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CIMZIA® Rheumatoid Arthritis Print Learning System Module 1: The Immune System

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Module 1: The Immune System

Table of Contents Introduction to Module 1.......................................................................................3 Overview of the Immune System .....................................................................................3

Case Study........................................................................................................................4 Lesson 1: Molecules and Cells of the Immune System ....................5 Learning Objectives ...........................................................................................................6 Important Immune System Molecules .............................................................................6 Cells of the Innate Immune Response .............................................................................9 Summary ..........................................................................................................................14 Self-Check Questions .......................................................................................................15

Lesson 2: Introduction to Adaptive Immunity.......................................18 Learning Objectives .........................................................................................................18 Types of Adaptive Immunity ...........................................................................................18 Characteristics of the Adaptive Immune Response .......................................................19 Cells of the Adaptive Immune Response .......................................................................20 Lymphocytes ....................................................................................................................21 Five Phases of the Adaptive Immune Response ............................................................21 Summary ..........................................................................................................................23 Self-Check Questions .......................................................................................................24

Lesson 3: Humoral and Cell-Mediated Immune Response .........27 Learning Objectives .............................................................................................................27 Humoral Immunity ..........................................................................................................27 B-Cell Activation ...............................................................................................................28 Antibodies ........................................................................................................................29 Cell-Mediated Immunity ..................................................................................................33 T-Cell Activation ...............................................................................................................33 T-Cell Differentiation and Proliferation ...........................................................................34

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Introduction to Module 1

Module 1: The Immune System

Summary ..........................................................................................................37 Self-Check Questions ........................................................................................39

Lesson 4: Inflammation and TNF-α ...............................................43 Learning Objectives ...........................................................................................43 Inflammatory Response ....................................................................................44 Development and Symptoms of Inflammation ...............................................44 Migration of White Blood Cells into Tissue ......................................................45 Cell Death and Inflammation ...........................................................................48 Overview of Tumor Necrosis Factor .................................................................48 Structure and Source of TNF-α ..........................................................................49 Sources and Targets of TNF-α ...........................................................................50 Biologic Actions of TNF-α ..................................................................................51 Summary.............................................................................................................53 Self-Check Questions ........................................................................................ 55

Lesson 5: Adverse Immune Response............................ 58 Learning Objectives.................................................................................... 58 Hypersensitivity Reactions....................................................................... 59 Autoimmune Disease................................................................................. 62 Summary ....................................................................................................... 64 Self-Check Questions.................................................................................. 65

Case Study.................................................................................................. 67 Answers to Self-Check Questions........................................ 68 Lesson 1.......................................................................................................... 68 Lesson 2.......................................................................................................... 68

Introduction to Module 1 The body’s immune system defends us daily from invaders that compromise our health. There are several components and actions of the immune system that provide this protection. Different units of the body’s immune system have specific functions, but work together to prevent infection and disease. A healthy immune system is regulated so that an immune response is initiated against infectious agents, such as viruses, bacteria, and other microorganisms that are foreign to the body. However, there are several disease conditions in which an abnormal immune response is mounted against the body’s own proteins and cells. Such diseases are called autoimmune diseases. This module will discuss the components of the immune system and their functions, as well as what happens in autoimmune disease. Solid background knowledge of the immune system will be key to understanding the therapeutic action of CIMZIA®, which will be covered in later modules.

Overview of the Immune System The immune system is the body’s protection against diseasecausing agents. Two basic divisions of the immune system are innate immunity and adaptive immunity. Innate immunity (also called natural or nonspecific immunity) includes anatomic and physiologic barriers as well as cellular and biochemical responders that are in place prior to infection and are ready to respond rapidly when infectious agents are presented to the body (1). Components of this innate immune response are the first to defend against infection. Other mechanisms are only activated upon exposure to a specific invader, and the response is amplified with each successive exposure to that specific invader (1). This is described as adaptive immunity. Most cells involved in both innate immunity and adaptive immunity (also called acquired immunity) are collectively called leukocytes, more commonly known as white blood cells.

Lesson 3.......................................................................................................... 69

leukocytes white blood cells; granular leukocytes are basophils, eosinophils, and neutrophils, and nongranular leukocytes are lymphocytes and monocytes (macrophages and dendritic cells)

white blood cells cells of the immune system; leukocytes

Lesson 4.......................................................................................................... 69 Lesson 5.......................................................................................................... 69

Glossary......................................................................................................... 70 References.................................................................................................. 73 Confidential – For Internal Training Purposes only.

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Lesson 1: Molecules and Cells of the Immune System

Module 1: The Immune System

Case Study Robert is 62 years old. He is a father of 3 and grandfather of 4. Until recently, Robert has enjoyed keeping up with his young grandchildren, teaching them how to play baseball and showing them how to grow vegetables in his garden. Lately he is experiencing more and more pain in his hands and wrists when gripping the baseball bat or digging in the garden. Though it may hurt, he still keeps active through the pain. Robert thinks he is fine—pain is just a part of getting older—however, his wife has pressured him into paying a visit to his general practitioner. Throughout this module and upcoming modules in this learning system, you will learn more about Robert and his experiences that will eventually lead to a diagnosis of rheumatoid arthritis (RA).

Lesson 1. Molecules and Cells of the Immune System Most people think of the immune system in terms of circulating white blood cells. In actuality, the immune system includes more than just white blood cells. Immune protection begins at the exterior of the body with the skin, which acts as an anatomic barrier. Other anatomic barriers include mucous membranes (7) and cilia (5, 8). Other non-cellular barriers are physiologic barriers such as: • Temperature: Febrile response inhibits growth of some pathogens (7)

cilia motile extensions of a cell surface

• Low pH: Acidity of certain body fluids (eg, gastric juice) can also provide protection by destroying microbes before they invade the body (5, 8)

febrile

• Chemical mediators: Lysozyme (an enzyme) cleaves the bacterial cell wall and complement lyses microorganisms or facilitates phagocytosis

complement

denoting or related to fever

microbe a minute living organism

a group of serum proteins involved in the control of inflammation, the activation of phagocytes, and the lytic attack on cell membranes

When anatomic and physiologic barriers do not inhibit invasion of the body by foreign substances, cellular and molecular immune system responses are initiated. These components of the immune system are crucial to protection against invasion and infection by foreign substances. Although each cell and molecule of the immune system has its own set of functions, they also work together to protect the body.

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Lesson 1: Molecules and Cells of the Immune System

Module 1: The Immune System

Learning Objectives

Figure 1: Cytokine Function

CYTOKINES

At the completion of this lesson, you should be able to: • Name 3 important types of immune system molecules and describe their functions • Describe which immune cells are of myeloid origin and which are of lymphoid origin • List cells that are phagocytic • State the functions of B cells and T cells

Important Immune System Molecules Some cells of the immune system release molecules to promote various immune system responses. Three very important molecules of the immune system are cytokines, antibodies, and complement.

Innate Immunity

Adaptive Immunity

Hematopoiesis

Viruses and lipopolysaccharide (LPS) secreted by bacteria stimulate macrophages to secrete cytokines

Secreted by macrophages activated by antigen-stimulated T cells

Produced by cells in bone marrow, leukocytes, and other cells to stimulate growth and differentiation of lymphocytes (B cells and T cells)

Regulate differentiation of T cells Act on endothelial cells and leukocytes to initiate an inflammatory response Regulate cells in the inflammatory response

Recruit phagocytes, neutrophils, and eosinophils in the cell-mediated immune response to eliminate antigens

Can be produced by NK cells

NK = natural killer.

Cytokines Cytokines are produced by many immune cell types and are principal mmatory mediators of inflammatory and immune reactions (1). One cytokine, tumor necrosis - factor-alpha (TNF-α), is the target of the therapeutic action of certolizumab pegol. Cytokines are involved in many aspects of both the innate and adaptive immune responses (Figure 1). For this reason, cytokines are targeted by several therapeutic agents for inflammatory disease conditions, such as rheumatoid arthritis (RA) and Crohn’s disease. General functions of cytokines include (1): endothelial cells the simple squamous cells forming the lining of blood and lymph vessels and the inner layer of the endocardium

phagocytes any cell capable of ingesting particulate matter

lymphocyte any of the nonphagocytic, mononuclear leukocytes found in the blood, lymph, and lymphoid tissues that are the body’s immunologically competent cells and their precursors; includes T cells, B cells, and natural killer cells

hematopoiesis the formation or development of blood cells

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• Mediation and regulation of other immune cells and endothelial cells to stimulate early inflammatory reactions • Recruitment of mononuclear phagocytes, neutrophils, and eosinophils (immune cells) • Stimulation and growth of lymphocytes (mostly T cells) in response to T-cell activation (part of the adaptive immune response) • Stimulation of hematopoiesis, including growth and differentiation of immature leukocytes

There are many classes of cytokines with different functions. The 5 primary classes of cytokines include (8): • Interferons (IFNs)—limit (or interfere with) the spread of viral infections and are the first line of defense against many viruses • I nterleukins (ILs)—involved in directing other cells to divide and differentiate • C olony-stimulating factors (CSFs)—involved in directing hematopoiesis • C hemokines—direct chemotaxis of immune cells from the blood stream into tissues

chemotaxis orientation of a cell along a chemical concentration gradient or movement in the direction of the gradient, either toward (positive chemotaxis) or away from (negative chemotaxis) the greater concentration of the substance, referred to as a chemotactic factor, chemotactin, or chemoattractant

inflammation a series of reactions that bring cells and molecules of the immune system to sites of infection or damage

• T umor necrosis factors (TNFs)—have a variety of functions and play important roles in mediating inflammation and cytotoxic reactions

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Lesson 1: Molecules and Cells of the Immune System

Module 1: The Immune System

Antibodies Antibodies are molecules released by a type of lymphocyte called B lymphocytes (or B cells). Antibodies alone do not cause the destruction and elimination of infectious microbes, but antibodies may activate complement proteins and cells of the innate immune system, leading to the eradication of substances that have been bound by the antibodies. Antibodies, also called immunoglobulins (Ig), will be discussed in detail in a later lesson.

Complement The complement system is made up of about 20 different serum and cell surface proteins that interact with one another and with other molecules of the immune system (1, 8). serum clear, watery fluid, especially that moistening the surface of serous membranes or exuded in inflammation of any of those membranes

Flash Forward Inflammation is a complex reaction of the innate immune system in which leukocytes accumulate at a site of tissue infection. Though inflammation controls infection and promotes tissue repair, it can also cause tissue damage and disease.

After birth, a process called hematopoiesis generates all blood cells—red and white—from stem cells in the bone marrow (Figure 2) (5). A type of stem cell called a pluripotent stem cell is differentiated into either a myeloid progenitor cell or a lymphoid progenitor cell. Myeloid progenitor cells produce various nonlymphocyte cells involved in the immune response, as well as red blood cells (erythrocytes) and platelets, and lymphoid progenitor cells produce B cells, T cells, and natural killer (NK) cells. Figure 2: Differentiation of B Cells and T Cells

Self-renewing stem cell

In innate immunity, activation of complement proteins leads to uptake of invading microbes by phagocytes (8). Complement proteins also mediate inflammation and are important to a type of adaptive immunity involving antibodies called complementdependent cytotoxicity.

Pluripotent stem cell Natural killer (NK) cells Myeloid progenitor

Lymphoid progenitor Thymus

Complement proteins can influence the following:

opsonization the process by which antibodies and certain complement proteins attract phagocytes for phagocytosis

phagocytosis the process by which certain cells of the immune system, including macrophages and neutrophils, engulf large particles such as intact microbes

mast cells the major effector cell of immediate hypersensitivity reactions; respond to microbes and various mediators by secreting substances that stimulate inflammation; derived from bone marrow and reside under many epithelia and in serosal cavities

histamine a biogenic amine stored in granules of mast cells that is one of the important mediators of immediate hypersensitivity

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Cells of the Innate Immune Response

T lymphocytes

• Chemotaxis Complement protein fragments can attract phagocytic cells to the site of complement activation, toward the microbe. •O psonization and Phagocytosis Certain complement proteins as well as the antibody IgG are called opsonins. The attachment of these proteins to a microbe is called opsonization (1). When complement is bound to a microbe, complement can bind to receptors on macrophages and neutrophils, causing phagocytosis (1, 5). • I nflammatory Response Certain complement proteins, when bound to a microbe, bind to mast cells causing the release of histamine. This leads to recruitment of leukocytes at the site of inflammation.

G ranu lo c ytes

M o no nu c lear phagocytes

B lymphocytes

Basophils

Eosinophils

Neutrophils

Monocytes

Dendritic cells

Macrophages

One pluripotent self-renewing stem cell can give rise to a copy of itself and an entire extended family of blood cells, including the white blood cells (eg, granulocytes, mononuclear phagocytes, and lymphocytes) and red blood cells (not shown). Lymphocytes are derived from lymphoid progenitor cells. Other blood cell types are derived from myeloid progenitor cells. Dendritic cells may be derived either from myeloid or lymphoid progenitor cells.

Let’s first look at immune cells of myeloid lineage. These cells are involved in the innate immune response, although some have a key role in the activation of lymphocytes for the adaptive immune response.

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Lesson 1: Molecules and Cells of the Immune System

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Module 1: The Immune System

Myeloid Cells

Mononuclear Phagocytes

Immune cells that are derivatives of myeloid lineage can have different properties. Two classifications of immune cells based on cell properties include phagocytes and granulocytes. Some cells may be both phagocytes and granulocytes, and some may only be classified as one or the other.

Mononuclear phagocytes develop in the bone marrow and circulate in the blood as monocytes (1). Mature monocytes called macrophages reside in body tissue. In addition to activity in the innate immune response, macrophages have an important function in the adaptive immune response (1).

Phagocytes

Dendritic Cells

A group of specialized immune cells can eradicate an invading organism by engulfing or ingesting it and then destroying it. This process, called phagocytosis, is a fundamental mechanism and is carried out by several cell types. Phagocytes can form pseudopods, projections of cytoplasm that look like fingers. These projections wrap around the invading microbe. Once the microbe is inside the phagocyte, different chemical processes, depending on the type of phagocyte, destroy the ingested microbe with enzymes (Figure 3) (8). Figure 3: A Phagocyte Engulfing a Microbe

Phagocyte Microbe

Lysosome

Enzyme

vesicle a closed structure surrounded by a single membrane

phagosome

Microbe digested by enzymes

a membrane-bound, acidic organelle abundant in Phagosome Microbe digested by enzymes phagocytic cells that contains proteolytic enzymes that degrade proteins; involved in class II major histocompatibility complex pathways of antigen processing

When a macrophage detects a bacterium, it engulfs the invader in a vesicle called a phagosome; another vesicle, an enzyme-filled lysosome, fuses with the phagosome, and the microbe is digested (lysed).

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a type of bone marrow-derived circulating blood cell that is a precursor of tissue macrophages

macrophages tissue-based phagocytic cells involved in innate and adaptive immune responses

antigen molecules that bind to antibodies or T-cell receptors

Granulocytes Granulocytes are cells that contain granules that, when signaled, release enzymes and other molecules that facilitate destruction of infectious organisms (8). Such cells include neutrophils, eosinophils, and basophils. These cells are also phagocytic, but are not mononuclear phagocytes. Basophils are a type of granulocyte that are not phagocytic (8). Basophils and another type of cell that is not a white blood cell called mast cells are considered auxiliary cells. The main function of auxiliary cells is to recruit other immune cells and soluble mediators of the inflammatory response at a site of infection through the release of inflammatory mediators (8).

Neutrophils

Phagosome

a membrane-bound intracellular vesicle that contains microbes or particulate material from the extracellular environment

lysosome

There is evidence that dendritic cells, a phagocytic cell type, may be derived from myeloid or lymphoid cells. These cells become activated upon interaction with an infectious microbe and cytokines. Immature dendritic cells capture antigens and upon stimulation by inflammatory cytokines, they mature and play an important role in the adaptive immune response.

monocytes

Neutrophils are a type of granulocyte that have phagocytic capability. Derived from bone marrow, neutrophils are the most abundant type of white blood cell in the circulation and are the major cell type that mediates acute inflammatory responses to bacterial infections (1). The enzymes contained in granules contribute to the destruction of invading microbes.

Flash Fact Mast cells are similar to basophils, but they are not a type of leukocyte. They reside within mucosae and in connective tissue. These cells also contain granules rich in the chemical histamine. Histamine increases vascular permeability and contraction of bronchial and intestinal smooth muscle.

mucosae plural of mucosa—a mucous tissue lining various tubular structures in the body consisting of epithelium, lamina propria, and, in the digestive tract, a layer of smooth muscle

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Lesson 1: Molecules and Cells of the Immune System

Module 1: The Immune System

Eosinophils These cells are active in inflammation and can release toxic substances to destroy microbes (1). A special feature of eosinophils is that they can target and eliminate large invaders, such as parasites (8). Eosinophils are also phagocytic.

Basophils

Helper T cells—Helper T cells perform a variety of functions depending on the cytokines they release, including activation of macrophages and promotion of antibody production by B cells (1). Cytotoxic T cells—Cytotoxic T cells directly recognize and kill host cells infected with viruses or other intracellular microbes (1).

Basophils release the chemical histamine. They do not reside in tissue but are recruited to a site of tissue infection by cytokines and T cells (8).

Flash Fact Neutrophils are sometimes called polymorphonuclear leukocytes (PML or PMN).

Lymphoid Cells With the exception of NK cells, lymphoid cells (lymphocytes) are the cells involved in the adaptive immune response. interferon-γ (IFN-γ) a cytokine produced by T cells and natural killer cells; its principal function is to activate macrophages in innate and adaptive cellmediated immune responses

A Closer Look What’s the difference between a microbe and an antigen? These terms are often used interchangeably to describe something that generates an immune response; however, they are different. Microbe – A microbe is simply defined as any very minute organism. Microbes that cause an immune response are often referred to as “infectious microbes.” Antigen – An antigen is a molecule (a protein or sugar) that binds to an antibody or T cell receptor. Antigens activate specific responders of the adaptive immune response. An antigen can be either foreign (a protein present on the cell surface of a non-self cell) or self (a protein present on the cell surface of a self cell). Antigens can be recognized by both B and T cells to initiate an adaptive immune response.

Lymphocytes are cells of the adaptive immune response. The exception to this rule is the NK cell, which is involved in innate immunity.

Natural Killer (NK) Cells Natural killer cells are lymphocytes that are the principal effector cells against viruses and act by directly releasing destructive enzymes and proteins. These cells secrete cytokines, mainly interferon gamma (IFN-γ) (1).

Flash Forward

B Lymphocytes (B Cells)

Immune system responses mediated by antibodies are called humoral responses.

B cells are the only cells in the body that can produce antibodies (1). When activated, a B cell is programmed to make only one type of antibody that specifically targets only one antigen.

T Lymphocytes (T Cells) T cells are not able to produce antibodies, but are very important to adaptive immune defenses. There are distinct subtypes of T cells that perform different functions. Two types of T cells are helper T (TH) cells and cytotoxic T (TC) cells. Furthermore, there are subtypes of TH cells (ie, type 1 and type 2 helper T cells) that release different cytokines with different functions. Another recently identified subset of TH cells called T17 cells, or IL-17-secreting helper T cells, will not be discussed

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Flash Fact

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Lesson 1: Molecules and Cells of the Immune System

Module 1: The Immune System

Summary • T hree important types of immune system molecules are cytokines, antibodies, and complement. • C ytokines are the principal mediators of inflammatory and immune reactions.

Self-Check Questions 1. The is the immune defense mechanism present in the body prior to exposure to a foreign substance. A. Cell-mediated immune response B. Humoral immune response C. Innate immune response

•A ntibodies are released by B cells and target specific antigens, leading to elimination of the targeted substance. • C omplement proteins interact with one another and other molecules of the immune system and have several actions. • I mmune cells of myeloid origin include mononuclear phagocytes (monocytes and tissue macrophages), neutrophils, eosinophils, and basophils.

D. Adaptive immune response 2. List 3 important molecular immune system mediators.

3. Which of the following is a function of phagocytes of the immune system?

• I mmune cells of lymphoid origin include B cells, T cells, and NK cells.

A. Regulate hematopoiesis

•D endritic cells may be of myeloid or lymphoid origin.

C. Differentiate naïve T cells into helper T cells or cytotoxic T cells

B. Engulf and destroy microbes

D. Produce antibodies •M ononuclear phagocytes, neutrophils, and eosinophils are phagocytic cells. •A ctivated B cells release antibodies. • T wo types of T cells are helper T cells and cytotoxic T cells. Helper T cells release cytokines and help B cells secrete antibodies. Cytotoxic T cells directly destroy cells infected with microbes.

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4. Which of the following is NOT a function of cytokines? A. Recruitment of immune cells to a site of infection B. T argeting of infectious microbes for elimination by complement- dependent cytotoxicity C. Stimulation of hematopoiesis D. Stimulation of growth and differentiation of T cells in response to T-cell activation

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Lesson 1: Molecules and Cells of the Immune System

Module 1: The Immune System

5. Which of the following is NOT a lymphoid cell?

9. Which of the following is NOT a phagocyte?

A. T cell

A. Basophil

B. B cell

B. Neutrophil

C. Eosinophil

C. Macrophage

D. Natural killer (NK) cell

D. Monocyte

6. Which of the following is NOT a type of cytokine? A. Tumor necrosis factor (TNF) B. Interleukin (IL) C. Interferon (IFN) D. Immunoglobulin (Ig) E. Chemokine F. Colony-stimulating factor (CSF) 7. True / False. Antibodies alone eliminate infectious substances by binding with antigens. 8. Lymphocytes are derived from progenitor cells in bone marrow while other immune cells are derived from progenitor cells. A. Granulocyte; phagocytic B. Non-phagocytic; phagocytic C. Myeloid; lymphoid D. Lymphoid; myeloid

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Lesson 2: Introduction to Adaptive Immunity

Module 1: The Immune System

Lesson 2: Introduction to Adaptive Immunity In Lesson 1, you learned about the important cellular and molecular responders of the immune system. Some of these responders are primarily involved in innate immune system responses and others are essential to adaptive immune responses. In this lesson, you will learn about the important responders of the adaptive immune system and mechanisms of adaptive immunity. Background knowledge of adaptive immune responses is important to understanding different aspects of the development of RA as well as the mechanism of action of different biologic drugs for the treatment of RA, including certolizumab pegol (CIMZIA®).

Learning Objectives At the completion of this lesson, you should be able to: • Name the 2 types of adaptive immunity • Name the 2 lymphocytes in adaptive immunity • Describe the maturation process of B cells and T cells • List and describe the characteristic features of adaptive immunity • Recognize the 5 phases of the adaptive immune response

Types of Adaptive Immunity

Characteristics of the Adaptive Immune Response Unlike the innate immune response, which is a general, primary response to invading pathogens, the adaptive immune response is able to recognize and react specifically to several microbial and non-microbial substances. It can specifically distinguish between closely related microbes and molecules (1). The adaptive immune response is activated after the innate immune response upon recognition of a specific antigen. Table 1 lists characteristics that are common to all mechanisms of the adaptive immune response. Table 1: Characteristics of the Adaptive Immune Response (1)

Ability to recognize and react to a particular antigen Diversity Ability to react to many different antigens Ability to remember a certain antigen and Memory mount a quick response upon subsequent exposure to that antigen Ability to mount the most appropriate Specialization response to a particular antigen Ability to regulate itself and return to the Self-limitation/ state it was in prior to activation by an homeostasis antigen Ability to distinguish self-antigens from Self-tolerance foreign antigens, which prevents the attack of self cells Specificity

The adaptive immune response provides a second level of protection from infection through a highly intricate cooperation of many cells and other components of the immune system. There are 2 types of adaptive immune response: humoral immunity and cell-mediated immunity. Humoral immunity originates with B cells, whereas cell-mediated immunity originates with T cells. While they have different functions, the 2 types work in collaboration to achieve their common goal: to eliminate the antigen.

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Lesson 2: Introduction to Adaptive Immunity

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Module 1: The Immune System

Cells of the Adaptive Immune Response

Lymphocytes

Lymphocytes are the primary cells of the adaptive immune response. There are 2 types of lymphocytes in the adaptive immune response: B lymphocytes (B cells) and T lymphocytes (T cells). Remember that the third type of lymphocyte, the NK cell, is considered a cell of the innate immune response.

Lymphocytes are the only cells in the body capable of recognizing and distinguishing between antigens (1). Once matured, lymphocytes migrate from primary lymphoid tissue (bone marrow and thymus) to secondary lymphoid tissues. Naïve (inactivated but mature) B cells and T cells reside in the secondary lymphoid organs and are activated upon exposure to an antigen. Each B cell and T cell expresses a receptor that is specific to a particular antigen. For the B cell, this receptor is a cell surface antibody. For the T cell, this receptor is the ‘T-cell [antigen] receptor’ (TCR). The body may produce 10 million different B cells and T cells, each being able to target a specific antigen (1).

Development, Differentiation, and Migration of Lymphocytes Where do B cells and T cells come from? Recall from Lesson 1 that lymphocytes are derived from lymphoid progenitor cells in the bone marrow (1). B lymphocytes fully mature within the bone marrow, but T lymphocytes migrate from the bone marrow to the thymus before they fully mature (Figure 4). After B cells and T cells mature, they enter circulation and migrate to secondary lymphoid organs and tissues, including (1, 8): lymph nodes, tonsils, and adenoids; skin; spleen; and gastrointestinal tract, urogenital tract, and respiratory tract tissue. adenoids epithelial and lymphatic encapsulated structures located on the posterior wall of the nasopharynx (above the soft palate of the mouth)

When activated by the presentation of an antigen or antigen fragment, B cells and T cells multiply—a process called proliferation—and further differentiate into cells with effector activity. This activity is different for the B cell and T cell. B-cell activation and differentiation leads to antibody production. For T cells, activation and differentiation leads to secretion of a variety of cytokines that influence the activity of other cells (8).

Flash Fact B cell = Bone marrow T cell = Thymus

proliferation growth and reproduction of similar cells

extracellular outside a cell

intracellular inside a cell

Figure 4: Lymphocyte Maturation

Five Phases of the Adaptive Immune Response The function of both the humoral immune response and the cellmediated immune response can be broken down into 5 phases (Figure 5).

Bone marrow

Stem cell

B cell

ymph nodes Tonsils Adenoids in t y tract

Thymus

Stem cell

T cell

While both B cells and T cells are derived from stem cells in the bone marrow, B cells mature in the bone marrow and T cells mature in the thymus. Both types of lymphocytes then migrate to peripheral lymphoid organs and circulate in the blood and lymph.

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Lesson 2: Introduction to Adaptive Immunity

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Module 1: The Immune System

Figure 5: Five Phases of the Adaptive Immune Response

Summary • The 2 types of adaptive immunity are humoral and cell-

1. Recognition Phase: B cells and T cells recognize a particular antigen

mediated. • The 2 main types of lymphocyte of the adaptive immune response are B cells and T cells.

2. Activation Phase: B cells and T cells proliferate (multiply)

• B cells are involved in humoral immunity. • T cells are involved in cell-mediated immunity. • B cells mature in the bone marrow, while T cells mature in the

3. Effector Phase: Extracellular and intracellular microbes are eliminated through various processes

thymus. Mature B and T cells migrate to secondary lymphoid tissue where they are then activated by specific antigens. • The characteristic features of adaptive immunity are: – Specificity

4. Homeostasis: After microbes are eliminated, the immune system returns to its resting state; most activated B cells and T cells are eliminated by apoptosis (programmed cell death)

– Diversity – Memory – Specialization – Self-limitation/homeostasis

5. Memory: Some activated B cells and T cells are preserved as memory cells that activate a more rapid and amplified response to repeat exposure by the same antigen; these memory cells are activated lymphocytes that were not destroyed by apoptosis during homeostasis, and may survive in a functionally quiescent or slowly cycling state for many years

– Self-tolerance • The 5 phases of the adaptive immune response are: – Recognition – Activation – Effector – Hoeostasis – Memory

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Lesson 2: Introduction to Adaptive Immunity

Module 1: The Immune System

Self-Check Questions 1. In the effector phase of adaptive immunity: A. B cells (B lymphocytes) and T cells (T lymphocytes) recognize a particular antigen. B. Extracellular and intracellular microbes are eliminated through various processes.

immunity is mediated by B cells and immunity is mediated by T cells.

A. Humoral; specific B. Humoral; cell-mediated C. Cell-mediated; specific D. Specific; cell-mediated

C. The immune system returns to its resting state. D. B cells and T cells proliferate. 2. Which of the following is NOT one of the 6 characteristics of the adaptive immune response?

5. Cells of the adaptive immune response are activated upon recognition of which of the following? A. An antigen B. A T cell

A. Self-limitation

C. A neutrophil

B. Diversity

D. A cytokine

C. Individuality D. Specificity 3. Which of the following is the ability of the adaptive immune system to distinguish self-antigens from foreign antigens, which prevents the attack of self cells? A. Self-tolerance B. Self-limitation C. Individuality D. Memory

6. In what phase of the adaptive immune response are lymphocytes preserved (lymphocytes that are not eliminated via apoptosis)? A. Activation B. Recognition C. Homeostasis D. Memory 7. B cells mature in the

, whereas T cells mature in the

A. Brain; thalamus B.Thymus; bone marrow C. Gastrointestinal tract; thyroid D. Bone marrow; thymus

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Lesson 3. Humoral and Cell- Mediated Immune Response

Module 1: The Immune System

8. List the 6 characteristics of the adaptive immune response. 1. 2. 3 4. 5.

Lesson 3. Humoral and CellMediated Immune Response One definition of humor found in Merriam-Webster dictionary is: “a secretion that is an excitant of activity.” Antibodies are secreted from B cells and “excite” activity of other immune system responders to eliminate infectious substances. You may think of this definition to distinguish humoral from cellmediated immunity. In this lesson, you will learn more about the activation and functions of the humoral and cell-mediated immune responses.

Learning Objectives At the completion of this lesson, you should be able to:

• Describe the functions of B cells • Label the general structure of an antibody • Name the 5 classes of immunoglobulin (Ig) and the subclasses of IgG • Differentiate complement-dependent cytotoxicity (CDC) from antibody-dependent cell-mediated cytotoxicity (ADCC) • Describe the functions of he lper T cells and of cytotoxic T cells • Describe how T cells recognize antigens for activation

Humoral Immunity Humoral immunity is the response mediated by antibodies that are present in the blood and mucosal secretions to attack foreign substances (1). Produced by B cells, antibodies recognize microbial antigens and neutralize them by binding to them, making them targets for elimination by the various immune cells and proteins discussed in Lesson 1. Antibodies are also called immunoglobulins.

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plasma cells a terminally differentiated antibody-secreting B cell with a characteristic appearance

B-Cell Activation

Antibodies

B cells are activated differently depending on the type of antigen. For most antigens, B-cell activation requires the assistance of a helper T cell. With some antigens, a naïve B cell is activated directly upon interaction of the antigen with an antigen receptor on the B cell (the cell-surface antibody). B-cell activation causes proliferation of that antigen-specific B cell.

Antibodies bind to antigens and trigger other immune cells to eradicate the infectious microbes. Antibodies alone do not cause the destruction of infectious microbes, but activation of complement proteins and phagocytic cells causes the eradication of the targeted cells. Plasma cells secrete large quantities of antibodies—up to 2,000 antibodies per second (5).

B-Cell Proliferation and Differentiation After the B cell has been activated and multiplies, the progeny B cells undergo maturation. Some mature into memory B cells while others mature into effector B cells. Effector B cells secrete antibodies and may also be called plasma cells (1). Antibodies can specifically target the antigen that stimulated the activation of the original naïve B cell. Memory B cells remain dormant in the immune system and rapidly activate upon subsequent exposure to the particular antigen that prompted their creation. The plasma cells secrete antibodies that can specifically target the antigen that stimulated the activation of the original naïve B cell (Figure 6). Figure 6: B-Cell Differentiation

Lymphocyte

Key Concept Antibodies are also called immunoglobulins. Different classes of antibodies are labeled with the prefix Ig. For example, one antibody found at high levels in mucosal secretions is IgA.

B lymphocyte (naïve)

Antibody-secreting B cell

Memory B cell

Structure of Antibodies In order to understand the structure of certolizumab pegol, it is important to first understand the structure of an antibody. When you think about the vast number of potential antigens, you can see the importance in having an immune responder with a structure that can interact with a diverse population of substances while still being able to exhibit a high degree of specificity for one antigen. Each antibody has a “Y” configuration with several identifiable fragments. The general construction of an antibody consists of 2 long, heavy chains, and 2 short, light chains (Figure 7) (5). The heavy chains extend beyond the short chains in a “tail.” This is the constant region of the antibody. The Fc region (the “tail” region that extends below the light chains) interacts with other components of the immune system, such as complement proteins and other immune cells. The antigen-binding site of the antibody is located at the top of the 2 branches of the “Y.” The 2 branches of the “Y” are the Fab regions. Variability in the region at the top of the 2 branches of the “Y” (called the variable region—shown in faded color) is what makes each antibody specific to a particular antigen (1). Furthermore, within the variable region of the antibody (on both the light and heavy chains), there are hypervariable regions called complementarity-determining regions, or CDRs. There are 3 CDRs: CDRs 1, 2, and 3.

Antibodies

Antibody-secreting B cells may also be called plasma cells

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Figure 7: General Antibody Structure

Antigen-binding site

Table 2: Classes and Function of Antibodies

Antigen

CDR1 CDR2 CDR3

Fab region

Light chain

Class

Function

Percent of Total Antibody Population

IgG

Main form of antibodies in circulation. Binds to receptors on macrophages and neutrophils.

70%–75%

IgM

Predominantly seen in early response. Functions as antigen receptors on lymphocyte surface.

~10%

IgA

Predominant antibody guarding the 15%–20% mucosal surfaces of the body, including the lining of the gastrointestinal tract. It is present in other seromucous secretions like saliva, breast milk, and tracheobronchial and genitourinary secretions.

IgD

Thought to play a role in B-cell differen- <1% tiation. Functions as antigen receptors on lymphocyte surface.

IgE

Responsible for allergic symptoms in immediate hypersensitivity reactions. Found predominantly on the surface of basophils and mast cells.

Light chain

Fc region

Heavy chain

Classes of Antibodies (Immunoglobulins) Each antibody is specific to one antigen. However, there are 5 classes of immunoglobulins based on structural differences in the constant region. Table 2 shows the 5 classes of immunoglobulins and their functions (5, 8).

Scarce

In humans, IgG and IgA can be further divided into subclasses. IgA has 2 subclasses (IgA1 and IgA2), and IgG has 4 subclasses (IgG1, IgG2, IgG3, and IgG4). Antibodies can be developed in a laboratory to target certain proteins in the body, and many antibodies created as therapy for autoimmune diseases are of the IgG1 antibody subtype.

Activity of Antibodies Antibodies travel throughout the circulation and to the tissue at the site of infection and contribute to protection from infection in the following ways (1): • Opsonization on the microbe, which recruits phagocytes to eliminate the microbe • Neutralization of microbes by blocking the ability of the microbe to bind to cells

Flash Fact Complement proteins as well as the antibody IgG are called opsonins. The attachment of these proteins to a microbe is called opsonization.

complement-dependent cytotoxicity (CDC) the process by which antigen-antibody complexes interact with complement, resulting in cell lysis

antibody-dependent cell-mediated cytotoxicity (ADCC) a process by which natural killer cells are targeted to IgG-coated cells, resulting in lysis of the antibody- coated cells

• Complement-dependent cytotoxicity (CDC) • Antibody-dependent cell-mediated cytotoxicity (ADCC) The latter 2 pathways by which antibodies cause destruction of infectious microbes, CDC and ADCC (Figure 8), are detailed below.

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Complement-Dependent Cytotoxicity (CDC) In CDC, antibodies serve to identify an antigen present on a cell as a target and activate complement to eliminate the cell by cell lysis (1, 13). Complement-dependent cytotoxicity can occur not only against infectious microbes but against other cells as well, including lymphocytes (13).

lysis the dissolution or disintegration of cells or microorganisms, caused by antibodies, complement, enzymes, or other substances

Antibody-Dependent Cell-Mediated Cytotoxicity (ADCC) A number of cells that have cytotoxic potential express membrane receptors for the Fc region of the antibody molecule (recall that this is the “stem” of the antibody). These Fc receptor-bearing cells can bind to the Fc region of an antibody that is already bound to a target cell, subsequently causing the destruction of that target cell. This type of cytotoxicity is referred to as antibody-dependent cellmediated cytotoxicity (ADCC). Among the effector cells that can mediate ADCC are NK cells, macrophages, monocytes, neutrophils, and eosinophils (6). The killing of target cells by ADCC appears to involve a number of different cytotoxic mechanisms, depending on the nature of the effector cell (6). Figure 8: Antibody-Dependent Cell-Mediated Cytotoxicity (ADCC) vs ComplementMediated Cytotoxicity (CDC)

Antibody-Dependent Cell-Mediated Cytotoxicity

Complement-Dependent Cytotoxicity Complement Activation

Macrophage Membrane Attack Complex (MAC)

Target cell

Antibody

Antigen Antibody

Antigen

Cell-mediated immunity, also called cellular immunity, is the division of adaptive immunity mediated by T cells (1). Effector T cells do not secrete antibodies, but secrete cytokines that signal for certain immune system reactions. Some T cells also directly eliminate invaders.

T-Cell Activation A TCR recognizes fragments of antigens. These fragments are presented to a T cell in association with a molecule on the surface of another immune cell or an infected cell of the body. These molecules are called major histocompatibility complex (MHC) molecules. There are 2 classes of MHC molecules: class I MHC molecules and class II MHC molecules. Class I MHC molecules are present on cells of the body that have been infected by an endogenously synthesized antigen (1). An example of an endogenously synthesized antigen is a virus that has infected a tissue cell (5). Class II MHC molecules are present on certain phagocytic immune system cells called antigen presenting cells (APCs) (1,5). Most APCs are either dendritic cells or macrophages. Fragmented antigens are presented on the surface of APCs in association with class II MHC molecules. Class II MHC molecules generally interact with TCRs on TH cells. Class I MHC molecules generally interact with TC cells. Thus, an MHC molecule on an APC presents an antigen to the T cell’s TCR. Figure 9 shows how a T cell recognizes an antigen.

Fc recepter

Target cell

Cell-Mediated Immunity

Cell Lysis

major histocompatibility complex (MHC) molecule a membrane protein that displays peptides for recognition by T cells

Flash Back TCR = T-cell [antigen] receptor

Flash Fact In general, helper T cells express a molecule on their surface called CD4 and cytotoxic T cells express a molecule called CD8. T cells expressing CD4 (CD4+) recognize antigen fragments presented by class II MHC molecules, and T cells expressing CD8 (CD8+) recognize antigen fragments presented by class I MHC molecules.

In ADCC, cells that have receptors for the Fc region of an antibody (in this illustration, a macrophage) can destroy antibody-targeted cells. In CDC, complement is recruited to cells or microbes that have been targeted by antibodies. The membrane attack complex (MAC) is an assembly of complement C5b through C9 that is inserted into the cell membrane causing the final stages of cell lysis.

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Figure 9: T-Cell Activation

Figure 9: T-Cell Activation Lymphocyte

Antigen-presenting cell (APC)

Class II MHC

Antigen fragment CD4

T lymphocyte

T cell Helper T

Cytotoxic T

TCR

An APC (a dendritic cell or macrophage) presents a digested antigen fragment to a T cell in association with an MHC molecule. In this figure, the T cell is a helper T cell that expresses CD4 on its surface, and this type of T cell interacts with class II MHC molecules.

T-Cell Differentiation and Proliferation Flash Fact Though the MHC molecule is a protein present on the surface of APCs, the major histocompatibility complex itself is a region of DNA that encodes the MHC molecule protein. MHC molecule = protein present on APCs MHC = genes In humans, the MHC molecule is also called HLA, which stands for human leukocyte antigen. Leukocytes recognize HLA as self and do not attack self cells in a healthy immune system.

When an antigen is presented to a T cell in association with an MHC molecule, a series of complex interactions between molecules on the APC and the T cell must occur in order for the T cell to become activated and proliferate, called costimulatory signals. After appropriate activation of the T cell, cytokines released from the T cell lead to proliferation and differentiation of the naïve T cells into effector T cells and memory T cells.

T H1

T H2

Helper T cells perform a variety of functions depending on the cytokines they release, including activation of macrophages and promotion of antibody production by B cells (1). Cytotoxic T cells directly recognize and kill host cells infected with viruses or other intracellular microbes. Table 3 lists different types of T cells and identifying characteristics of each type.

Effector T cells can be helper T cells, including type 1 helper T (TH1) cells or type 2 helper T (TH2) cells, or cytotoxic T (TC) cells (Figure 10).

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Summary

Table 3: Different Types of T Cells

Action

Type 1 Helper T Cell (T H 1)

Type 2 Helper T Cell (T H 2)

Cytotoxic T Cell (T C )

• The humoral immune response involves B cells, which secrete antibodies that target microbes for destruction.

Secretes cytokines, including IFN-γ, LT, and TNF-α.

Secretes cytokines, including IL-4, IL-5, IL-10, and IL-13. These cytokines inhibit macrophage activation and T H 1-mediated reactions.

• Recognizes and kills host cells infected with viruses or other intracellular microbes

• Antibodies have a “Y” configuration, with 2 heavy chains and 2 light chains. The branches of the “Y” are the Fab regions, and the stem of the “Y” is the Fc region. The variable regions encode the antibody’s ability to recognize a specific antigen. The antigen- binding sites reside in the variable regions.

• IFN-γ : – Upregulates MHC expression on APCs – Stimulates phagocytosis by • IL-4, IL-13, and IL-10: macrophages – Antagonize the actions – Stimulates B cells to of IFN- γ and inhibit produce IgG antibodies macrophage activation that opsonize microbes for • IL-4: phagocytosis – Acts on B cells to – Inhibits proliferation of T H 2 stimulate production of antibodies that bind to • TNF-α and LT: mast cells, such as IgE – Activate neutrophils and stimulate inflammation • IL-5: – Activates eosinophils Cell surface protein most commonly expressed by naïve T cell

CD4

Class of MHC molecule with which the naïve T cell interacts

Class II MHC

CD4

• Releases destructive enzymes from granules in its cytoplasm • Can secrete cytokines, mostly IFN- γ, LT, and TNF- α, which activate phagocytes and induce inflammation

CD8

• The 5 classes of immunoglobulins are IgG, IgM, IgD, IgA, and IgE; IgA has 2 subclasses (IgA1 and IgA2) and IgG has 4 subclasses (IgG1, IgG2, IgG3, and IgG4). • Antibodies target cells for destruction by: – Opsonization on the microbe, which recruits phagocytes to eliminate the microbe – Neutralization of microbes by blocking the ability of the microbe to bind to cells – Complement-dependent cytotoxicity (CDC) – Antibody-dependent cell-mediated cytotoxicity (ADCC) • In CDC, antibodies serve to identify the infectious microbe as a target and cause lysis of the target cell.

Class II MHC

Class I MHC

• In ADCC, NK cells, macrophages, monocytes, neutrophils, and eosinophils target antibody-coated cells, resulting in destruction of the targeted cell. • The cell-mediated immune response involves T cells.

Cytokines: LT = lymphotoxin; IFN = interferon; IL = interleukin; TNF = tumor necrosis factor.

• Helper T cells release cytokines that stimulate activation of phagocytes and B cells. • Cytotoxic T cells directly destroy (self) cells infected with viruses or other intracellular microbes. • In the helper T-cell–mediated immune response, phagocytic cells called APCs, such as macrophages and dendritic cells, engulf an antigen, digest it, and present the digested antigen on the cell

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surface in association with a protein called the MHC molecule. The antigen is then presented to a T cell.

Self-Check Questions

• Helper T-cell activation results in proliferation and differentiation of:

1. In

– TH1 cells

, cells of the innate immune response

target antibody-coated cells, resulting in destruction of the cell, whereas in

– TH2 cells

, antibodies target the microbe

activating complement-mediated cell lysis.

– Memory T cells

A. Delayed-type hypersensitivity; antibody-dependent cellmediated cytotoxicity (ADCC)

Immune System Innate Immune System

B. Complement-dependent cytotoxicity (CDC); T-cell activation

Adaptive Immune System

C. ADCC; T-cell activation Cytokines

Barriers

Complement

Phagocytes Antibodies

Mast Cells

Cell-Mediated Response (T Cells)

Humoral Response (B Cells)

Helper T Cells

Cytotoxic T Cells

2. In humoral immunity, microbes are targeted for elimination

Granulocytes Cytokines

D. ADCC; CDC

Type 1 Helper T Cells

when bind to antigens on the microbial

Type 2 Helper T Cells

membrane. A. Natural killer (NK) cells B. Antibodies C. B cells (B lymphocytes) D. T cells (T lymphocytes)

3.The 5 classes of antibodies are: A. IgU, IgI, IgG, IgM, and IgA B. IgA, IgG, IgM, IgE, and IgU C. IgA, IgB, IgG, IgD, and IgE D. IgG, IgA, IgM, IgD, and IgE

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4. Match the labels (letters) on the diagram with the appropriate antibody region.

5. Cell-mediated immunity is initiated by activation of

A. Natural killer (NK) cells B. Antibodies

Fc regions

C. B cells (B lymphocytes)

Heavy chains

D. T cells (T lymphocytes)

Antigen-binding sites

6. Phagocytes (including macrophages or dendritic cells) act as antigen presenting cells (APCs) to present processed antigens to T cells. Antigens are presented to T cells by binding between the T cell receptor (TCR) and the:

Light chains Fab regions

A. B cell

Antigen

B. CD4 protein CDRs

C. Major histocompatibility complex (MHC) molecule D. Cytokine F

7. Which of the following is NOT a result of helper T-cell activation? A. Release of cytokines B. Proliferation of cytotoxic T cells

C. Development of memory cells D. Stimulation of B cells D

8. Which of the following is NOT a proinflammatory cytokine released from type 1 helper T cells (TH1 cells)? A. Interleukin (IL)-10 B. Lymphotoxin (LT)

C. Interferon gamma (IFN-γ) D. Tumor necrosis factor-alpha (TNF-α)

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9. Antigen presenting cells (APCs) are usually: A. B cells or neutrophils B. N eutrophils or macrophages C. Dendritic cells or neutrophils D. Dendritic cells or macrophages 10. Helper T cells release cytokines and while cytotoxic T cells

A. A ctivate macrophages and promote antibody production by B cells; directly kill cells infected with intracellular microbes B. D irectly kill cells infected with intracellular microbes; activate macrophages and promote antibody production by B cells C. Complement; directly kill cells infected with intracellular microbes D. P romote antibody production by B cells; cause cell lysis by promoting interaction of antibody-targeted microbes with complement

Lesson 4: Inflammation and TNF-α Have you ever had a fever? In humans, the normal internal body temperature is 98.6°F (37°C). Body temperature can vary from day to day, throughout a day, or by age; however, a temperature over 100°F (37.8°C) usually indicates infection or illness. Recall from Lesson 1 that a febrile response can inhibit growth of some pathogens (a physiologic barrier of the innate immune system). Heat is one of the primary signs of inflammation. Inflammation produces a variety of systemic changes in the host that enhance the ability of the innate immune system to eradicate infection. These changes are thought to be mediated by cytokines and consist of increased production of leukocytes, fever, and changes in levels of several plasma proteins (1). This lesson will discuss the process of inflammation and the role of TNF-α in inflammation.

Learning Objectives At the completion of this lesson, you should be able to: • List the 4 major signs of inflammation • Explain how leukocytes migrate to inflamed tissue from circulation • Differentiate necrosis from apoptosis • Recall the role of proinflammatory cytokines, particularly TNF-α in inflammation • Recognize the characteristic structure of the TNF cytokine family • State the primary sources of TNF-α • Describe the 2 TNF-α receptors

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Inflammatory Response

Migration of White Blood Cells into Tissue

Inflammation is a complex reaction of the immune system in vascularized tissue (tissue containing blood vessels) involving increased vascular permeability and an influx of immune cells such as leukocytes and plasma proteins to the site of infection, toxin exposure, or cell injury. Primary signs of inflammation include

During inflammation, leukocytes circulating in the blood migrate from blood vessels into tissue. Neutrophils are usually the first to arrive at a site of infection, and as inflammation progresses, macrophages become more prevalent (1), as do activated lymphocytes (8). The steps of leukocyte migration have been best established for the neutrophil, and the following steps are those that have been identified for neutrophil migration. The process by which neutrophils leave circulation and enter tissue can be broken down into 4 sequential steps: (1) rolling, (2) activation by chemokines, (3) arrest and adhesion, and (4) transendothelial migration.

• Swelling • Redness • Pain • Heat Each of these symptoms is the result of a complex series of activities produced by the cells and molecules that initiate changes in blood vessels. For example, pain is caused by increased vascular diameter, leading to increased blood flow and causing redness and swelling. When faced with an invading microorganism, the innate and adaptive immune systems communicate with each other through various chemical mediators and cellular components, allowing the 2 systems to interact, send signals, activate each other, and work together toward the goal of eliminating the invader (1).

Development and Symptoms of Inflammation The inflammatory response consists of 3 major events (8):

Adhesion molecules regulate the passing of leukocytes from the blood to the site of tissue inflammation. Adhesion molecules include selectins (present on endothelial surfaces and neutrophils), integrins (present on neutrophils), and cell adhesion molecules (CAMs; present on endothelial surfaces). The following list describes in more detail the 4 steps of neutrophil migration (8): 1. Rolling: Selectins, which are present on the endothelial wall of a blood vessel and are always active, cause a passing leukocyte to slow its motion when passing through the vessel.

selectins any of the 3 proteins that mediate adhesion of leukocytes to endothelial cells

integrins cell surface proteins whose major functions are to mediate the adhesion of leukocytes to other leukocytes, endothelial cells, and extracellular matrix proteins; important for migration of leukocytes from blood to tissues

cell adhesion molecules (CAMs) a group of proteins involved in intracellular adhesion

2. Activation by chemokines: The release of cytokines (especially the chemokine IL-8) from endothelial cells of the blood vessel activates integrins present on rolling neutrophils.

1. Blood supply as well as the presence of leukocytes and molecular mediators of immunity to the infected area increases

3. Arrest and adhesion: The integrins on leukocytes bind to CAMs present on the vascular endothelium, causing the neutrophils to concentrate and adhere.

2. C apillary permeability increases, allowing for the larger molecular mediators to escape from the capillaries to reach the infection site

4. Transendothelial migration: Concentrated neutrophils migrate through the vascular wall. The migrating neutrophils move beneath the endothelium and release chemicals that allow them to escape into tissue.

3. L eukocytes migrate to the site of tissue infection

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Neutrophil Degranulation

Cytokines

Once a neutrophil has passed through the endothelium, it must be directed to the site of infection. Fragments of complement proteins are involved in recruiting leukocytes to a site of inflammation and can activate leukocyte mechanisms (8). One of these mechanisms is neutrophil degranulation, in which granules contained in neutrophils release cytotoxic enzymes (1). Neutrophil degranulation also causes further expression of adhesion molecules (8).

Cytokines play a key role in the inflammatory response. Tumor necrosis factor-alpha, the predominant mediator of the inflammatory response, is the target of therapeutic action of certolizumab pegol. Its primary function is to stimulate the recruitment of neutrophils and monocytes to sites of infections to eradicate microbes.

Other Inflammatory Mechanisms in Tissue: Macrophages and Mast Cells Macrophages supplement the activity of neutrophils and participate in the processing and presenting of antigens to lymphocytes. Macrophages persist longer at the site of inflammation and can release cytokines such as TNF-α and IL-1, which perpetuate expression of adhesion molecules on leukocytes and vascular endothelium (1). They cause lysis of ingested microbes and release growth factors that participate in tissue repair after inflammatory injury. Additionally, mast cells at the site of inflammation can release histamine, which causes vasodilation and increased vascular permeability, leading to more influx of leukocytes. Mast cells can also release TNF-α, which recruits more neutrophils to the site of infection (5). C-reactive protein (CRP) a plasma protein involved in innate immune responses to bacterial infections; also an acute phase reactant and binds to the capsule of pneumococcal bacteria

Table 4 lists the properties and inflammatory actions of a few prevalent proinflammatory cytokines (1). Table 4: Proinflammatory Cytokines and Their Functions Cytokine

Principal Cell Source

Within minutes after an injury or invasion, the inflammatory process of innate immunity begins with the activation of many small messengers, including complement and cytokines. Another group of proteins that aid in the inflammatory response are the acute phase proteins. C-reactive protein (CRP) is an important member of these acute phase proteins (1). Levels of CRP in the blood in addition to other serum markers can be measured to determine disease state in people with inflammatory diseases. This will be discussed further in a later module.

Principal Inflammatory Effects

TNF-α

• Mostly mononuclear phagocytes • T cells • NK cells • Mast cells

• Stimulates the recruitment of neutrophils and monocytes to sites of infection to eliminate microbes • Causes vascular endothelial cells to bind with leukocytes • Stimulates endothelial cells and macrophages to induce leukocyte recruitment • Acts on the hypothalamus to induce fever

TNF-β (also called lymphotoxin)

• T cells

• Recruits and activates neutrophils • Stimulates endothelial cells to induce leukocyte recruitment

IL-1

• Macrophages • Endothelial cells • Some epithelial cells

• Mediates inflammatory response to infections and other stimuli • Activates resting T cells • Stimulates endothelial cells to induce leukocyte recruitment • Causes fever

IFN-γ

• NK cells • T cells

• Activates macrophages • Activates neutrophils and NK cells • Antiviral action

C-Reactive Protein

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Proinflammatory cytokines such as TNF-α and IL-1 promote elimination of microbes by activating cells of the innate immune response and stimulating filtration of leukocytes from the blood to a site of tissue infection (1).

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If the injury or invasion by microorganisms continues (the invader is not eradicated by the innate response), the inflammatory response will be enhanced and amplified by the elements of adaptive immunity including antibodies and cell-mediated immunity.

Cell Death and Inflammation

necrosis cell death cause by progressive degradation by enzymes

Overview of Tumor Necrosis Factor

TNF- α is the principal mediator of the acute inflammatory response to gram-negative bacteria and other infectious microbes.

Tumor necrosis factor-alpha is one of the primary proinflammatory cytokines. Nearly all human cells display receptors for TNF on their surfaces. Because of the diverse roles of TNF, it is important that a careful balance of immune responses is maintained to keep TNF activities to only those necessary. When control is lost, severe inflammatory diseases can result.

Key Concept TNF-α may simply be called TNF in literature.

Figure 11: Structure of TNF-α

TNF-α is made up of 3 protein chains (represented in 3 different colors)—a structure called a homotrimer. Each protein chain of TNF interacts with a protein chain of a TNF receptor.

Tumor necrosis factor-alpha exists in both membrane-bound and soluble (circulating) forms. The membrane-bound form is cleaved into a secreted form by TNF-α converting enzyme (TACE). The secreted form can then bind to and activate its receptors. Each protein chain of TNF interacts with a protein chain of a TNF receptor.

There are 2 types of TNF: TNF-α and TNF-β. Tumor necrosis factorbeta is also called lymphotoxin (LT); therefore TNF-α is often simply referred to as TNF. Tumor necrosis factor-alpha is the primary mediator of the inflammatory response to gram-negative bacteria and other infectious microbes and is responsible for many of the systemic complications of severe infections such as septic shock (1).

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Tumor necrosis factor-alpha is a cytokine; its chemical composition is that of a protein. Structurally, TNF-α is made up of 3 protein chains, a structure called a homotrimer (Figure 11). This structure is characteristic of all members of the TNF cytokine family.

The death of certain cells in the body may or may not result in inflammation, depending on the mechanism of cell death. Two forms of cell death are apoptosis and necrosis. Apoptosis is a specific programmed cell death in which cells are systematically disassembled. Cells that are dying by apoptosis attract mononuclear phagocytes and are taken up by phagocytosis and broken down. Apoptosis does not result in inflammation and is a normal process of cell homeostasis, the maintenance of cell balance in the body (16). Conversely, necrosis, a form of cell death resulting from cell damage, triggers an inflammatory response (8). Necrosis is caused by enzymatic degradation and is characterized by uncontrolled cell lysis among other morphological characteristics of cell destruction. In cell necrosis, enzymes and chemicals normally contained within the cell are released into the surrounding tissues, leading to inflammation. The presence of these chemicals in tissue may result in cellular damage (1).

Key Concept

Structure and Source of TNF-α

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Both membrane-bound TNF-α and soluble TNF-α bind to TNF receptors on cell surfaces. There are 2 TNF-α receptors: TNF-RI (also known as p55, CD120a) and TNF-RII (also known as p75, CD120b) (1). TNF-RI is widely expressed on many cell types. TNF-RII is found predominantly on leukocytes and endothelial cells. Tumor necrosis factor-alpha and -beta can bind with either TNF-RI or TNF-RII. Some receptors of TNF on the cell have the ability to separate from the cell but still maintain their ability to bind with TNF (6). Depending on their relative concentrations, soluble TNF receptors may neutralize TNF-α and act as a TNF inhibitor or antagonist (4).

Sources and Targets of TNF-α Sources The primary source of TNF-α is mononuclear phagocytes in inflammatory processes; however, it is also secreted from T cells, NK cells, and mast cells. The most common stimulus for mononuclear phagocytes to produce TNF is the presence of lipopolysaccharide (LPS), the toxin released from gram-negative bacteria (1). Flash Fact p55 and p75 represent the molecular weight of the receptors (55 and 75 kilodaltons for TNFRI and TNF-RII, respectively).

Targets

Biologic Actions of TNF-α Systemic Actions Tumor necrosis factor-alpha is one of the primary proinflammatory cytokines. It stimulates the expression of adhesion molecules in endothelial cells so that leukocytes are recruited to the site of inflammation. It activates neutrophils, which are the first leukocytes to migrate to a site of infected tissue, and, in addition to activating neutrophils, TNF-α stimulates macrophages and endothelial cells to release chemokines that further recruit leukocytes (phagocytes and lymphocytes) to the inflamed tissue. Apoptosis can either be inhibited or promoted by TNF-α. Apoptosis stimulated by TNF-α can cause destruction of lymphocytes (a way of maintaining cell balance in the body) and can occur through interaction of TNF-α with TNF-R1 (1). The synthesis of other proinflammatory cytokines, such as IL-1, IL-6, and granulocyte macrophage colony-stimulating factor (GM-CSF), are also stimulated by TNF-α (Figure 12). Additionally, TNF-α enhances proliferation of B cells and T cells, differentiation of B cells, and increases activity of NK cells. Figure 12: Actions of TNF-α

The primary cell or tissue targets of TNF-α include (1): Modulates leukocyte development

1. Endothelial cells 2. Neutrophils 3. The hypothalamus (an area of the brain that controls body temperature, hunger, and thirst, and has other regulatory functions)

Regulates macrophage activation and immune responses in tissues

TNF-

Mediates hematopoiesis

4. The liver Promotes leukocyte adhesion and migration into tissue

5. Muscle and fat

Prothrombic action (assists blood clotting)

Adaptation from Male 2006.

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Organ/Tissue-Specific Actions In the hypothalamus, TNF-α induces fever—a symptom of an inflammatory response. In the liver, TNF-α causes production of acute- phase reactants (proteins that respond to inflammatory reactions and mediate immune responses), including CRP (1). Levels of CRP in the blood are often measured to help in the diagnosis and clinical designation of certain inflammatory diseases. thrombosis the development of a stationary blood clot

Prolonged production of TNF-α can cause wasting of muscle and fat cells, a process called cachexia (1). Tumor necrosis factor-alpha can also be referred to as cachectin for this reason. The mechanism by which TNF-α causes necrosis of tumors is its ability to build blockages in the blood vessels, cutting off the blood supply to the tumor (1). Tumor necrosis factor- alpha can cause vascular thrombosis—formation of a stationary blood clot—by promoting blood coagulation and recruitment of neutrophils to the vascular endothelium.

Summary • Inflammation is a complex reaction of the immune system in vascularized tissue in which leukocytes and plasma proteins migrate from the blood to a site of tissue infection, toxin exposure, or cell injury. • The primary signs of inflammation are: – Swelling – Redness – Pain – Heat • Leukocytes migrate from the vasculature and into the site of infection via proteins called adhesion molecules. Different types of adhesion molecules on vascular endothelium and leukocytes, including selectins, integrins, and cell-adhesion molecules (CAMs), mediate this migration by slowing the movement of leukocytes in circulation and making them stick to the vascular endothelium. Cytokines play an important role in this migration process. • Some proinflammatory cytokines include TNF-α, TNF-β (lymphotoxin or LT), IL-1, and IFN-γ. • All proinflammatory cytokines promote elimination of microbes by stimulating cells of the innate immune response and allowing filtration of leukocytes from the blood to a site of tissue infection. • Cells can die by either necrosis, caused by enzymatic degradation, or apoptosis, specific programmed cell death in which cells are systematically disassembled. • Tumor necrosis factor-alpha is the principal mediator of the acute inflammatory response to gram-negative bacteria and other infectious microbes. Its primary function is to stimulate the recruitment of neutrophils and monocytes to sites of infections and eradicate microbes.

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Lesson 4: Inflammation and TNF-α

Module 1: The Immune System

• The TNF family of cytokines is structurally defined by its homotrimer structure (3 identical protein chains that aggregate into a complex).

Self-Check Questions 1. What is the first step in the inflammatory process? A. Blood supply to the affected area increases

• Mononuclear phagocytes are the main source of TNF-α. T cells, NK cells, and mast cells can also release TNF-α.

B. Permeability of blood vessels increases C. Leukocytes migrate to tissue

• The most common trigger of release of TNF-α is LPS, a toxin released from gram-negative bacteria.

D. Neutrophils recruit more leukocytes into tissue 2. Molecules called

• There are 2 TNF-α receptors: TNF-RI, also known as p55, and TNF-RII, also known as p75.

mediate the slowing and

sticking of leukocytes to the vascular endothelium in the inflammatory process. A. Adhesion molecules B. Eosinophils C. Monoclonal antibodies D. Caspases 3.

is cell death that follows a structured,

programmed process of cell deconstruction. A. Necrosis B. Lysis C. Cytotoxicity D. Apoptosis 4. Which of the following is NOT a sign of inflammation? A. Redness B. Swelling C. Heat D. Abrasions

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Lesson 4: Inflammation and TNF-α

Module 1: The Immune System

5. W hich of the following is NOT a result of action of TNF-α? A. Stimulates the recruitment of neutrophils and monocytes to sites of infection to eliminate microbes

8. T he TNF-RI receptor is also called RII receptor is also called

B. p55; p75

C. Causes vascular endothelial cells to bind with leukocytes

C. p90; p55

6. T he structure of the TNF family of cytokines can be classified as a: A. Heterotrimer B. Homotrimer C. Monomer D. Heterodimer 7. T umor necrosis factor-alpha can be released by NK cells, mast cells, and T lymphocytes; however, it is mostly secreted by such as . A. Mononuclear phagocytes; macrophages

A. p65; p75

B. Acts on the hypothalamus to reduce fever

D. Stimulates endothelial cells and macrophages to induce leukocyte recruitment

and the TNF-

D. p75; p65 9. T umor necrosis factor-alpha is the primary cytokine mediator of the inflammatory response. Which of the following is NOT an action of TNF-α in inflammation? A. Stimulates the expression of adhesion molecules in endothelial cells so that leukocytes are recruited to the site of inflammation B. A ctivates neutrophils C. Stimulates macrophages and endothelial cells to release chemokines, which further recruit leukocytes to inflamed tissue D. Inhibits synthesis of other proinflammatory cytokines

B. Basophils; chemokines C. Primary lymphoid organs; the thymus D. Effector cells; B lymphocytes

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Lesson 5: Adverse Immune Response

Module 1: The Immune System

Lesson 5: Adverse Immune Response Do you have any allergies? Allergic reactions are exaggerated or pathological reactions (such as sneezing, respiratory distress, itching, or skin rashes) to substances, situations, or physical states that do not normally cause adverse reactions. These substances, situations, or physical states that are normally inert are called allergens. Examples of allergens are pollen, dust, or animal dander. Some people have severe allergic reactions to peanuts or shellfish that can result in anaphylactic shock, an often severe and sometimes fatal systemic reaction that is characterized especially by respiratory symptoms, fainting, itching, and hives. During allergic reactions, allergens act as the antigens that stimulate an immune response. Allergy is a form of hypersensitivity. A reaction of the body’s immune system in response to exposure to its own antigens is called autoimmunity. In autoimmunity, the body attacks itself. Hypersensitivity and autoimmunity are discussed in this lesson.

Learning Objectives At the completion of this lesson, you should be able to:

Hypersensitivity Reactions Excessive or inappropriate immune responses may cause tissue injury or disease (1). Such reactions are hypersensitivity reactions, and diseases caused by these immune responses are called hypersensitivity diseases (8). Four different forms of hypersensitivity were first defined by 2 researchers, Coombs and Gell; therefore, these definitions of hypersensitivity are sometimes called the Coombs and Gell classification of hypersensitivity. Though the mechanistic differences in the development of these 4 hypersensitivity reactions are clear (Table 5), it is important to point out that secondary effects blur the boundaries between the 4 categories (7). Some diseases cannot be clearly categorized. The following reviews the mechanisms by which the established 4 classes of hypersensitivity develop, labeled type I through type IV. The outcome of each of these mechanisms is tissue injury and disease. Let’s explore each type of hypersensitivity. Table 5: Characteristics of the 4 Types of Hypersensitivity Hypersensitivity Number Type I

Hypersensitivity Name

Description

Immediate

Invading allergens stimulate release of histamine from mast cells and basophils covered with allergen-specific IgE.

Antibody-mediated

Antibodies (IgM-, IgA-, and IgG-type antibodies) bind to antigens on cells or tissues, causing damage in a particular site.

Immune complexmediated

Antibodies (IgM-, IgA-, and IgGtype antibodies) are directed against soluble antigens, forming immune complexes that can circulate in the blood or plant into tissue.

T-cell–mediated or delayed-type

T cells react against self antigens or foreign antigens bound to cells or tissues. T cells activate macrophages to release cytokines and other cell toxins.

• Define hypersensitivity • Describe a type I hypersensitivity reaction • Describe a type II hypersensitivity reaction

Type II

• Describe a type III hypersensitivity reaction • Describe a type IV hypersensitivity reaction • Define an autoimmune reaction

Type III

• Recognize the 2 most prevalent triggers of autoimmune disease Type IV

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Lesson 5: Adverse Immune Response

Module 1: The Immune System

Type I: Immediate Hypersensitivity

Examples of allergic reactions include hay fever, asthma, atopic dermatitis, and anaphylaxis. Allergens are the substances that cause type I hypersensitivity (8).

atopic dermatitis inflammation of the skin, caused by a type I allergic reaction associated with the IgE antibody

In immediate hypersensitivity, an allergen stimulates release of histamine from mast cells and basophils covered with allergenspecific IgE antibody (8). The IgE protein has a special region that can only bind to a receptor found mostly on mast cells and basophils. Histamine causes the following to occur (1): • Leukocyte migration into tissue

anaphylaxis

• Vasodilation

anaphylactic shock; a result of immediate hypersensitivity and results in life-threatening respiratory distress, usually followed by vascular collapse and shock and accompanied by urticaria, pruritis, and angioedema

• Constriction of intestinal and bronchial smooth muscle, leading to increased peristalsis and bronchoconstriction

An example of type II hypersensitivity would be Rhesus (Rh) incompatibility between an Rh-negative mother pregnant with an Rh-positive child. Upon interaction of the mother’s blood with the blood of the fetus, antibodies from the mother may attack and destroy blood cells of the fetus. Symptoms of Rh incompatibility may range from mild to fatal for the infant (14).

Type III: Immune Complex-Mediated Hypersensitivity Type III hypersensitivity reactions are called immune complexmediated reactions (1). These hypersensitivity reactions tend to be systemic. They are important in systemic autoimmune conditions such as systemic lupus erythematosus (SLE or simply “lupus”), a disease condition in which antibodies are directed against self cells and tissues (1). Lupus is a systemic disease and affects many different tissues throughout the body, causing inflammation and damage.

Type II: Antibody-Mediated Hypersensitivity

In type II hypersensitivity reactions, antibodies bind to antigens on cells or tissues (1). The reactions occur at a specific cell or tissue site, and are often not systemic diseases. Though immediate hypersensitivity is mediated by the antibody IgE, type II hypersensitivity is called antibody-mediated hypersensitivity and involves the antibodies IgM, IgA, and IgG. There are 3 ways by which these antibodies can lead to hypersensitivity (1):

Key Concept Systemic diseases can affect any part of the body.

Flash Flash Back Back The 5 classes of antibodies are

The 5 classes of antibodies are IgA, IgG, IgE,Which IgM, and IgD.antibody IgE,IgA, IgM,IgG, and IgD. of these Which of these antibody classes has antibody subtypes? classes

An immune complex is an antigen-antibody combination that is present in circulation and not attached to a microbe or cell (Figure 13) (5). The immune complexes circulate in the blood and deposit in tissues (8). They trigger complement and cellmediated inflammatory responses that injure the tissues and organs at the site of deposition. The antibody classes involved in immune complex-mediated hypersensitivity include IgM, IgA, and IgG antibodies—the same antibodies involved in type II hypersensitivity (1). Figure 13: Immune Complex

1. Antibodies directed against cell surface antigens mediate cell destruction via complement activation or ADCC (eg, neutrophils and macrophages are attracted and release destructive chemicals) (7) 2. Antibodies or attached complement proteins bind with neutrophils and macrophages, which release destructive chemicals 3. Antibodies bind to normal cellular receptors and interfere with the normal function of the cell

Antigen

has antibody subtypes?

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Lesson 5: Adverse Immune Response

Module 1: The Immune System

There are 3 mechanisms of inflammation and tissue injury in immune complex-mediated hypersensitivity (8):

Figure 14: Hypersensitivity and Autoimmunity

• C omplexes interact directly with basophils and platelets

Hypersensitivity

• S timulated macrophages release cytokines, such as TNF-α and IL-1 • C omplexes interact with complement proteins that stimulate the release of histamine and that recruit basophils, eosinophils, and neutrophils delayed-type hypersensitivity (DTH) a form of type IV hypersensitivity; an immune reaction in which T-cell–dependent macrophage activation and inflammation cause tissue injury

Type IV hypersensitivity is triggered by either delayed-type hypersensitivity (DTH) reactions mediated by TH1 cells, or by direct attack against cells by TC cells (1). In DTH, T-cell activation of macrophages causes the macrophages to release cytokines and other cell toxins, leading to inflammation and damage to tissues. A well-recognized example of type IV hypersensitivity is insulindependent diabetes mellitus (type I diabetes). In type I diabetes, the immune system destroys cells in the pancreas called islet cells, which produce insulin.

Autoimmune Disease unresponsiveness of the immune system to self antigens, largely as a result of inactivation or apoptotic death of self-reactive lymphocytes induced by exposure to those self antigens

Flash Forward

Immune response to a normally innocuous substance

Immune response to self antigen

Type IV: T-Cell–Mediated Hypersensitivity

In type IV hypersensitivity, T cells may react against self antigens or against foreign antigens that are bound to self cells or tissues (1).

self-tolerance

Exaggerated response to pathogens

Autoimmunity is characterized by inappropriate reaction to self antigens, that is, normal constituents of the body (Figure 14) (8). It represents a breakdown of the mechanisms that normally maintain self-tolerance— the property by which the immune system does not normally react to self antigens. An autoimmune disease can result from breakdown of normal humoral or cell-mediated immune responses, or a combination of both.

Autoimmunity

Autoimmunity is an immune response against self antigens.

Autoimmune diseases range from organ-specific disorders, which affect primarily 1 organ, to systemic diseases, which affect many organs. Many organ-specific diseases develop from DTH reactions induced by autoreactive T cells (T cells that attack self cells) (1). Some important autoimmune diseases include type 1 diabetes mellitus (a DTH reaction), RA, and SLE. The major factors that contribute to autoimmune disease are genetics and environmental triggers, such as bacterial or viral infections (1).

Rheumatoid arthritis (RA) is a systemic disease that affects small joints and other tissues. Though the exact cause of RA is unknown, it is considered to be an autoimmune disease. It is thought to result from T-cell– mediated inflammation; however, antibodies may also contribute to joint inflammation in patients with RA.

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Lesson 5: Adverse Immune Response

Module 1: The Immune System

Summary

Self-Check Questions 1. A hypersensitivity reaction is:

•A hypersensitivity reaction is an excessive or inappropriate immune response that may cause tissue injury or disease. • I n type I hypersensitivity (also called immediate hypersensitivity), the invading antigens stimulate the binding of IgE to mast cells and basophils, causing histamine to be released. Histamine causes leukocyte migration to tissues, vasodilation, and increased peristalsis and bronchoconstriction. • I n type II hypersensitivity reactions (also called antibodymediated hypersensitivity), antibodies bind to antigens on cells or tissues. The reactions occur at a specific cell or tissue site, and are usually not systemic diseases. • I n type III hypersensitivity (also called immune complexmediated immunity), an antigen-antibody complex circulates in the blood and then deposits in tissues. This triggers complement and cell-mediated inflammatory responses, which injure the tissues and organs at the site of deposition. • T ype IV hypersensitivity (also known as T-cell mediated hypersensitivity) is triggered by either delayed-type hypersensitivity (DTH) reactions mediated by TH1 cells, or by direct attack against cells by TC cells. In DTH, T-cell activation of macrophages causes release of cytokines and other cell toxins that lead to inflammation and damage tissues.

A. A reaction in which the immune system has a breakdown in self-tolerance B. Another term for allergy C. An excessive or inappropriate immune response D. When the immune system does not activate a response when it should 2. A delayed-type hypersensitivity (DTH) reaction, which is mediated by helper T (TH) cells, is 1 of the 2 forms of: A. Type I hypersensitivity B. Type II hypersensitivity C. Type III hypersensitivity D. Type IV hypersensitivity 3. Type II hypersensitivity is also called and occurs when binds to antigens on cells or tissues. A. Antibody-mediated hypersensitivity; IgM, IgA, or IgG B. Immune complex-mediated hypersensitivity; IgE, IgA C. Delayed-type hypersensitivity; IgM or IgG D. Autoreactive hypersensitivity; IgM, IgA, or IgE

•A n autoimmune reaction is one in which self-tolerance is not working properly and an immune response is mounted against self cells. • T he major factors contributing to the development of autoimmune disease include environmental triggers, such as bacterial or viral infection, or genetics.

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Case Study

Module 1: The Immune System

4. In type I hypersensitivity (also called immediate hypersensitivity), an allergen causes the release of from basophils and mast cells. A. Alanine B. Histamine C. Lipopolysaccharide (LPS) D. Interferon-gamma (IFN-γ) 5. Which of the following is a disease caused by type III hypersensitivity?

Case Study Robert has pain in both of his wrists and the knuckles of his 3rd, 4th, and 5th finger on each hand. The pain and stiffness is worst in the morning, and subsides during the day. His knuckles also seem to be more swollen than normal. In the next module, you will learn the anatomic terms for these joints used in medical practice. Recall that pain and swelling are 2 of the primary signs of inflammation. Can you list 2 more?

A. Type 1 diabetes (insulin-dependent diabetes mellitus) B. Systemic lupus erythematosus (SLE) C. Acquired immune deficiency syndrome (AIDS) D. Hay fever 6. Which of the following is true about autoimmune diseases? A. They cannot be genetically inherited. B. They are only initiated by viral infections. C. The immune system is unable to produce T cells. D. T he immune system mounts a response against self cells and tissues.

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Answers to Self-Checks

Module 1: The Immune System

Answers to Self-Check Questions

Lesson 3

Lesson 4

Lesson 1

1. D

1. A

2. B

2. A

3. D

4. D Fc regions

4. D

1. C 2. Cytokines, antibodies, complement 3. B 4. B 5. C 6. D 7. False 8. D 9. A

Lesson 2

C Heavy chains

5. B

E Antigen-binding sites

6. B

B Light chains

7. A

A Fab regions

8. B

F Antigen

9. D

G CDRs 5. D 6. C 7. B

1. B 2. C 3. A

8. A 9. D 10. A

4. B

Lesson 5 1. C 2. D 3. A 4. B 5. B 6. D

5. A 6. D 7. D 8. Specificity, diversity, memory, specialization, self-limitation/ homeostasis, self-tolerance

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Glossary

Module 1: The Immune System

Glossary adenoids

anaphylaxis

epithelial and lymphatic encapsulated structures located on the posterior wall of the nasopharynx (above the soft palate of the mouth) anaphylactic shock; a result of immediate hypersensitivity and results in life-threatening respiratory distress, usually followed by vascular collapse and shock and accompanied by urticaria, pruritis, and angioedema

antibody-dependent cellmediated cytotoxicity (ADCC)

a process by which natural killer cells are targeted to IgG-coated cells, resulting in lysis of the antibody-coated cells

antigens

molecules that bind to antibodies or T-cell receptors

atopic dermatitis

inflammation of the skin, caused by a type I allergic reaction associated with the IgE antibody

C-reactive protein (CRP)

a plasma protein involved in innate immune responses to bacterial infections; also an acute phase reactant and binds to the capsule of pneumococcal bacteria

cell adhesion molecules (CAMs) cilia

chemotaxis

complement

extracellular

outside a cell

febrile

denoting or related to fever

hematopoiesis (hem-ah-toe-poi-ee-sis)

the formation or development of blood cells

histamine

a biogenic amine stored in granules of mast cells that is one of the important mediators of immediate hypersensitivity

inflammation

a series of reactions that bring cells and molecules of the immune system to sites of infection or damage

integrins

cell surface proteins whose major functions are to mediate the adhesion of leukocytes to other leukocytes, endothelial cells, and extracellular matrix proteins; important for migration of leukocytes from blood to tissues

interferon-γ (IFN-γ)

a cytokine produced by T cells and natural killer cells; its principal function is to activate macrophages in innate and adaptive cell-mediated immune responses

intracellular

inside a cell

leukocytes

white blood cells; granular leukocytes are basophils, eosinophils, and neutrophils, and nongranular leukocytes are lymphocytes and monocytes (macrophages and dendritic cells)

lymphocyte

any of the nonphagocytic, mononuclear leukocytes found in the blood, lymph, and lymphoid tissues that are the body’s immunologically competent cells and their precursors; includes T cells, B cells, and natural killer cells

a group of proteins involved in intracellular adhesion motile extensions of a cell surface orientation of a cell along a chemical concentration gradient or movement in the direction of the gradient, either toward (positive chemotaxis) or away from (negative chemotaxis) the greater concentration of the substance, referred to as a chemotactic factor, chemotactin, or chemoattractant a group of serum proteins involved in the control of inflammation, the activation of phagocytes, and the lytic attack on cell membranes

lysis

the dissolution or disintegration of cells or microorganisms, caused by antibodies, complement, enzymes, or other substances a membrane-bound, acidic organelle abundant in phagocytic cells that contains proteolytic enzymes that degrade proteins; involved in class II major histocompatibility complex pathways of antigen processing

complement- dependent cytotoxicity (CDC)

the process by which antigen-antibody complexes interact with complement, resulting in cell lysis

lysosome

delayed-type hypersensitivity (DTH)

a form of type IV hypersensitivity; an immune reaction in which T-cell–dependent macrophage activation and inflammation cause tissue injury

macrophages

tissue-based phagocytic cells involved in innate and adaptive immune responses

major histocompatibility complex (MHC) molecule

a membrane protein that displays peptides for recognition by T cells

endothelial cells

the simple squamous cells forming the lining of blood and lymph vessels and the inner layer of the endocardium

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Glossary

Module 1: The Immune System

mast cells

the major effector cell of immediate hypersensitivity reactions; respond to microbes and various mediators by secreting substances that stimulate inflammation; derived from bone marrow and reside under many epithelia and in serosal cavities

References 1. Abbas AK, Lichtman AH. Cellular and Molecular Immunology. 5th ed (Updated Edition). Philadelphia, PA: Saunders; 2005.

microbe

a minute living organism

monocytes

a type of bone marrow-derived circulating blood cell that is a precursor of tissue macrophages

mucosae

plural of mucosa—a mucous tissue lining various tubular structures in the body consisting of epithelium, lamina propria, and, in the digestive tract, a layer of smooth muscle

necrosis

cell death cause by progressive degradation by enzymes

Opsonization

the process by which antibodies and certain complement proteins attract phagocytes for phagocytosis

phagocytes

any cell capable of ingesting particulate matter

phagocytosis

the process by which certain cells of the immune system, including macrophages and neutrophils, engulf large particles such as intact microbes

phagosome

a membrane-bound intracellular vesicle that contains microbes or particulate material from the extracellular environment

plasma cells

a terminally differentiated antibody-secreting B cell with a characteristic appearance

proliferation

growth and reproduction of similar cells

selectins

any of the 3 proteins that mediate adhesion of leukocytes to endothelial cells

self-tolerance

unresponsiveness of the immune system to self antigens, largely as a result of inactivation or apoptotic death of self-reactive lymphocytes induced by exposure to those self antigens

serum

clear, watery fluid, especially that moistening the surface of serous membranes or exuded in inflammation of any of those membranes

thrombosis

the development of a stationary blood clot

15. Shortman K, Caux C. Dendritic cell development: multiple pathways to nature’s adjuvants. Stem Cells. 1997;15:409-419.

vesicle

a closed structure surrounded by a single membrane

16. Stedman’s Medical Dictionary. 28th ed. Baltimore, MD: Lippincott Williams & Wilkins; 2006.

white blood cells

cells of the immune system; leukocytes

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2. Arthritis Foundation. Rheumatoid Arthritis: Causes. http://www.arthritis.org/ conditions/ diseasecenter/ra/ra_causes.asp. Accessed March 26, 2007. 3. Dorland’s Illustrated Medical Dictionary. 30th ed. Philadelphia, PA: Saunders; 2003. 4. Enbrel [package insert]. Thousand Oaks, CA: Immunex Corporation; 2006. 5. Fox SI. Human Physiology. 6th ed. Boston, MA: McGraw-Hill; 1999. 6. Glossop JR, Dawes PT, Nixon NB, Mattey DL. Polymorphism in the tumour necrosis factor receptors II gene is associated with circulating levels of soluble tumour necrosis factor receptors in rheumatoid arthritis. Arthritis Res Ther. 2005;7:R1227-R1234. 7. Goldsby RA, Kindt TJ, Osborne BA, Kuby J. Immunology. 5th ed. New York, NY: W.H. Freeman and Company; 2003. 8. Male D, Brostoff J, Roth DB, Roitt I. Immunology. 7th ed. Edinburgh, Scotland: Mosby; 2006. 9. MedlinePlus Medical Dictionary. http://www.nlm.nih.gov/medlineplus/ mplusdictionary.html. Accessed March 26, 2007. 10. MedlinePlus Medical Encyclopedia. http://www.nlm.nih.gov/medlineplus/ encyclopedia.html. Accessed March 26, 2007. 11. Merriam-Webster Online. http://www.m-w.com/. Accessed March 26, 2007. 12. Pfizer Consumer Healthcare. Benadryl® Allergy & Cold Tablet. http://www.pfizerch. com/ product.aspx?id=252. Accessed March 26, 2007. 13. Reff ME, Carner K, Chambers KS, et al. Depletion of B cells in vivo by a chimeric mouse human monoclonal antibody CD20. Blood. 1994;83:435-445. 14. Salem L. Rh Incompatibility. http://www.emedicine.com/emerg/topic507.htm. Accessed March 26, 2007.

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