The Immune System

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165 Immune System Overview The Immune System The animal body is a selfcontained, stable environment rich in nutrients that provides ideal habitat for many microorganisms, including bacteria, fungi, and protists. While some of these microorganisms are able to form a neutral or mutually beneficial relationship with their host, others live at the expense of the host. Left unchecked, these organisms, known collectively as pathogens, can destroy cells and damage tissues, resulting in disease that may lead to death. Another threat to the animal body is cancer cells that arise from spontaneous mutations in the DNA. Cancer cells exhibit unregulated cell division and, like a pathogen, can damage or destroy tissues. The immune system provides a collection of defenses against pathogens and cancer cells (Figure 1). All animals have an innate immune system that provides a rapid, general defense against pathogens. Vertebrates additionally have an adaptive immune system that is able to recognize specific molecular determinants, known as antigens, which are present on certain pathogens. The adaptive immune response is slow, and the innate immune system provides the first line of defense against pathogens.

Figure 1: The immune system. All animals have an innate immune system that provides general, rapid defense. Additionally, vertebrates have an adaptive immune system that provides a slower specific immunity against certain pathogens. © 2014 Nature Education All rights reserved.

The innate immune system. The innate immune system includes barrier, cellmediated, and humoral http://www.nature.com/principles/ebooks/principlesofbiology104015/29145887/1 1/4 4/7/2015 Immune System Overview | Principles of Biology from Nature Education defenses. Barrier defenses, which include physical barriers and chemical defenses, are provided by the epithelium. Epithelial tissue, which includes skin and mucus membranes, blocks pathogen entry into the body and produces mucus, saliva, tears, sweat, and digestive fluids, all of which have antibacterial properties. Innate cellmediated immunity is provided by phagocytes, which are able to engulf and digest pathogens and cancer cells, and by cells that secrete cytotoxins or cytokines. Cytotoxins are chemicals that are able to kill cells. Cytokines are chemicals that bind receptors on target cells and trigger a response. Some cytokines trigger apoptosis in infected or damaged cells, while others modulate the immune response. One immune response, called the inflammatory response, causes vasodilation and increased permeability of blood vessels, resulting in pain, redness, and swelling. Patternrecognition receptors (PRRs) present in the plasma membrane of many innate immune cells are able to recognize molecular signatures associated with certain pathogens, called pathogenassociated molecular patterns (PAMPs). Molecules that circulate in body fluid provide innate humoral immunity. In vertebrates, these components include the complement system and two circulating proteins: mannosebinding lectin and Creactive protein. The complement system, which consists of about thirty proteins, is able to kill pathogens and to trigger an immune response. Mannosebinding lectin is a protein that recognizes carbohydrates commonly found on microbes and activates the complement system. Creactive protein, which binds a chemical present on the surface of damaged cells and some bacteria, also activates the complement system. Test Yourself

Describe the components of the innate immune system.

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The adaptive immune system. Adaptive immunity is mediated by T cells and B cells, which both express an antigen receptor on the cell surface. The gene encoding the antigen receptor undergoes genetic recombination during B cell and T cell development, and, as a result, each B cell and T cell expresses a unique receptor capable of recognizing a different antigen. Binding of antigen to the receptor causes the cell to divide, a process called clonal expansion, and differentiate into effector cells and memory cells. Effector cells carry out the immune response, and memory cells remain in the body and produce a much faster, stronger response if the same pathogen is encountered again. T cells, which are responsible for adaptive cellmediated immunity, can be divided into three classes: cytotoxic T cells (TC), helper T cells (TH), and regulatory T cells (Treg). Cytotoxic T cells are capable of killing infected or cancerous cells. Helper T cells stimulate the immune response, and regulatory T cells dampen the immune response. T cells are only able to recognize antigens that are displayed in association with major histocompatibility complex (MHC) molecules on the surface of cells. The presence of an antigenMHC complex on antigenpresenting cells (APCs) activates helper T cells. The presence of antigen on infected or damaged cells activates cytotoxic T cells. B cells are responsible for adaptive humoral immunity. When an antigen binds a B cell antigen receptor, the cell undergoes clonal expansion and differentiates into a type of effector cell called plasma cells. These cells are http://www.nature.com/principles/ebooks/principlesofbiology104015/29145887/1 2/4 4/7/2015 Immune System Overview | Principles of Biology from Nature Education able to secrete soluble antigen receptors, which are called antibodies. Coating of a pathogen by antibody flags it for destruction by phagocytic cells, a process called opsonization, and also activates the complement system. Test Yourself

Describe the adaptive immune response.

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IN THIS MODULE

The Immune System Types of Immune Cells Summary Test Your Knowledge

WHY DOES THIS TOPIC MATTER?

Stem Cells Stem cells are powerful tools in biology and medicine. What can scientists do with these cells and their incredible potential?

PRIMARY LITERATURE

Synthetic ligand may help treat autoimmune disorders Suppression of TH17 differentiation and autoimmunity by a synthetic ROR ligand. View | Download

Biodiversity loss increases infectious diseases among humans Impacts of biodiversity on the emergence and transmission of infectious diseases. View | Download

A new technique for detecting autoimmune diseases Autoantigen discovery with a synthetic human peptidome. View | Download

Classic paper: T cells mediate immunity through MHC restriction (1974) Restriction of in vitro T cellmediated cytotoxicity in lymphocytic choriomeningitis within a syngeneic or semiallogeneic system. View | Download

Controlling inflammation to stop sepsis Amelioration of sepsis by inhibiting sialidasemediated disruption of the CD24 SiglecG interaction. View | Download

Live imaging tracks immune rejection of transplanted tissue Visualizing the innate and adaptive immune responses underlying allograft rejection by twophoton microscopy. View | Download

Geneticallymatched iPS cells more immunogenic than ES cells Immunogenicity of induced pluripotent stem cells. View | Download

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165 Immune System Overview Types of Immune Cells Invertebrate immune cells are called hemocytes. Vertebrate immune cells are called leukocytes or white blood cells. Leukocytes, which are derived from bone marrow stem cells, may differentiate into one of two progenitor lines: the myeloid line and the lymphoid line (Table 1). Myeloid cells are primarily involved in innate immunity. Four types of myeloid cells are phagocytes: neutrophils, eosinophils, basophils, and monocytes. Neutrophils, which primarily target bacteria and fungi, are the most abundant leukocyte and are often the first to arrive at the site of an injury or infection. Neutrophils secrete cytotoxins, and, upon death, they release a web referred to as a neutrophil extracellular trap that can trap pathogens. Neutrophils are a major component of pus. Eosinophils and basophils primarily target large parasites and are involved in the inflammatory response. Basophils also produce heparin, a molecule with anticoagulant (bloodthinning) properties. Monocytes are able to differentiate into two cell types: macrophages and dendritic cells. Both macrophages and dendritic cells are antigenpresenting cells that stimulate T cells. Macrophages often stay at the site of injury or infection and can engulf dead or dying neutrophils and other injured cells. Dendritic cells travel to the lymph nodes, where they present antigen to T cells. Another type of myeloid cell, called mast cells, releases histamine, a molecule that stimulates the inflammatory response, and heparin. Basophils and mast cells are both involved in allergic reactions, which are a type of inappropriate immune response. There are three different lymphoid cells, or lymphocytes: B cells, T cells, and natural killer cells. B cells and T cells are involved in the adaptive immune response. B cells are also antigenpresenting cells. Natural killer cells, which target infected and cancerous cells, are part of the innate immune system. Immune cells may also be categorized based on histology, or microscopic anatomy. Granulocytes have cytoplasmic granules that are visible using light microscopy. The granules are secretory vesicles containing cytokines and cytotoxins that can be released during a process called degranulation. Neutrophils, eosinophils, basophils, and mast cells are granulocytes. Agranulocytes, including lymphocytes, monocytes, and macrophages, do not have visible granules. Leukocytes are also characterized based on the shape of the nucleus.

Category Type Function Histology Phagocytic cell that targets bacteria and fungi. Releases Granulocyte, neutrophil cytotoxins and neutrophil multilobed extracellular traps that destroy nucleus pathogens.

Phagocytic cell that targets Granulocyte, parasites. Releases cytotoxins eosinophil bilobed and cytokines; involved in nucleus inflammatory response. Phagocytic cell that targets parasites. Releases cytotoxins Granulocyte, http://www.nature.com/principles/ebooks/principlesofbiology104015/29145887/2 1/3 4/7/2015 Immune System Overview | Principles of Biology from Nature Education myeloid basophil and cytokines; involved in bilobed or cell inflammatory response. trilobed Releases the anticoagulant nucleus heparin. Releases heparin and histamine. Granulocyte, mast cell Plays a key role in the round inflammatory response. nucleus Phagocytic cell that matures into macrophages and dendritic cells, Agranulocyte, which are both antigen kidney monocyte presenting cells. Macrophages shaped usually stay at the site of nucleus infection, and dendritic cells travel to the lymph nodes. Produce antibodies, responsible Agranulocyte, for humoral adaptive immune B cells round response; primarily target nucleus extracellular pathogens. Responsible for cellmediated Agranulocyte, lymphocyte adaptive immunity; primarily T cells round target intracellular pathogens nucleus and cancer cells.

Agranulocyte, natural Release cytotoxins that kill virus round killer cells infected and cancerous cells. nucleus Table 1: Mammalian leukocytes.

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Describe the properties of myelocytes and lymphocytes.

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IN THIS MODULE

The Immune System Types of Immune Cells Summary Test Your Knowledge

WHY DOES THIS TOPIC MATTER?

Stem Cells Stem cells are powerful tools in biology and medicine. What can scientists do with these cells and their incredible potential?

PRIMARY LITERATURE

Synthetic ligand may help treat autoimmune disorders Suppression of TH17 differentiation and autoimmunity by a synthetic ROR ligand. View | Download

Biodiversity loss increases infectious diseases among humans Impacts of biodiversity on the emergence and transmission of infectious diseases. http://www.nature.com/principles/ebooks/principlesofbiology104015/29145887/2 2/3 4/7/2015 Immune System Overview | Principles of Biology from Nature Education View | Download

A new technique for detecting autoimmune diseases Autoantigen discovery with a synthetic human peptidome. View | Download

Controlling inflammation to stop sepsis Amelioration of sepsis by inhibiting sialidasemediated disruption of the CD24 SiglecG interaction. View | Download

Live imaging tracks immune rejection of transplanted tissue Visualizing the innate and adaptive immune responses underlying allograft rejection by twophoton microscopy. View | Download

Geneticallymatched iPS cells more immunogenic than ES cells Immunogenicity of induced pluripotent stem cells. View | Download

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165 Immune System Overview Summary OBJECTIVE Describe the properties of the innate immune system. The innate immune system includes barrier defenses, cellmediated defenses, and humoral defenses. Barrier defenses are provided by epithelial tissue, including skin and mucosal tissue. Epithelial tissues form a physical barrier that physically blocks pathogen entry into the body. These tissues also produce secretions with antimicrobial properties. Cellmediated defense is provided by phagocytic cells and cells that produce cytotoxins and cytokines. Molecules present in body fluids provide humoral defense. In vertebrates, humoral defenses include the complement system, mannose binding lectin, and Creactive protein.

OBJECTIVE Describe the properties of the adaptive immune system. The adaptive immune response is mediated by B cells and T cells. Both B cells and T cells have antigen receptors embedded in the plasma membrane that are able to recognize antigen. Upon antigen binding, clonal expansion occurs. Clonal expansion results in the production of effector cells and memory cells. There are three types of effector T cells: cytotoxic T cells, helper T cells, and regulatory T cells. Cytotoxic T cells are able to kill infected cells and cancer cells. Helper T cells stimulate an immune response, and regulatory T cells dampen an immune response. Effector B cells are called plasma cells. Plasma cells produce antibody that is secreted into the blood. Binding of antibody to antigen triggers an immune response. Memory cells circulate in the blood after the pathogen is gone in case it is encountered again.

OBJECTIVE Describe the properties of various leukocytes. Leukocytes can be divided into two classes: myelocytes and lymphocytes. Myelocytes are primarily involved in innate immunity. Cell types include phagocytic neutrophils, eosinophils, basophils, macrophages, and dendritic cells. Neutrophils target bacteria and fungi. Eosinophils and basophils target large parasites. Macrophages and dendritic cells are antigenpresenting cells. Basophils and another type of myelocyte, mast cells, are involved in the inflammatory response. Lymphocytes include B cells, T cells, and natural killer cells. T cells are responsible for cellmediated adaptive immunity, and B cells produce antibodies involved in humoral adaptive immunity. Natural killer cells, which are part of the innate immune system, kill infected cells and cancer cells.

Key Terms adaptive immune system The part of the vertebrate immune system that is able to recognize and respond to specific antigens.

agranulocyte Immune cell that does not have visible granules; includes lymphocytes, monocytes, and macrophages.

antibody A soluble antigen receptor that is secreted by B cells; part of the humoral adaptive immune response.

antigen A substance that binds an antigen receptor.

http://www.nature.com/principles/ebooks/principlesofbiology104015/29145887/3 1/5 4/7/2015 Summary of Immune System Overview | Principles of Biology from Nature Education antigenpresenting cells (APCs) Immune cells that present antigens to T cells; include dendritic cells, macrophages, and B cells. B cell Lymphocytes that mediate the humoral adaptive immune response; differentiate into antibodyproducing plasma cells. barrier defense Chemical and physical barriers that provide the first line of defense against pathogens; barrier defenses involve epithelial tissue, including skin and mucus membranes. basophil Granulocyte of the innate immune system that primarily defends against parasitic infections. Releases cytokines that trigger an inflammatory response; involved in allergies. Creactive protein A protein that binds a chemical present on the surface of damaged cells and some bacteria; activates the complement system. cellmediated immunity An immune response that involves cells of the immune system. clonal expansion Proliferation of T and B cells after activation to create both effector cells responsible for fighting the current infection as well as memory cells for future exposures to the same antigen. complement system A collection of proteins circulating in the blood that, upon activation, trigger cellular responses leading to the destruction of pathogens. cytokine A molecule, particularly one secreted by immune cells, used to communicate with other cells during immune responses; effects can include proliferation, cell migration, and apoptosis. cytotoxin A chemical that kills cells. degranulation Process in which granules are secreted from a cell. dendritic cell An antigenpresenting immune cell that processes antigen material and presents it on its surface for detection by other cells of the immune system. eosinophil Phagocyte of the innate immune system that targets parasites; also secretes cytokines. granulocytes Immune cells that can be identified by the presence of granules in their cytoplasm; includes mast cells, basophils and eosinophils, and neutrophils that participate in the innate immune response. hemocytes Phagocytic cell present in some invertebrates; also secretes antimicrobial peptides; evolutionary precursor to phagocytes in mammals. heparin A chemical secreted by mast cells that has anticoagulant properties. histamine A small molecule secreted by some granulocytes that induces vasodilation in blood vessels and increases their permeability to fluid; involved in allergic and inflammatory responses. histology The study of microscopic cellular structures.

http://www.nature.com/principles/ebooks/principlesofbiology104015/29145887/3 2/5 4/7/2015 Summary of Immune System Overview | Principles of Biology from Nature Education humoral immunity Immune system response that involves molecules secreted into body fluids. immune system A collection of physical, molecular, and cellular defenses against pathogens and cancer cells. immunological memory Memory cells of the adaptive immune system recognize a pathogen that was previously encountered, resulting in a stronger, faster secondary response. inflammatory response A series of events that serve as a protective mechanism during an infection or injury; involves local vasodilation, changes in vascular permeability, and increased blood flow at the affected site, all of which facilitate entry of immune cells and chemical mediators into the tissue. innate immune system Includes nonspecific defenses against a broad range of pathogens; present all animals. leukocyte A cell of the human immune system; informally known as a "white blood cell."

lymphocyte Type of white blood cell; includes B cells, T cells, and natural killer cells. major histocompatibility complex (MHC) A protein complex on the cell surface that presents antigen to T cells. mannosebinding lectin A protein that recognizes carbohydrates commonly found on microbes and activates the complement system. mast cell Granulocyte of the innate immune system that releases heparin and histamine; responsible for inflammatory responses and allergic reactions. memory cell Cell type that is formed when a B cell or T cell is activated; circulates in the blood for response to subsequent infections by the same pathogen. monocyte The immature form of a macrophage that circulates in the blood; infection stimulates its differentiation into a macrophage and migration into body tissues. myeloid cell One of two types of leukocyte; includes most innate immune cells. natural killer (NK) cell A lymphocyte that uses cytotoxic compounds to kill infected or cancerous host cells; part of the innate immune system. neutrophil A small, mobile phagocytic cell that is usually the first cell type to respond in an inflammatory response; releases granules containing cytotoxins and cytokines; capable of forming neutrophil extracellular traps after death. opsonin A molecule, such as an antibody, that coats a pathogen to flag it for destruction by the immune system. opsonization A process by which an antigen is flagged for destruction by the immune system. pathogen An organism or virus that can trigger disease in a host. pathogenassociated molecular pattern (PAMP) A conserved molecular signature that is used by an innate immune system to identify certain groups of pathogens. patternrecognition receptors (PRRs) Receptors of the innate immune system that recognize pathogenassociated http://www.nature.com/principles/ebooks/principlesofbiology104015/29145887/3 3/5 4/7/2015 Summary of Immune System Overview | Principles of Biology from Nature Education molecular patterns. phagocyte A cell that engulfs and digests pathogens. plasma cell Antibodyproducing cell that is formed when a B cell becomes activated. T cells Lymphocytes involved in cellmediated adaptive immunity.

IN THIS MODULE

The Immune System Types of Immune Cells Summary Test Your Knowledge

WHY DOES THIS TOPIC MATTER?

Stem Cells Stem cells are powerful tools in biology and medicine. What can scientists do with these cells and their incredible potential?

PRIMARY LITERATURE

Synthetic ligand may help treat autoimmune disorders Suppression of TH17 differentiation and autoimmunity by a synthetic ROR ligand. View | Download

Biodiversity loss increases infectious diseases among humans Impacts of biodiversity on the emergence and transmission of infectious diseases. View | Download

A new technique for detecting autoimmune diseases Autoantigen discovery with a synthetic human peptidome. View | Download

Controlling inflammation to stop sepsis Amelioration of sepsis by inhibiting sialidasemediated disruption of the CD24 SiglecG interaction. View | Download

Live imaging tracks immune rejection of transplanted tissue Visualizing the innate and adaptive immune responses underlying allograft rejection by twophoton microscopy. View | Download

Geneticallymatched iPS cells more immunogenic than ES cells Immunogenicity of induced pluripotent stem cells. View | Download

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Hunt for the Malaria Vaccine Learn how clinical trials are proceeding for this important disease therapy.

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165 Immune System Overview

Test Your Knowledge

1. In vertebrates, what are the two types of immune systems?

barrier and humoral physical and chemical innate and adaptive antigen and antibody None of the answers are correct.

2. Which term best describes a substance that is recognized by the adaptive immune system?

antigen receptor antibody pathogen antigen cytokine

3. What is humoral adaptive immunity?

Humoral adaptive immunity is an immune response mediated by antibodies that are secreted into the blood by plasma cells. Humoral adaptive immunity is an immune response mediated by T cells. Humoral adaptive immunity is an immune response involving complement. Humoral adaptive immunity is an immune response involving phagocytic cells. All of the answers are correct.

4. Which of the following is NOT part of the body's first line of defense?

skin mucous membrane saliva antibody production None of the answers are correct.

5. Which of the following is involved in innate immunity?

phagocytic cells natural killer cells cytotoxins inflammatory response All answers are correct.

6. Which cell types are most likely to target a parasite?

basophils and eosinophils mast cells and dendritic cells B cells and T cells natural killer cells and mast cells None of the answers are correct.

7. Which of the following statements about immune cells is true? http://www.nature.com/principles/ebooks/principlesofbiology104015/29145887/4 1/2 4/7/2015 Immune System Overview | Principles of Biology from Nature Education B cells and T cells are myeloid cells. Natural killer cells are part of the adaptive immune system. Macrophages give rise to monocytes and dendritic cells. Neutrophils, eosinophils, and basophils are all phagocytic. None of the answers are correct.

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IN THIS MODULE

The Immune System Types of Immune Cells Summary Test Your Knowledge

WHY DOES THIS TOPIC MATTER?

Stem Cells Stem cells are powerful tools in biology and medicine. What can scientists do with these cells and their incredible potential?

PRIMARY LITERATURE

Synthetic ligand may help treat autoimmune disorders Suppression of TH17 differentiation and autoimmunity by a synthetic ROR ligand. View | Download

Biodiversity loss increases infectious diseases among humans Impacts of biodiversity on the emergence and transmission of infectious diseases. View | Download

A new technique for detecting autoimmune diseases Autoantigen discovery with a synthetic human peptidome. View | Download

Controlling inflammation to stop sepsis Amelioration of sepsis by inhibiting sialidasemediated disruption of the CD24 SiglecG interaction. View | Download

Live imaging tracks immune rejection of transplanted tissue Visualizing the innate and adaptive immune responses underlying allograft rejection by twophoton microscopy. View | Download

Geneticallymatched iPS cells more immunogenic than ES cells Immunogenicity of induced pluripotent stem cells. View | Download

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Hunt for the Malaria Vaccine Learn how clinical trials are proceeding for this important disease therapy.

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166 Innate Immunity

The innate immune system, which is present in all animals, provides a rapid, nonspecific response against a wide range of pathogens. Innate immunity begins with barrier defenses, including skin and other tissues that prevent entry of the pathogen. If barrier defenses are breached, cells of the innate immune system can target and destroy pathogens or cancer cells through either phagocytosis or the release of chemicals, a process called cell mediated immunity. Pathogens may also be destroyed through a non cellular pathway called the complement system. In immunology, a noncell mediated response, such as the complement system, is referred to as humoral immunity.

Barrier Defenses The outer layer of tissue in animals is called the epithelium. The epithelium covers both the exterior of the body and internal cavities, such as the digestive tract. In many invertebrates and vertebrates, the epithelium acts as a barrier that blocks entry of pathogens. An example of an invertebrate defensive barrier is the exoskeleton of arthropods such as insects and crustaceans. The exoskeleton, made from a tough polysaccharide called chitin, provides an excellent protective barrier against the entry of many pathogens. In mammals, skin and mucous membranes that line the digestive, respiratory, urinary, and reproductive tracts act as protective barriers. Mucous membranes produce mucus, a gelatinous fluid that traps pathogens. Ciliated cells in the trachea are able to move the mucustrapped microbes out of the airways. Mucus and other fluids, such as saliva and tears, all contain lysozyme, an enzyme that destroys bacterial cell walls. Lysozyme is also present in the insect digestive system. Acidic gastric juices also kill many pathogens that enter the stomach, and acidic secretions from oil and sweat glands in the skin kill many surface pathogens. If the barrier defenses are breached, cells and humoral components of the innate immune system provide the next line of defense.

IN THIS MODULE

Barrier Defenses Cellmediated Innate Immunity The Complement System The Inflammatory Response Microbial Offense Mechanisms Summary Test Your Knowledge

WHY DOES THIS TOPIC MATTER?

Stem Cells Stem cells are powerful tools in biology and medicine. What can scientists do with these cells and their incredible potential?

PRIMARY LITERATURE

Biodiversity loss increases infectious diseases among humans Impacts of biodiversity on the emergence and transmission of infectious diseases. View | Download

A new technique for detecting autoimmune diseases Autoantigen discovery with a synthetic http://www.nature.com/principles/ebooks/principlesofbiology104015/29145892/1 1/2 4/7/2015 Innate Immunity | Principles of Biology from Nature Education human peptidome. View | Download

Synthetic ligand may help treat autoimmune disorders Suppression of TH17 differentiation and autoimmunity by a synthetic ROR ligand. View | Download

Controlling inflammation to stop sepsis Amelioration of sepsis by inhibiting sialidasemediated disruption of the CD24 SiglecG interaction. View | Download

Live imaging tracks immune rejection of transplanted tissue Visualizing the innate and adaptive immune responses underlying allograft rejection by twophoton microscopy. View | Download

Geneticallymatched iPS cells more immunogenic than ES cells Immunogenicity of induced pluripotent stem cells. View | Download

Identifying genes linked to cystic fibrosis Genomewide association and linkage identify modifier loci of lung disease severity in cystic fibrosis at 11p13 and 20q13.2. View | Download

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Extravasation of a white blood cell Watch the interior processes that occur and allow a white blood cell to leave the bloodstream and travel to the site of infection.

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166 Innate Immunity Cellmediated Innate Immunity Cellmediated immunity evolved in invertebrates, and many commonalities exist between the innate immune system of vertebrates and invertebrates. In all animals, the innate immune system must be able to recognize and eliminate pathogens. Mechanisms of recognition and elimination, and cellular components of the innate immune system, are discussed in the following sections.

Recognition of pathogens by cells of the innate immune system. A group of receptors, collectively known as pattern recognition receptors (PRRs), are embedded in the plasma membrane of many types of immune cells from both vertebrates and invertebrates. PRRs are able to bind Pathogenassociated molecular patterns, or PAMPs. PAMPS are molecules and molecular components associated with various pathogens. Besides PAMPS, PRRs are also able to recognize DamageAssociated Molecular Patterns (DAMPs), molecules or molecular components that are typically present when one of the animal's own cells is damaged. A group of PRRs found in insects, called Toll receptors, share homology with Tolllike receptors (TLRs) found in vertebrates. In the fruit fly Drosophila melanogaster, certain Toll receptors are activated by the presence of Gram positive bacteria or fungi. In mammals, over 10 Tolllike receptors are each able to recognize different molecules present on pathogens. For example, TLR3 recognizes doublestranded RNA, which composes the genome of certain viruses. TLR4 recognizes lipopolysaccharides found on many bacteria. TLR5 recognizes a component of bacterial flagella. Another superfamily of carbohydratebinding proteins, called lectins, is also involved in immune recognition in both vertebrates and invertebrates. Vertebrates are also able to recognize pathogens through a process called antibody opsonization. Antibodies, which are excreted protein receptors produced by the adaptive immune system, bind specific determinants, called antigens, on pathogens. Opsonization is the process by which pathogens are coated in antibodies to tag them for destruction by the innate immune system.

Response of cells of the innate immune system. Once a pathogen is recognized, cells of the innate immune may engulf and digest it through a process called phagocytosis (Figure 1). In invertebrates, waste is excreted from the cell through exocytosis. In vertebrates, antigens from the digested pathogen may be attached to a protein receptor called major histocompatibility complex II (MHC II) and displayed on the exterior of the cell. If a T cell from the adaptive immune system recognizes the antigenMHC II complex, it becomes activated.

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Figure 1: Phagocytosis of a pathogen by an immune cell. Certain cells of the innate immune system are able to engulf and digest microbes through phagocytosis. In vertebrates, digested components of the pathogen, called antigens, are displayed on major histocompatibility complex (MHC) II receptors embedded in the plasma membrane. Antigen MHC II complexes are able to activate T cells of the adaptive immune system. © 2014 Nature Education All rights reserved.

Innate immune cells may also secrete chemicals that aid in the destruction of pathogens. These chemicals can be divided into two broad classes: cytotoxins and cytokines. Cytotoxins are chemicals that have the ability to kill cells. Cytokines are small proteins that bind to receptors on target cells of the host organism and trigger a response. Antimicrobial peptides, which are found in all living organisms, are cytotoxins that are active against a wide range of pathogens, including bacteria, protozoa, and fungi. The cytotoxic activity of most antimicrobial peptides results from the ability of these molecules to insert themselves in cell membranes and form a pore. Antimicrobial peptides may also have antiviral activity because they are able to either inhibit association of the virus with the plasma membrane or inhibit egress of the virus from the cell. Cytokines are separated into groups based on the response they induce. Chemokines are cytokines that attract immune cells to a site of injury or infection. Lymphokines, which are produced by lymphocytes of the adaptive immune system, also attract immune cells. Interferons, which are released from cells infected by a virus, destroy RNA and dampen protein synthesis in nearby cells, thereby inhibiting viral replication. Interferons can also send signals leading to apoptosis. Tumor necrosis factor is a cytokine that triggers apoptosis, or programmed cell death. Interleukins, which are produced by immune and nonimmune cells, are a family of proteins with a broad range of activities. Cytokines have only recently been characterized in invertebrates. Thus, the function of these chemicals in invertebrates and their relationship to vertebrate cytokines is still only poorly understood.

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Name four types of cytokines involved in the innate immune response and describe their function.

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Innate immune system cell types. Hemocytes are invertebrate immune cells. In arthropods and mollusks, hemocytes are present in the circulatory fluid, or hemolymph. Some hemocytes are able to engulf pathogens by phagocytosis. Other hemocytes secrete antimicrobial peptides that circulate in the hemolymph. A variety of cells of the mammalian immune system, called leukocytes, are involved in innate immunity. The primary phagocytic cells are neutrophils, macrophages, and dendritic cells. Neutrophils, the most abundant leukocyte, target bacteria and fungi and are typically recruited to the site of an injury or infection first. They have a short lifespan of about 5 days and, upon death, are able to release their chromatin and proteases to form neutrophil extracellular traps. The chromatin fibers act as a web that traps microbes, and the proteases and other antibacterial secretions kill them. Living and dead neutrophils are a major component of pus in an infected wound. Neutrophils attract monocytes, which mature into macrophages. Macrophages engulf pathogens directly as well as neutrophils that have engulfed pathogens. Macrophages also secrete the proinflammatory cytokines.

Dendritic cells and macrophages are both antigenpresenting cells: after they engulf and digest pathogens, they present antigens on a cell surface receptor called major histocompatibility complex II (MHC II). If a T cell from the adaptive immune system recognizes the antigenMHC II complex, it becomes activated. B cells of the adaptive immune system are also antigen presenting cells. Antigenpresenting dendritic cells may travel to the lymph nodes to present antigen to Tcells. Two other cells capable of phagocytosis are eosinophils and basophils. Both cell types target large parasites, and, because many parasites are often too large to engulf, they also release cytotoxins. Basophils and another type of granulocyte, called mast cells, are involved in inflammation and in allergic reactions. Two types of lymphocytes, B cells and T cells, are involved in adaptive immunity, but a third type, natural killer (NK) cells, is involved in innate immunity. Natural killer cells target host cells that are infected by pathogens such as viruses and therefore must be able to distinguish healthy cells from infected ones. The missing self hypothesis proposes a mechanism by which this recognition might occur. According to the missing self hypothesis, NK cells have two types of receptors: an activating receptor and an inhibitory receptor. Activating receptors, which stimulate killing activity, bind activating ligands that are typically associated with viral infection. Inhibitory receptors bind a molecule called major histocompatibility complex I (MHC I) that is present on virtually all vertebrate cells. Often, MHC I is downregulated in infected cells, so lack of MHC I can indicate that a cell is infected. If an activating ligand is present and MHC I is absent, the NK is strongly activated and the cell is killed through the release of cytotoxins. If MHC I and activating ligands are both present, the outcome depends on the presence of other signals. If no activating ligand is present, the cell is left alone regardless of the presence of MHC I.

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Figure 2: The missing self hypothesis of natural killer cell activation. Activation of natural killer cells depends on binding of ligands associated with body cells to two types of receptor found on the natural killer cell: antigen receptors and killing inhibitory receptors. Antigen receptors bind antigens that are typically associated with viral infection. Binding of antigen to an antigen receptor stimulates killing activity. Killing inhibitory receptors bind major histocompatibility complex (MHC) I molecules that are present on most healthy cells but often downregulated in infected cells. Binding of MHC I to killing inhibitory receptors blocks killing activity, even if antigen is present. © 2014 Nature Education All rights reserved.

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IN THIS MODULE

Barrier Defenses Cellmediated Innate Immunity The Complement System The Inflammatory Response Microbial Offense Mechanisms Summary Test Your Knowledge

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PRIMARY LITERATURE

Biodiversity loss increases infectious diseases among humans Impacts of biodiversity on the emergence and transmission of infectious diseases. View | Download

A new technique for detecting autoimmune diseases Autoantigen discovery with a synthetic human peptidome. View | Download

Synthetic ligand may help treat autoimmune disorders Suppression of TH17 differentiation and autoimmunity by a synthetic ROR ligand. View | Download

Controlling inflammation to stop sepsis Amelioration of sepsis by inhibiting sialidasemediated disruption of the CD24 SiglecG interaction. View | Download

Live imaging tracks immune rejection of transplanted tissue Visualizing the innate and adaptive immune responses underlying allograft rejection by twophoton microscopy. View | Download

Geneticallymatched iPS cells more immunogenic than ES cells Immunogenicity of induced pluripotent stem cells. View | Download

Identifying genes linked to cystic fibrosis Genomewide association and linkage identify modifier loci of lung disease severity in cystic fibrosis at 11p13 and 20q13.2. View | Download

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166 Innate Immunity The Complement System The complement system is able to lyse invading cells. In vertebrates, complement is composed of about 30 proteins that are synthesized in the liver and circulate in the blood as inactive precursors. Some invertebrates also have complementlike proteins, but their function has not been elucidated. The complement system can be activated by three pathways (Figure 3). In the classical pathway, complement is activated by antigen antibody complexes. In the alternative pathway, complement proteins bind to pathogens directly. In the lectin pathway, the binding of mannosebinding lection to bacterial carbohydrates activates the complement system. Regardless of the mechanism, complement activation initiates a proteolytic cascade that results in the cleavage of inactive C3 and C5 complement precursors into active molecules that mediate a number of antimicrobial functions. For example, C3b, produced from cleavage of C3, coats a pathogen and "marks" it for phagocytosis, a process known as opsonization. C3a, another active complement protein created from C3 cleavage, promotes the release of proinflammatory substances from other immune cells. Finally, C5b, produced from C5 cleavage, is a component of a membrane attack complex that lyses pathogens by forming a pore in the plasma membrane.

Figure 3: The complement system. The complement system can be activated by three different pathways. © 2004 Nature Publishing Group Carroll, Michael C. A protective role for innate immunity in systemic lupus erythematosus. Nature Reviews Immunology 4, 825–831 (2004) doi:10.1038/nri1456. Used with permission.

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PRIMARY LITERATURE

Biodiversity loss increases infectious diseases among humans Impacts of biodiversity on the emergence and transmission of infectious diseases. View | Download

A new technique for detecting autoimmune diseases Autoantigen discovery with a synthetic human peptidome. View | Download

Synthetic ligand may help treat autoimmune disorders Suppression of TH17 differentiation and autoimmunity by a synthetic ROR ligand. View | Download

Controlling inflammation to stop sepsis Amelioration of sepsis by inhibiting sialidasemediated disruption of the CD24 SiglecG interaction. View | Download

Live imaging tracks immune rejection of transplanted tissue Visualizing the innate and adaptive immune responses underlying allograft rejection by twophoton microscopy. View | Download

Geneticallymatched iPS cells more immunogenic than ES cells Immunogenicity of induced pluripotent stem cells. View | Download

Identifying genes linked to cystic fibrosis Genomewide association and linkage identify modifier loci of lung disease severity in cystic fibrosis at 11p13 and 20q13.2. View | Download http://www.nature.com/principles/ebooks/principlesofbiology104015/29145892/3 2/3 4/7/2015 Innate Immunity | Principles of Biology from Nature Education

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166 Innate Immunity The Inflammatory Response The inflammatory response, which is launched at the site of an injury or infection, is initiated when mast cells release a proinflammatory molecule called histamine and when other immune cells, such as macrophages, release pro inflammatory cytokines. Histamines and proinflammatory cytokines cause the permeability of nearby blood vessels to increase, allowing molecular and cellular immune mediators to access the infected or injured area, a process called extravasation. At the same time, vasodilation, or widening, of local blood vessels occurs. The increase in blood flow causes the redness, pain, swelling, and increase in temperature characteristic of inflammation (Figure 4). Increased temperature, which is triggered by chemicals called pyrogens, impedes the growth and the replication of pathogens, and swelling prevents pathogens from spreading from the site of infection. Pyrogens are also responsible for fever. In addition, platelets enter the wound and form a clot to stop bleeding. Inflammation is also critical for the healing of wounds because inflammatory mediators are also responsible for the proliferation of new cells.

Figure 4: Inflammation as an immune response to infection. The inflammatory response is initiated by histamines released from mast cells and cytokines released from macrophages. Histamine and pro inflammatory cytokines cause blood vessels to dilate and become leaky, facilitating blood cell flow and diffusion of cells and molecules necessary for healing. © 2014 Nature Education All rights reserved.

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IN THIS MODULE

Barrier Defenses Cellmediated Innate Immunity The Complement System The Inflammatory Response Microbial Offense Mechanisms Summary Test Your Knowledge

WHY DOES THIS TOPIC MATTER?

Stem Cells Stem cells are powerful tools in biology and medicine. What can scientists do with these cells and their incredible potential?

PRIMARY LITERATURE

Biodiversity loss increases infectious diseases among humans Impacts of biodiversity on the emergence and transmission of infectious diseases. View | Download

A new technique for detecting autoimmune diseases Autoantigen discovery with a synthetic human peptidome. View | Download

Synthetic ligand may help treat autoimmune disorders Suppression of TH17 differentiation and autoimmunity by a synthetic ROR ligand. View | Download

Controlling inflammation to stop sepsis Amelioration of sepsis by inhibiting sialidasemediated disruption of the CD24 SiglecG interaction. View | Download

Live imaging tracks immune rejection of transplanted tissue Visualizing the innate and adaptive immune responses underlying allograft rejection by twophoton microscopy. View | Download

Geneticallymatched iPS cells more immunogenic than ES cells Immunogenicity of induced pluripotent stem cells. View | Download

Identifying genes linked to cystic fibrosis Genomewide association and linkage identify modifier loci of lung disease severity in cystic fibrosis at 11p13 and 20q13.2. View | Download

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contents Principles of Biology

166 Innate Immunity Microbial Offense Mechanisms As the immune system has evolved to destroy pathogens, the pathogens, in turn, have evolved structures or mechanisms that facilitate evasion of the immune system. For example, many bacteria have polysaccharide capsules that help them avoid detection by phagocytes. Listeria monocytogenes, a bacterial strain associated with foodborne illness from unpasteurized milk and spoiled meats, has a different strategy: to avoid detection by the immune system, L. monocytogenes allows itself to be engulfed by phagocytes. Once inside the cell, the bacterium escapes the phagolysosome and lives and replicates in the cytoplasm, where it uses the host cell's cytoskeleton to move around. Listeria can even move through the plasma membrane from one cell to another (Figure 5).

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Figure 5: Evasion of the immune system by Listeria monocytogenes. Listeria monocytogenes is a Grampositive bacterium that is able to escape the phagolysosome of phagocytic cells and live and replicate inside the cytoplasm. The bacteria use the host cell's cytoskeleton to move around and can move through the plasma membrane from one cell to another. © 2014 Nature Education All rights reserved.

IN THIS MODULE

Barrier Defenses Cellmediated Innate Immunity The Complement System The Inflammatory Response Microbial Offense Mechanisms Summary Test Your Knowledge http://www.nature.com/principles/ebooks/principlesofbiology104015/29145892/5 2/3 4/7/2015 Innate Immunity | Principles of Biology from Nature Education

WHY DOES THIS TOPIC MATTER?

Stem Cells Stem cells are powerful tools in

biology and medicine. What can scientists do with these cells and their incredible potential?

PRIMARY LITERATURE

Biodiversity loss increases infectious diseases among humans Impacts of biodiversity on the emergence and transmission of infectious diseases. View | Download

A new technique for detecting autoimmune diseases Autoantigen discovery with a synthetic human peptidome. View | Download

Synthetic ligand may help treat autoimmune disorders Suppression of TH17 differentiation and autoimmunity by a synthetic ROR ligand. View | Download

Controlling inflammation to stop sepsis Amelioration of sepsis by inhibiting sialidasemediated disruption of the CD24 SiglecG interaction. View | Download

Live imaging tracks immune rejection of transplanted tissue Visualizing the innate and adaptive immune responses underlying allograft rejection by twophoton microscopy. View | Download

Geneticallymatched iPS cells more immunogenic than ES cells Immunogenicity of induced pluripotent stem cells. View | Download

Identifying genes linked to cystic fibrosis Genomewide association and linkage identify modifier loci of lung disease severity in cystic fibrosis at 11p13 and 20q13.2. View | Download

SCIENCE ON THE WEB

Extravasation of a white blood cell Watch the interior processes that occur and allow a white blood cell to leave the bloodstream and travel to the site of infection.

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contents Principles of Biology

166 Innate Immunity Summary OBJECTIVE Describe how cells of the innate immune system are able to recognize and respond to pathogens. A group of receptors, collectively known as pattern recognition receptors (PRRs), are embedded in the plasma membrane of many types of immune cells from both vertebrates and invertebrates. PRRs are able to recognize pathogenassociated molecular patterns (PAMPs) and damage associated molecular patterns (DAMPs). In the vertebrate immune system, pathogens are coated with antibodies, a process called opsonization, so that they are recognized by phagocytes. When an innate immune cell is activated, it may engulf the pathogen by phagocytosis, or it may release cytotoxins that kill the cell or cytokines that mediate an immune response.

OBJECTIVE Describe the cell types involved in innate immunity. Hemocytes are phagocytes found in some invertebrates that may engulf pathogens through phagocytosis or secrete antimicrobial peptides. In vertebrates, many cell types are involved in innate immunity. Macrophages, neutrophils, and dendritic cells are the primary phagocytic cells of the innate immune system. Eosinophils and basophils target large parasites and are capable of both phagocytosis and secreting cytotoxins. Mast cells secrete histamine. Basophils secrete proinflammatory cytokines and play a major role in the inflammatory response and in allergic reactions. NK cells are lymphocytes that target and kill cells with intracellular infections.

OBJECTIVE Describe how the complement system is activated and what it does. The complement system can be activated by three different pathways: the classical pathway, the lectin pathway, and the alternative pathway. The classical pathway is activated by antigenantibody complexes. The lectin pathway is activated when mannosebinding lectin binds carbohydrates associated with bacteria, and the alternative pathway is activated when a complement protein binds a pathogen directly. All pathways promote lysis, phagocytosis, or binding of the pathogen to erythrocytes that travel to the liver or spleen for disposal.

OBJECTIVE Describe the inflammatory response and its purpose. The inflammatory response is triggered by the release of histamines and pro inflammatory cytokines in response to an injury or infection. Vasodilation occurs, and the blood vessels become permeable, allowing cellular and molecular components of the immune system to enter the tissues. Swelling also results, which helps prevent the pathogen from leaving the tissue. Temperature increases, which inhibits the proliferation of pathogens. The inflammatory response also promotes tissue healing.

Key Terms antimicrobial peptide A broad group of peptides found in all living organisms that are able to kill pathogen cells. barrier defense Epithelial tissue that blocks the entry of pathogens into the body.

http://www.nature.com/principles/ebooks/principlesofbiology104015/29145892/6 1/4 4/7/2015 Summary of Innate Immunity | Principles of Biology from Nature Education basophil Phagocytic cell of the innate immune system that targets parasites and mediates the inflammatory response. Also involved in allergic reactions. capsule Polysaccharide coating on bacterial cells that helps them to avoid detection by the immune system. chemokines Cytokines that attract immune cells to the site of an injury or infection. complement system A collection of proteins circulating in the blood that, upon activation, trigger cellular responses leading to the destruction of pathogens. cytokine A molecule, particularly one secreted by immune cells, used to communicate with other cells during immune responses; effects can include proliferation, cell migration, and apoptosis. cytotoxin A chemical that kills cells.

dendritic cell An antigenpresenting immune cell that processes antigen material and presents it on its surface for detection by other cells of the immune system. eosinophil Phagocyte of the innate immune system that targets parasites; also secretes cytokines.

extravasation The process by which immune cells exit the walls of a blood vessel and infiltrate the surrounding tissue. granules Specialized intracellular vesicles in granulocytes containing cytokines and cytotoxins that are released during an immune response.

granulocytes A class of immune cells identified by the presence of granules in their cytoplasm; participate in a variety of innate immune responses; include basophils, eosinophils, and neutrophils. hemocytes Phagocytic cell present in some invertebrates; also secretes antimicrobial peptides; evolutionary precursor to phagocytes in mammals. histamine A secretion of mast cells that triggers the inflammatory response. inflammatory response A series of events that serve as a protective mechanism during an infection or injury; involves local vasodilation, changes in vascular permeability, and increased blood flow at the affected site, all of which facilitate entry of immune cells and chemical mediators into the tissue. interferon A cytokine secreted by cells during an infection that interferes with the replication of viruses and certain microorganisms. interleukin A family of cytokines with a broad range of activities. lymphokine A cytokine released by lymphocytes that attracts immune cells. lysozyme A class of enzyme secreted by many innate immune system cells that cleaves the cell walls of bacteria and other microorganisms. macrophage A large phagocytic cell that engulfs pathogens and presents antigens to cells of the adaptive immune system; can circulate in the blood or be resident in body http://www.nature.com/principles/ebooks/principlesofbiology104015/29145892/6 2/4 4/7/2015 Summary of Innate Immunity | Principles of Biology from Nature Education tissues. mannosebinding lectin A protein that binds certain carbohydrates associated with bacteria and activates complement. mast cell Cell of the innate immune system that releases histamine; triggers inflammatory response and is responsible for allergic reactions. membrane attack complex Pore formed in the cell membrane of a pathogen from several complement proteins, causing cell lysis. missing self hypothesis A hypothesis stating that natural killer cells are able to recognize and kill cells lacking the self antigen MHC I. monocyte The immature form of a macrophage that circulates in the blood; infection stimulates its differentiation into a macrophage and migration into body tissues. mucus Viscous secretion from specialized cells in epithelial tissue. natural killer (NK) cell A lymphocyte that kills host cells infected with intracellular pathogens using cytotoxic compounds; killing is regulated through a balance between inhibitory and activating signals. neutrophil A small, mobile phagocytic cell that is usually the first cell type to respond in an inflammatory response; releases granules containing cytotoxins and cytokines; capable of forming neutrophil extracellular traps after death. opsonization Coating of a pathogen with molecules, such as antibodies, to flag it for phagocytosis. pathogenassociated molecular pattern (PAMP) Molecules or molecular entities associated with pathogens that are recognized by patternrecognition receptors. patternrecognition receptors (PRRs) Receptors of the innate immune system that recognize pathogenassociated molecular patterns. phagocyte A cell that engulfs and digests pathogens. phagocytosis The form of endocytosis in which the plasma membrane of a cell (phagocyte) extends pseudopodia to engulf a large object, such as a pathogen, into a vesicle (phagosome). proinflammatory cytokines A subgroup of cytokines that promote the inflammatory response. pyrogens Substances that induce fever, or an increase in core body temperature; also responsible for the heat caused by inflammation at a site of injury or infections. Tolllike receptor (TLR) A class of PRRs that are homologous to the Toll receptor in Drosophila and other receptors found in other invertebrate species; recognize pathogenic molecules such as virus RNA and various bacterial components. tumor necrosis factor A cytokine that triggers apoptosis.

IN THIS MODULE

Barrier Defenses Cellmediated Innate Immunity http://www.nature.com/principles/ebooks/principlesofbiology104015/29145892/6 3/4 4/7/2015 Summary of Innate Immunity | Principles of Biology from Nature Education The Complement System The Inflammatory Response Microbial Offense Mechanisms Summary Test Your Knowledge

WHY DOES THIS TOPIC MATTER?

Stem Cells Stem cells are powerful tools in biology and medicine. What can scientists do with these cells and their incredible potential?

PRIMARY LITERATURE

Biodiversity loss increases infectious diseases among humans Impacts of biodiversity on the emergence and transmission of infectious diseases. View | Download

A new technique for detecting autoimmune diseases Autoantigen discovery with a synthetic human peptidome. View | Download

Synthetic ligand may help treat autoimmune disorders Suppression of TH17 differentiation and autoimmunity by a synthetic ROR ligand. View | Download

Controlling inflammation to stop sepsis Amelioration of sepsis by inhibiting sialidasemediated disruption of the CD24 SiglecG interaction. View | Download

Live imaging tracks immune rejection of transplanted tissue Visualizing the innate and adaptive immune responses underlying allograft rejection by twophoton microscopy. View | Download

Geneticallymatched iPS cells more immunogenic than ES cells Immunogenicity of induced pluripotent stem cells. View | Download

Identifying genes linked to cystic fibrosis Genomewide association and linkage identify modifier loci of lung disease severity in cystic fibrosis at 11p13 and 20q13.2. View | Download

SCIENCE ON THE WEB

Extravasation of a white blood cell Watch the interior processes that occur and allow a white blood cell to leave the bloodstream and travel to the site of infection.

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166 Innate Immunity

Test Your Knowledge

1. Which of the following are responsible for the movement of immune cells to the site of infection?

pyrogens chemokines cytokines interferons proinflammatory cytokines

2. Which of the following steps results in the destruction of a pathogen during phagocytosis?

binding to pattern recognition receptor phagocytosis phagosomelysosome fusion exocytosis endocytosis

3. Which of the following statements about the complement system is true?

The complement system can be activated by three different mechanisms. The complement system can only be activated if antibodies are present. The complement system is part of the innate cellular response. The result of complement activation depends on the way the system was activated. None of the answers are correct.

4. Which of the following would trigger the inflammatory response?

raising temperature at the site of infection dilation of blood vessels release of histamine from mast cells tissue remodeling neutrophil extravasation from blood vessels

5. Which of the following innate immune components would be found in invertebrates but NOT vertebrates?

hemocytes phagocytes monocytes granulocytes mast cells

6. Which of the following components of the innate immune system would be most beneficial in fighting off a viral infection in humans that is intracellular?

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IN THIS MODULE

Barrier Defenses Cellmediated Innate Immunity The Complement System The Inflammatory Response Microbial Offense Mechanisms Summary Test Your Knowledge

WHY DOES THIS TOPIC MATTER?

Stem Cells Stem cells are powerful tools in biology and medicine. What can scientists do with these cells and their incredible potential?

PRIMARY LITERATURE

Biodiversity loss increases infectious diseases among humans Impacts of biodiversity on the emergence and transmission of infectious diseases. View | Download

A new technique for detecting autoimmune diseases Autoantigen discovery with a synthetic human peptidome. View | Download

Synthetic ligand may help treat autoimmune disorders Suppression of TH17 differentiation and autoimmunity by a synthetic ROR ligand. View | Download

Controlling inflammation to stop sepsis Amelioration of sepsis by inhibiting sialidasemediated disruption of the CD24 SiglecG interaction. View | Download

Live imaging tracks immune rejection of transplanted tissue Visualizing the innate and adaptive immune responses underlying allograft rejection by twophoton microscopy. View | Download

Geneticallymatched iPS cells more immunogenic than ES cells Immunogenicity of induced pluripotent stem cells. View | Download

Identifying genes linked to cystic fibrosis Genomewide association and linkage identify modifier loci of lung disease severity in cystic fibrosis at 11p13 and 20q13.2. View | Download

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Extravasation of a white blood cell Watch the interior processes that occur and allow a white blood cell to leave the bloodstream and travel to the site of infection.

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167 Adaptive Immunity

In many organisms, barrier defenses and innate immunity are the only mechanisms available for protection against pathogens. In vertebrates, an additional line of defense exists if both of these are breached — the adaptive immune system. The adaptive immune system is able to specifically target particular pathogens.

The Adaptive Immune System Two types of cells are involved in adaptive immunity: T cells and B cells. Both T cells and B cells are lymphocytes, or white blood cells involved in immune response. All lymphocytes arise from stem cells of the bone marrow. T cells develop from lymphocytes that migrate to the thymus, an immune organ located in the chest. B cells mature in the bone marrow. A third type of lymphocyte, called natural killer cells, is part of the innate immune system. Both T cells and B cells have antigen receptors embedded in the plasma membrane. Each antigen receptor is able to recognize a particular antigen. Typically, antigens are large molecules such as proteins or polysaccharides. A small part of the antigen, called an epitope, binds the antigen receptor. The immune system is capable of producing millions of different antigen receptors, but a given B or T cell only expresses a single type. Initially, the adaptive immune system responds more slowly than the innate immune system because the adaptive immune system must recognize a pathogen before it can respond to it. However, the adaptive immune system is able to store information about previously encountered pathogens, an ability referred to as immunological memory. Immunological memory allows the adaptive immune system to respond quickly if the same pathogen is encountered again.

Antigen receptors. A B cell receptor is Y shaped and consists of two copies each of two different polypeptide chains linked by disulfide bridges: a heavy chain and a light chain (Figure 1, lower portion). The bottom of the heavy chain is embedded in the plasma membrane. Each chain has a constant region and a variable region. The constant region is the same in all B cell receptors, while the variable region varies. Together, the variable regions of the heavy and light chains form the epitopebinding site. The gene encoding the light chain of the B cell receptor has many copies of three different types of segment: a variable (V) segment, a joining (J) segment, and a constant (C) segment. An undifferentiated human B cell has 40 different V segments, five different J segments, and a single C segment (figure 1, upper portion). During B cell differentiation, an enzyme called recombinase splices a V segment to a J segment. Splicing occurs randomly, so any V segment may be spliced to any J section. The spliced gene is transcribed into premRNA that contains an intron between the J and C segments. The intron is spliced out to form a mature mRNA encoding a light chain polypeptide. The gene encoding the heavy chain gene is recombined in a similar manner, but the heavy chain gene has an additional segment, called the diverse (D) segment, which is first spliced to the J segment and then to the V segment. The VJ portion of the light chain gene forms the variable region of the light chain, and the VDJ portion of the heavy chain gene form the variable region of the heavy chain. Recombination of DNA to form heavy and light chains is referred to as V(D)J recombination. Besides antigen receptors, B cells are http://www.nature.com/principles/ebooks/principlesofbiology104015/29145901/1 1/4 4/7/2015 Adaptive Immunity | Principles of Biology from Nature Education also able to make antibodies. Antibodies have variable regions similar to those found in antigen receptors but are secreted into the blood and therefore do not have a membranespanning region.

Figure 1 : Unique B cell receptors arise from gene splicing. The gene encoding the antigen receptor light chain has multiple V and J segments, and the gene encoding the heavy chain has multiple V, D, and J segments. As an undifferentiated B cell matures, the segments undergo V(D)J recombination, which fuses the segments together to form the portion of the gene encoding the variable region. During RNA processing, this portion is fused to the portion encoding the constant region. © 2014 Nature Education All rights reserved.

The T cell receptor (TCR) consists of two chains, an α chain and a β chain, both embedded in the plasma membrane and linked together by a single disulfide bridge (Figure 2). As in the B cell receptor, the polypeptide chains of the T cell receptor each have a constant and a variable region that are joined together by DNA and mRNA splicing. The constant region is involved in signal transduction and in anchoring the TCR to the plasma membrane. The variable regions make up an antigenbinding site, which allows the T cell to recognize antigenic epitopes. Unlike B cells, a T cell can only recognize an epitope that is associated with major histocompatibility complex (MHC) molecules. MHC molecules are expressed on the surface of cells, as will be discussed in the next section.

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Figure 2: The structure of the T cell receptor. The T cell receptor (TCR) is composed of an α chain and a β chain linked by a single disulfide bridge. The constant region anchors the receptor to the plasma membrane and is involved in signal transduction. The variable regions make up an antigenbinding site that recognizes specific epitopes associated with MHC molecules. © 2012 Nature Education All rights reserved. Test Yourself

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IN THIS MODULE

The Adaptive Immune System CellMediated and Humoral Response Modulation of the Immune Response Summary Test Your Knowledge

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Stem Cells Stem cells are powerful tools in biology and medicine. What can scientists do with these cells and their incredible potential?

PRIMARY LITERATURE

Biodiversity loss increases infectious diseases among humans http://www.nature.com/principles/ebooks/principlesofbiology104015/29145901/1 3/4 4/7/2015 Adaptive Immunity | Principles of Biology from Nature Education Impacts of biodiversity on the emergence and transmission of infectious diseases. View | Download

A new technique for detecting autoimmune diseases Autoantigen discovery with a synthetic human peptidome. View | Download

Synthetic ligand may help treat autoimmune disorders Suppression of TH17 differentiation and autoimmunity by a synthetic ROR ligand. View | Download

Controlling inflammation to stop sepsis Amelioration of sepsis by inhibiting sialidasemediated disruption of the CD24 SiglecG interaction. View | Download

Live imaging tracks immune rejection of transplanted tissue Visualizing the innate and adaptive immune responses underlying allograft rejection by twophoton microscopy. View | Download

Geneticallymatched iPS cells more immunogenic than ES cells Immunogenicity of induced pluripotent stem cells. View | Download

Identifying genes linked to cystic fibrosis Genomewide association and linkage identify modifier loci of lung disease severity in cystic fibrosis at 11p13 and 20q13.2. View | Download

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contents Principles of Biology

167 Adaptive Immunity CellMediated and Humoral Response There are two types of adaptive immune response: a cellmediated response and a humoral response. In the cellmediated immune response, receptors responsible for the recognition and destruction of pathogens are embedded in the plasma membrane. In the humoral response, receptors called antibodies are secreted into the blood. T cells are responsible for the cell mediated response, which targets intracellular pathogens and cancer cells. Antibodysecreting B cells are responsible for the humoral response, which targets bacteria and other pathogens in the bloodstream and other tissues.

Cellmediated response. T cells, which are responsible for the cellmediated response, have receptors embedded in the plasma membrane that are able to bind antigen fragments presented on MHC molecules. The antigen fragments are derived from a foreign pathogen that was engulfed by a cell or that entered the cell during infection. The antigen fragments are bound to newly synthesized MHC molecules in vesicles passing through the endomembrane system on the way to the plasma membrane. When the MHC molecule reaches the cell surface, it presents an epitope of the antigen fragment to other immune cells. Because this process relies on the internalization of mostly extracellular antigens through endocytosis, it is also known as the endocytic pathway of antigen presentation. There are two classes of MHC: class I and class II. Class I MHC (MHC I) molecules, which are present on the surface of virtually all nucleated cells, are used by the immune system to detect infected cells or other anomalous cells, such as cancerous cells. Class II MHC (MHC II) molecules are present primarily on antigenpresenting cells (APCs). APCs are used by the immune system to communicate with and activate other cells needed for eliminating the pathogen. Dendritic cells, macrophages, and B cells are all APCs.

APCs are able to activate a type of T cell called a Helper T cell (TH). Often, this activation occurs in the lymph nodes, where antigenpresenting cells + migrate after engulfing a pathogen. TH cells are also called CD4 T cells because of the presence of the CD4 glycoprotein on their cell surface. The CD4 glycoprotein, together with the antigen receptor, is able to recognize and bind a MHC IIantigen complex. Binding causes both the APC and the helper T cell to release cytokines, small proteins that regulate other cells, inducing them to divide, migrate, change gene expression, or undergo apoptosis. Cytokines induce the helper T cell to proliferate through a process called clonal expansion. During clonal expansion, TH cells differentiate into memory cells and several types of effector cells, which also release cytokines (Table 1). Memory cells remain in the bloodstream where they can elicit a future response to the same pathogen. Effector cells activate other cells of the immune system, including B cells and another type of T cell called cytotoxic T cells.

CD4+ T Cytokine(s) Function cell type produced

TH1 IFNγ, TNFβ Activates TC cells and macrophages IL4, IL5, IL6, Stimulates B cell proliferation and isotype T 2 H IL10, IL13 switching

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TH17 IL17 Stimulates response against bacteria and fungi Modulates immune responses; maintains T TGFβ and IL10 reg peripheral tolerance Table 1: CD4+ helper T cells can differentiate into different subtypes. IFN: interferon; TNF: tumor necrosis factor; IL: interleukin

+ Cytotoxic T cells (TC) are also known as CD8 T cells because of the presence of CD8 protein on their cell surface. Cytotoxic T cells are able to recognize and bind antigens displayed on MHC I molecules. Although virtually all nucleated cells express MHC I, cytotoxic T cells typically only target cells displaying a foreign antigen. If the TC cell is activated by cytokines released by TH cells, upon binding a MHC Iantigen complex, the cytotoxic T cell releases perforin molecules that form pores in the plasma membrane of the infected cell and granzymes that enter the infected cell and cleave precaspases, releasing caspases. Caspases are involved in a cascade leading to apoptosis.

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Figure 3: The interaction of TH cells and TC cells in cellmediated response. Upon binding to an MHC IIantigen complex presented on the surface of an antigenpresenting cell, a TH cell is activated and proliferates, forming memory and effector cells. Effector TH cells activate a TC cell, which destroys an infected cell presenting an MHC Iantigen complex. © 2014 Nature Education All rights reserved.

Cytotoxic T cells can also kill cells through another pathway that involves interaction between FasL, a ligand expressed on cytotoxic T cells, and the Fas receptor, which is expressed on the surface of most cells. Binding of FasL to Fas triggers a caspasesignaling cascade that results in apoptosis of the target cell. http://www.nature.com/principles/ebooks/principlesofbiology104015/29145901/2 3/6 4/7/2015 Adaptive Immunity | Principles of Biology from Nature Education Humoral response. B cell receptors are able to recognize epitopes unassociated with MHC molecules. When an antigen binds to a B cell receptor, the B cell undergoes clonal expansion and differentiates into memory B cells and plasma cells. Plasma cells are able to secrete antibodies into body fluids such as blood, lymph, mucus, and milk.

Figure 4: Clonal expansion of B cells. Each mature B cell has a unique antigen receptor that recognizes a particular antigen. Upon antigen binding, a B cell undergoes clonal expansion and differentiates into memory cells and plasma cells, which secrete antibodies. © 2014 Nature Education Adapted from Nossal, G. J. V. The double helix and immunology. Nature 421, 440–444 (2003) doi:10.1038/nature01409. All rights reserved.

During differentiation, plasma cells develop the ability to produce different forms, or isotypes, of antigen receptor. Humans produce five different isotypes, called immunoglobulins (Ig): IgA, IgD, IgE, IgG, and IgM (Table 2). Isotype D is the antigen receptor found in naive B cells (B cells that have not been exposed to antigen). After exposure to antigen, isotype switching occurs, and the B cell begins to produce immunoglobulin of a different isotype. The type of immunoglobulin produced depends on the stimulating signals the B cell received during differentiation. IgD is embedded in the plasma membrane. The other isotypes are all secreted as antibodies. Mature B cells may switch from producing one immunoglobulin type to another in the presence of certain stimulatory signals. http://www.nature.com/principles/ebooks/principlesofbiology104015/29145901/2 4/6 4/7/2015 Adaptive Immunity | Principles of Biology from Nature Education

Antibody Stimulating Primary antibody Antibody isotype cytokine(s) from function distribution CD4+ T cells Mucous Neutralization of secretions, IgA TGFβ pathogens milk, saliva, etc. Produced by default Cellsurface B cell IgD without cytokine Blood receptor stimulation Activation of mast cells IgE IL4 and basophils in Tissues allergic reactions Opsonization of IgG (4 IFNγ, IL4, or TGFβ pathogens, Blood, subclasses (depending on complement activation lymph, in humans) subclass) (depending on tissues subclass) Initially produced by default on cell Responsible for early IgM surface; later immunity; activates Blood secreted as complement pentamer Table 2: Types of antibodies. The constant region of an antibody determines its isotype and function. The isotype produced by a given B cell depends on whether it is activated and what type of cytokines it encountered.

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Antibodies prevent damage by an invading pathogen in a number of different ways. They may simply neutralize a pathogen by binding to epitopes that are necessary for its biological function or infective potential. They may target the pathogen for phagocytosis by macrophages or neutrophils, a process called opsonization. Or they may activate the complement system, which forms pores in the plasma membrane and lyses the cell. B cells can also internalize antigen and present it on MHC II molecules, which activates TH cells. Cytokines released from effector TH cells, in turn, can activate B cells. A single receptorantigen interaction is also not enough to activate B and T cells; a threshold of intracellular signaling must occur for the cell to clonally expand. Thus, a variety of mechanisms are used to ensure that an immune response is only launched when it is appropriate.

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PRIMARY LITERATURE

Biodiversity loss increases infectious diseases among humans Impacts of biodiversity on the emergence and transmission of infectious diseases. View | Download

A new technique for detecting autoimmune diseases Autoantigen discovery with a synthetic human peptidome. View | Download

Synthetic ligand may help treat autoimmune disorders Suppression of TH17 differentiation and autoimmunity by a synthetic ROR ligand. View | Download

Controlling inflammation to stop sepsis Amelioration of sepsis by inhibiting sialidasemediated disruption of the CD24 SiglecG interaction. View | Download

Live imaging tracks immune rejection of transplanted tissue Visualizing the innate and adaptive immune responses underlying allograft rejection by twophoton microscopy. View | Download

Geneticallymatched iPS cells more immunogenic than ES cells Immunogenicity of induced pluripotent stem cells. View | Download

Identifying genes linked to cystic fibrosis Genomewide association and linkage identify modifier loci of lung disease severity in cystic fibrosis at 11p13 and 20q13.2. View | Download

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contents Principles of Biology

167 Adaptive Immunity Modulation of the Immune Response The adaptive immune system must be capable of responding to a pathogen quickly enough to minimize damage; yet at the same time the adaptive immune system must be able to recognize self so that the body's own cells are not destroyed.

Immunological memory. Initially, the adaptive immune response is relatively slow: for a pathogen not previously encountered, the adaptive immune response does not begin until 3 days after infection and peaks around 7–10 days. Subsequent response is much faster, peaking around 3 days. The secondary response is also stronger because of the relatively large pool of existing memory cells. This enhanced response is important because the same pathogens may often be encountered numerous times. However, although the adaptive immune system is able to remember a particular strain it encountered previously, it is often unable to recognize new, slightly different strains. For example, more than 100 strains of rhinovirus, which causes the common cold, exist, and the adaptive immune system only recognizes ones previously encountered. Many pathogens are also able to rapidly evolve so they are no longer recognized by the immune system. For example, the influenza virus mutates at such a rapid pace that new vaccines must be produced each year. The specificity of immune response makes it difficult for the immune system to respond quickly to new threats, but it is also protective: the specificity helps ensure that the immune system does not attack the body's own cells.

Selfrecognition and dampening of the immune response. The immune system has two mechanisms called central tolerance and peripheral tolerance to avoid inappropriate activation. Central tolerance is a process that prevents the maturation of selfreactive B and T cells. If a B or T cell expresses a receptor that reacts with self antigens (antigens on the body's own cells), it is induced to undergo apoptosis, a process called clonal deletion. Clonal deletion of B cells occurs in the bone marrow, and clonal deletion of T cells occurs in the thymus. Prior to clonal deletion, T cells undergo a process called positive selection. During positive selection, only T cells capable of binding MHC molecules receive stimuli necessary for maturation. T cells that do not recognize MHC molecules die. This process ensures that all mature T cells are able to recognize MHC molecules. Although many B cells are removed through clonal deletion, some are able to alter a selfreactive receptor through receptor editing. In receptor editing, gene rearrangements occur in a mature receptor, changing its specificity so that it is no longer selfreactive. Peripheral tolerance includes a number of processes that inactivate mature selfreactive lymphocytes that escaped clonal deletion, and dampen immune responses against harmless antigens that are abundant in the environment. Immune dampening is mediated in part by a type of helper T cell called regulatory T cells (Treg). Another peripheral tolerance process is called anergy. In anergy, immune cells that encounter an antigen in the absence of costimulatory signals, such as cytokines, may be rendered inactive. When central or peripheral tolerance fails, an autoimmune response — an inappropriate attack against the body's own tissues — can occur. Failure of peripheral tolerance may also result in an inappropriate immune response, or allergic reaction, against a harmless antigen called an allergen. http://www.nature.com/principles/ebooks/principlesofbiology104015/29145901/3 1/3 4/7/2015 Adaptive Immunity | Principles of Biology from Nature Education Test Yourself

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The Adaptive Immune System CellMediated and Humoral Response Modulation of the Immune Response Summary Test Your Knowledge

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Stem Cells Stem cells are powerful tools in biology and medicine. What can scientists do with these cells and their incredible potential?

PRIMARY LITERATURE

Biodiversity loss increases infectious diseases among humans Impacts of biodiversity on the emergence and transmission of infectious diseases. View | Download

A new technique for detecting autoimmune diseases Autoantigen discovery with a synthetic human peptidome. View | Download

Synthetic ligand may help treat autoimmune disorders Suppression of TH17 differentiation and autoimmunity by a synthetic ROR ligand. View | Download

Controlling inflammation to stop sepsis Amelioration of sepsis by inhibiting sialidasemediated disruption of the CD24 SiglecG interaction. View | Download

Live imaging tracks immune rejection of transplanted tissue Visualizing the innate and adaptive immune responses underlying allograft rejection by twophoton microscopy. View | Download

Geneticallymatched iPS cells more immunogenic than ES cells Immunogenicity of induced pluripotent stem cells. View | Download

Identifying genes linked to cystic fibrosis Genomewide association and linkage identify modifier loci of lung disease severity in cystic fibrosis at 11p13 and 20q13.2. View | Download

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contents Principles of Biology

167 Adaptive Immunity Summary OBJECTIVE Explain how gene splicing results in differentiated receptors. An antigen receptor has two regions: a constant region that is the same among all receptors of that class and a variable region that is different. The variable region is composed of two or more gene segments. For example, in the B light chain, the variable region consists of a V (variable) segment and a J (joining) segment. The heavy chain has an additional segment, called the D (diverse) segment. In an undifferentiated cell, the gene encoding the antigen receptor contains multiple unique copies of each of these segments. During maturation of the leukocyte, an enzyme called recombinase catalyzes V(D)J recombination, a process in which two segments are chosen at random and spliced together. In the mature cell, an intron remains between the variable region and the constant region. This intron is spliced out during mRNA processing. As a result of gene and mRNA splicing, each antigenexpressing leukocyte expresses a unique antigen receptor.

OBJECTIVE Describe the cellmediated response. The cellmediated immune response targets intracellular pathogens, such as viruses, and cancer cells. In the first step of the cellmediated response, antigenpresenting cells (APCs) such as dendritic cells and macrophages engulf and destroy pathogens and present antigen fragments on MHC II molecules embedded in the plasma membrane. Helper T cells (TH) that recognize MHC IIantigen complex undergo clonal expansion and differentiate into memory cells and effector cells. Some effector cells release cytokines that activate a second type of T cell, called a cytotoxic T cell (TC). If an activated TC cell binds an MHC Iantigen complex present on an infected cell, it release granzymes and perforins that kill the cell.

OBJECTIVE Describe the humoral response. The humoral response targets extracellular pathogens. B cells that are able to recognize antigens on the pathogen undergo clonal expansion and differentiate into memory cells and plasma cells. Plasma cells release antibodies that target the antigen on the pathogen. Antigen binding may render the pathogen inactive directly, for example by covering receptors essential for infection, or antigen binding may target the pathogen for destruction by other components of the immune system. Destruction of an antibodytagged pathogen by macrophages or neutrophils is called opsonization. The pathogen may also be destroyed by the complement system.

OBJECTIVE Describe how immunological memory is formed. Memory cells are created during clonal expansion of T and B cells during the primary adaptive immune response. During a secondary infection, these memory cells are able to react quickly, and because the pool of memory cells is relatively large, the response is stronger than the initial one. Thus, the secondary response occurs in 3 days rather than the 7–10 days needed for an initial response.

OBJECTIVE Describe how the immune system prevents inappropriate immune responses. In central tolerance, developing B and T cells that respond to self antigens are destroyed in the bone marrow and thymus, through a process called clonal deletion. Prior to clonal deletion, only T cells that are able to recognize MHC molecules are allowed to mature, ensuring that all T cells can http://www.nature.com/principles/ebooks/principlesofbiology104015/29145901/4 1/4 4/7/2015 Summary of Adaptive Immunity | Principles of Biology from Nature Education recognize MHC molecules. In peripheral tolerance, various mechanisms of the immune system dampen immune response. For example, Treg cells release cytokines that dampen some immune responses, and immune cells that encounter an antigen in the absence of immune signals, such as cytokines, undergo anergy, a process in which they are inactivated.

Key Terms adaptive immunity Specific immune response induced by the presence of a particular antigen. antibody An antigen receptor that is secreted into fluids of the body. antigen A substance that elicits a response from the adaptive immune system; typically a large molecule such as a protein or polysaccharide. antigen receptor A receptor, present in B or T cells, that binds antigen.

antigenpresenting cells (APCs) Immune cells that engulf and process antigens into epitopes for presentation on MHC II molecules at the cell surface; can be used to induce or continue immune responses; include dendritic cells, macrophages, and B cells. autoimmune response An inappropriate immune response mounted by the immune system against the body's own cells or tissues. B cell The main component cell of the humoral adaptive immune response; differentiates into antibodyproducing plasma cells and memory B cells upon activation. B cell receptor (BCR) The cell surface receptor on B cells that is responsible for binding antigenic epitopes; membranebound form of the secreted antibody produced by the same B cell. CD4+ T cell Also known as helper T cells or TH cells; cell in the adaptive immune response that coordinates immune responses by secreting cytokines and interacting with other immune cells; required for B cell activation and cytotoxic T cell activation. CD8+ T cell Also known as cytotoxic T cells or TC cells; cell in the adaptive immune response that secretes substances to directly destroy infected or aberrant host cells. cellmediated response The arm of the adaptive immune system mediated by CD4+ and CD8+ T cells; used to fight intracellular infections or destroy cancerous cells. central tolerance The mechanisms that prevent the formation of selfreactive T or B cells during development in the thymus or bone marrow, respectively, by deleting any T or B cell precursors with a receptor that responds to self antigens.

clonal expansion Proliferation of T and B cells after activation to create both effector cells responsible for fighting the current infection as well as memory cells for future exposures to the same antigen. cytokine A small protein secreted from immune cells that triggers a response in other cells.

dendritic cell One type of antigenpresenting immune cell that processes antigenic material and presents it on its surface for detection by other cells of the immune system; resident in skin and mucous membranes. epitope A specific surface feature of an antigen that is recognized by an antigen receptor; http://www.nature.com/principles/ebooks/principlesofbiology104015/29145901/4 2/4 4/7/2015 Summary of Adaptive Immunity | Principles of Biology from Nature Education a given antigen may have many epitopes. granzyme Cytotoxic enzyme secreted from the granules of cytotoxic T cells that induces apoptosis in the target cell by cleaving and activating caspases. humoral response The arm of the adaptive immune system mediated by B cells; produces antibodies, which disable pathogens or mark them for destruction or phagocytosis. immunoglobulin Also known as an antibody; a soluble complex polypeptide which circulates through the body searching for the specific antigen; secreted, soluble form of the B cell receptor of the B cell that created the antibody.

immunoglobulin (Ig) heavy chain In an antibody molecule or BCR, one of the two longer polypeptide chains. immunoglobulin (Ig) light chain In an antibody molecule or BCR, one of the two shorter polypeptide chains. immunological memory The adaptive immune system produces memory cells that are able to trigger a faster, stronger response if the same pathogen is encountered again. isotype switching Process of switching the type of heavy chain constant region of an antibody, as determined by the cytokine profile of the immune response; accomplished at the DNA level. lymphocyte Type of blood cell in the vertebrate immune system that includes B cells, T cells, and natural killer cells. major histocompatibility complex (MHC) A protein complex on the cell surface used to present antigens on the cell surface for signaling to other immune cells. neutralization Mechanism by which antibodies disable pathogens by binding to epitopes required for biological activity or infective potential. opsonization Mechanism by which antibodies coat pathogens, marking them for phagocytosis. perforin Cytotoxic molecule secreted by cytotoxic T cells that inserts itself in the plasma membrane of target cells, making a pore that results in lysis. peripheral tolerance Mechanisms that inactivate or dampen immune response of mature selfreactive T or B cells that have escaped central tolerance and entered the circulation; includes mechanisms such as induction of anergy and suppression by Treg cells. recombinase An enzyme that splices antigen receptor genes in B and T cells to produce mature antigen receptors. + regulatory CD4 T cells (Treg) Effector cells that promote peripheral tolerance by suppressing immune responses by other cells. self antigens Antigens present on the body's own cells. T cell receptor (TCR) Receptor on T cells that is responsible for binding antigenic epitopes presented on MHC molecules. V(D)J recombination DNA splicing that occurs with antigen receptor genes of immature lymphocytes; results in a unique variable region for each mature B or T cell receptor.

IN THIS MODULE http://www.nature.com/principles/ebooks/principlesofbiology104015/29145901/4 3/4 4/7/2015 Summary of Adaptive Immunity | Principles of Biology from Nature Education

The Adaptive Immune System CellMediated and Humoral Response Modulation of the Immune Response Summary Test Your Knowledge

WHY DOES THIS TOPIC MATTER?

Stem Cells Stem cells are powerful tools in biology and medicine. What can scientists do with these cells and their incredible potential?

PRIMARY LITERATURE

Biodiversity loss increases infectious diseases among humans Impacts of biodiversity on the emergence and transmission of infectious diseases. View | Download

A new technique for detecting autoimmune diseases Autoantigen discovery with a synthetic human peptidome. View | Download

Synthetic ligand may help treat autoimmune disorders Suppression of TH17 differentiation and autoimmunity by a synthetic ROR ligand. View | Download

Controlling inflammation to stop sepsis Amelioration of sepsis by inhibiting sialidasemediated disruption of the CD24 SiglecG interaction. View | Download

Live imaging tracks immune rejection of transplanted tissue Visualizing the innate and adaptive immune responses underlying allograft rejection by twophoton microscopy. View | Download

Geneticallymatched iPS cells more immunogenic than ES cells Immunogenicity of induced pluripotent stem cells. View | Download

Identifying genes linked to cystic fibrosis Genomewide association and linkage identify modifier loci of lung disease severity in cystic fibrosis at 11p13 and 20q13.2. View | Download

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