[ 77 ]). In the case of irritable bowel syndrome, stress increases the movement (contractility and motility) of the large intestine (Mönnikes et al., 2001[ 77 ]). Previous studies have revealed that CRH increases movement in the terminal sections of the GI tract and decreases the movements in the proximal sections of the GI tract (Mönnikes et al., 2001[ 77 ]). A delay in stomach emptying is likely accomplished through CRH-2 receptors, while type 1 receptors affect the colon (Mönnikes et al., 2001[ 77 ]). The effects produced by CRH are so prominent that CRH is now considered an ideal candidate for the treatment of irritable bowel syndrome (Martinez and Taché, 2006[ 69 ]). When serotonin is released in response to stress (Chaouloff, 2000[ 14 ]), it leads to an increase in the motility of the colon by stimulating 5HT-3 receptors (Mönnikes et al., 2001[ 77 ]). Moreover, it has also been suggested that stress, especially mental and emotional types of stress, increase visceral sensitivity and activate mucosal mast cells (Mönnikes et al., 2001[ 77 ]). Stimulation of the CNS by stress has a direct effect on GI-specific nervous system ( i.e. , the myenteric system or plexus) and causes the above mentioned changes in the movements of the GI tract (Bhatia and Tandon, 2005[ 5 ]). In fact, stress has a direct effect on the brain-bowel axis (Konturek et al., 2011[ 55 ]). Various clinical studies have suggested a direct effect of stress on irritable bowel syndrome, intestinal inflammation, and peptic ulcers (Konturek et al., 2011[ 55 ]).

In conclusion, the effects of stress on the GI system can be classified into six different actions: GI tract movement disorders, increased visceral irritability, altered rate and extent of various GI secretions, modified permeability of the intestinal barrier, negative effects on blood flow to the GI tract, and increased intestinal bacteria counts (Konturek et al., 2011[ 55 ]).

Stress and the Endocrine System

There is a broad and mutual relationship between stress and the endocrine system. On one hand, stress has many subtle and complex effects on the activity of the endocrine system (Sapolsky, 2002[ 97 ]; Charmandari et al., 2005[ 15 ]), while on the other hand, the endocrine system has many effects on the response to stress (Ulrich-Lai and Herman, 2009[ 117 ]; Selye, 1956[ 110 ]). Stress can either activate, or change the activity of, many endocrine processes associated with the hypothalamus, pituitary and adrenal glands, the adrenergic system, gonads, thyroid, and the pancreas (Tilbrook et al., 2000[ 116 ]; Brown-Grant et al., 1954[ 11 ]; Thierry et al., 1968[ 115 ]; Lupien and McEwen, 1997[ 64 ]). In fact, it has been suggested that it is impossible to separate the response to stress from the functions of the endocrine system. This premise has been advanced due to the fact that even a minimal amount of stress can activate the hypothalamic-pituitary-adrenal axis, which itself is intricately involved with the activation of several different hormone secreting systems (Sapolsky, 2002[ 97 ]). In different locations throughout this article, we have already discussed the effects of stress on hormones and various endocrine factors and, thus, they will not be further addressed.

Altogether, stress may induce both beneficial and harmful effects. The beneficial effects of stress involve preserving homeostasis of cells/species, which leads to continued survival. However, in many cases, the harmful effects of stress may receive more attention or recognition by an individual due to their role in various pathological conditions and diseases. As has been discussed in this review, various factors, for example, hormones, neuroendocrine mediators, peptides, and neurotransmitters are involved in the body's response to stress. Many disorders originate from stress, especially if the stress is severe and prolonged. The medical community needs to have a greater appreciation for the significant role that stress may play in various diseases and then treat the patient accordingly using both pharmacological (medications and/or nutraceuticals) and non-pharmacological (change in lifestyle, daily exercise, healthy nutrition, and stress reduction programs) therapeutic interventions. Important for the physician providing treatment for stress is the fact that all individuals vary in their response to stress, so a particular treatment strategy or intervention appropriate for one patient may not be suitable or optimal for a different patient.

Yunes Panahi and Amirhossein Sahebkar (Department of Medical Biotechnology, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran, P.O. Box: 91779-48564, Iran; Tel: 985118002288, Fax: 985118002287, E-mail: [email protected], [email protected]) contributed equally as corresponding authors.

Conflict of interest

The authors declare that have no conflict of interest in this study.

Acknowledgement

The authors would like to thank the "Neurosciences Research Center of Baqiyatallah University of Medical Sciences" and the “Clinical Research Development Center of Baqiyatallah (a.s.) Hospital” for providing technical supports.

What caused Dubai floods? Experts cite climate change, not cloud seeding

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DID CLOUD SEEDING CAUSE THE STORM?

CAN'T CREATE CLOUDS FROM NOTHING

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Iraq's Popular Mobilization Forces post hit in air strike, sources say

Iraq's Popular Mobilization Forces, an official security force, said its command post at Kalso military base about 50 km (30 miles) south of Baghdad was hit by a huge explosion late on Friday, and two security sources said it resulted from an air strike.

The governor of Russia's western region of Smolensk said on Saturday that a Ukrainian drone hit a fuel depot overnight, setting it on fire, while an attack on the regional centre has been repelled.