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Chapter 10

Immunology, Organ Interaction and Homeostasis

Gabi Nindl Waite, Ph.D.

Active Learning Objectives

Upon mastering the material in this chapter you should be able to:

Explain what triggers an immune response and where in the body the immune response occurs

Understand how the immune system handles exogenous and endogenous antigen differently

Define the differences between innate and adaptive immunity and their complementary activities

Discuss how antigen specificity is achieved in the immune system

Understand the different roles of immune cells and their communication

Describe the structure and functions of different antibodies

Outline the functions of acute inflammation and separate them from chronic inflammation

Explain the immune-related requirements for organ transplantation

Present an overview of immune system disorders

Explain the immune system’s role in allergic and immune system disorders

Portray how the immune system interacts with other systems to maintain homeostasis

Talk about some novel immune topics in clinics and research

The immune system is the body’s primary defense system against all harmful agents. Harmful agents

might be living matter such as bacteria, parasites, fungi and viruses, or non-living matter such as toxins,

chemicals, drugs or foreign particles. The immune system is composed of a complex system of organs,

tissues, specialized cells and a circulatory system. It tries to prevent the agents from entering the body,

and if they do enter, attacks them. When the immune system functions optimally, the substances are

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eliminated before the host shows disease symptoms. The immune system is also involved in detecting

aberrant cellular structures such as tumor cells. A body without an immune system would not be able to

survive more than a few days.

Understanding the immune system is of crucial importance to understanding how the body functions,

and hence is an important part of physiology. However, one chapter about the immune system cannot do

justice to such a fascinating aspect of our body. The aim of the current chapter is to place the functioning

of the immune system within the framework of the whole human organism and its homeostasis, and to

provide the foundation on which one can expand in the specialty courses immunology, microbiology and

pathophysiology.

<h1>ACTIVATION AND LOCATION OF THE IMMUNE SYSTEM

The ultimate function of the immune system is to recognize and to destroy foreign substances in the

body. Any substance that provokes the immune system is called an immunogen. Organisms that might

cause diseases are called pathogens. They may enter the body through a cut in the skin, as in the case of

the hepatitis B virus, through membranes of the respiratory tract, as in the case of the measles virus, or

through membranes of the digestive tract, as in the case of salmonella bacteria. Pathogens may further

be transmitted by insect bites, as in the case of malaria, or by sexual encounter, as in the case of the HIV

virus. Antigens are substances that bind to receptors on T and B cells or antibodies. Haptens are similar

to antigens, but are only immunogenic when linked to a carrier molecule. In addition to pathogens, a

large number of other foreign substances can be antigenic. Pesticides, cosmetics and exhaust particles

are examples of such substances, whose number increases with the advancement of technology in our

society.

Exogenous antigens such as bacteria and foreign particles are most accessible to immune elimination.

They first activate the innate immunity (see Innate Immune System below). As part of it, immune cells

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might engulf the antigen or destroy it with enzymes and oxygen radicals. Complement proteins might

lyse the organism and promote inflammation (see Inflammation below). If the pathogen evades the

innate immune system, the adaptive immunity response is triggered, where cells and antibodies work

together to eliminate the antigen (see Adaptive Immune System below).

Endogenous (intracellular) antigens such as viruses, protozoan parasites, and intracellular bacteria are

eliminated together with the infected host cell. Antibodies can bind directly to the infected cell and

activate complement, if some immunogenic parts of the microorganism are present on the plasma

membrane of the host cell (see humoral immunity below). If the antigen cannot immediately be

recognized on the surface of the cell, it is degraded intracellularly into smaller pieces. These are then

incorporated into the host cells’ plasma membranes and together with major histocompatibility complex

(MHC) proteins presented to T cells (see T cell mediated immunity below).

<h2>A Molecule Must Be Recognized as Foreign to Elicit a Physiological Immune Response

Any antigen that is not recognized as being a normal part of the body is marked as being potentially

dangerous to the body. This discrimination of self from non-self is one of the core tasks of the immune

system. Body cells carry molecules that label them as “self” so that the immune system ignores them, a

process called self-tolerance. Foreign molecules also carry distinctive markers, and the immune system

recognizes many millions of them. There are some exemptions. We generally tolerate food-derived

foreign particles; although some foods induce allergic reactions (see Immune Diseases below). A mother

does not reject the fetal molecules that are derived from the father. Identical twins can accept skin grafts

from each other without causing immune reactions (see Organ Transplantation below). On the other

hand, when a body erroneously mounts an immune response against its own tissues, it leads to

autoimmune diseases (see Immune Diseases below).

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Each part of the antigen bound by a unique antibody is called an epitope. Most protein antigens have

several epitopes that are recognized by different B cells and induce a polyclonal antibody response.

Antibodies of a single specificity (monoclonal) are used for immune diagnostic tests and

immunotherapy. Epitopes may be shared by closely related antigens (cross-reactivity). For instance, the

vaccine against tetanus disease contains tetanus toxoid, which makes the body produce antibodies that

also recognize tetanus toxin, the poisonous substances produced by Clostridium tetani bacteria.

Proteins are by far the best immunogens. Polysaccharides, lipids and nucleic acids by themselves

induce either weak or no immune responses, but their antigenicity is greatly improved when attached to

proteins. This principle is used for many vaccines. For instance, the vaccine targeting the carbohydrate

capsule of Streptococcus pneumoniae is conjugated to protein carriers to enhance its effectiveness. The

immunogenicity of substances increases with their complexity. For instance, polymers made of only one

type of nucleotide are poor immunogens regardless of their size, while polymers made of more than one

base are usually good immunogens. Nevertheless, size matters, and typically, only molecules with a

molecular weight of 4000 Dalton or above elicit an immune response. Other factors that increase the

likelihood of being recognized by the immune defenses are protein aggregation, protein charges and

complex three-dimensional conformation.

<h2>Body Defenses After Injury Can Occur With or Without Immune Activation

Immune responses are tied in with other body defenses and reactions. When the body sustains injury,

whether from physical force, cellular breakdown, or biological infection, the decision for immune

activation depends on the severity and type of the injury. If the cells are not too severely injured, cells

may adapt to the event by changing their size, number and functions. For instance, skeletal muscle cells

in a patient on bed rest respond with downsizing to the cellular stress of lack of physiological stimuli, an

event that is usually not associated with immune responses. On the other hand, the replacement of

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glandular epithelium in the lungs of a smoker by a better protecting squamous epithelium goes along

with inflammation of the airway cells, triggered by strongly irritating smoke particles.

If the damage to a cell is too great to cope with, the cell will die by necrosis. The immune system is

activated when the cells collapse and their cellular contents leak into the surrounding tissue. As a result,

various types of immune cells are attracted by chemokines to the injury site and initiate the inflammatory

response, which further activates the immune response. On the other hand, cell death by apoptosis will

not cause immune activation. The cells die without bursting apart, and as a result, no damaging

substances are released from the cells and an inflammatory response is avoided. Apoptosis is the body’s

non-pathological process of removing cells. This is especially important for the role of the immune

system in keeping homeostasis and regulating tolerance. Every day, several millions of B and T cells are

generated and the majority of those dies apoptotically by processes called negative selection, or

activation-induced-cell-death.

<h2>The Immune System Encompasses Distinct Immunological Organs As Well As Cells and

Non-cellular Elements That Are Part of Every Tissue

Thymus and bone marrow are primary (or central) lymphatic organs (Fig. 10.1). These are the

organs where the cells mature to become immunocompetent. All immune cells derive from a common

precursor stem cell in the bone marrow (see Chapter 9). While most immune cells including B

lymphocytes begin a life of patrol once they are released from the bone marrow, T lymphocytes first

undergo further maturation in the thymus. Lymph nodes, tonsils, lymph follicles of mucous membranes

and the spleen belong to the list of secondary (or peripheral) lymphatic organs. These are the organs

where mature immune cells participate in specific immune defense reactions. Figure 10.1 also shows the

different types of immune cells. Their morphology was introduced in chapter 9. Their immune function

is presented as part of the sections on innate and adaptive immunity (see below).

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Lymph nodes are the sites through which blood, lymph and immune cells are filtered. These

encapsulated organs are located throughout the body at junctions of lymphatic vessels and are optimized

for interaction between antigen-presenting cells and T and B lymphocytes. During a bacterial infection,

lymph nodes swell due to proliferation of immune cells. Palpation of lymph nodes to give an indication

of the activity level of the immune system is part of most orderly clinical examinations. The movement

of lymph through lymph vessels and lymph nodes is supported by skeletal muscle movement, but is

otherwise passive. There is no organ similar to the heart to pressurize the lymph flow.

There is an abundance of non-cellular immune elements in blood and lymph. They include, but are not

limited to, antibodies (see Table 10.4), communication molecules (see Table 10.5), and complement.

Additionally, the innate immune system encompasses a variety of fluids and other non-cellular

components with antimicrobial character (see Innate Immunity below).

<h1>THE INNATE IMMUNE SYSTEM:

The ability of cells and tissues to respond to and to get rid of environmental challenges is an ancient

evolutionary development that has persisted through vertebrate development as innate immunity (Table

10.1). It is also called nonspecific or natural immunity. In humans it is present at birth. It is always in

place throughout life, can be rapidly mobilized, and it acts quickly. All antigens are attacked pretty

much equally and there is no long-term change in the quantity or quality of the response.

<h2>Elements of the Innate Immune System Include Anatomic and Physiologic Barriers and

Antibacterial Agents

Our skin is a good anatomical and physiological barrier against microorganisms. The cells of the

epidermal layers are dry and densely packed making it an inhospitable environment to many bacteria.

Salty secretions from sweat glands and oily secretions from the sebaceous glands associated with hair

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follicles create a hyperosmotic and slightly acidic skin environment, which dehydrates bacteria and

discourages those that prefer a neutral pH for colonization. Additionally, the continuous desquamation

of skin cells eliminates bacteria adhering to epithelial cells. Lastly, a large number of non-invasive, non-

pathogenic commensal (part of normal flora) microorganisms on the skin prevent growth of harmful

microorganisms in a process called competitive exclusion.

Acidity is also used in other places of the body as an antimicrobial tool. For example, natural

microflora alters the fluids of the vaginal and urinary tract to an acidic pH below 4.5, so that yeast and

other microorganisms cannot grow. Parietal cells of the stomach create highly acidic gastric juice below

pH 3. Other factors such as low oxygen tension and fever are said to contribute to the innate barrier

defenses, but their physiologic impact is still under discussion. For instance, the role of fever is thought

to have a direct negative effect on certain microorganisms. It may also be helpful to enhance the

efficiency of phagocytosis.

Various types of cellular secretions destroy and eliminate germs. Mucus prevents microorganisms

from adhering to epithelial cells and contains antibacterial components. The mucus of the gut blocks,

inactivates, or destroys pathogens associated with food before they can enter the body. A thin layer of

mucus covering the airway from the nose to the bronchioles traps inhaled viruses, bacteria, pollens and

other particles and facilitates their removal before they can damage the airway lining cells. The flow of

saliva helps to wash away bacteria attached to food particles, while attacking them with thiocyanates

and lysozymes. Saliva can also contain antibodies that destroy oral bacteria in certain people. Tears and

nasal secretions contain similar antibacterial components.

The list of chemical factors with antimicrobial character is long and includes pepsin in the stomach,

defensins produced by immunological cells, and surfactant proteins of the lung, to name a few.

Interferons are a group of proteins that are produced by cells following viral infection. Complement is a

group of serum proteins that circulate in an inactive state and can be activated by a variety of specific

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and non-specific immunologic mechanisms. It is sometimes called the humoral component of the innate

immune system. Its action is discussed again below. These chemical factors often connect the innate

immune system with the adaptive immune system, the system that comes into play when the innate

system is overwhelmed by the invaders or unable to detect them.

<h2>Cellular Elements of the Innate Immune System Involve Phagocytes, Killer Cells,

Eosinophils, and Mast Cells

Figure 10.1 illustrates the cells of the immune system. Table 10.2 identifies neutrophils, macrophages

and dendritic cells as the main cells capable of phagocytosis, an ongoing process of the innate immunity.

Phagocytes are activated by T cell cytokines, and can directly sense the pathogens through a group of

transmembrane receptors, Toll-like receptors. Upon activation, phagocytes engulf the microorganism,

particle, or cell debris. The engulfed matter is enclosed within vacuoles and enzymatically digested,

after fusion with lysosomes. Some pathogens have been coated with opsonins in a process called

opsonization to render them more attractive to phagocytosis. Examples of opsonins are IgG antibody

and the C3b molecule of the complement system.

Neutrophils (or polymorphonuclear leukocytes) recognize chemicals produced by bacteria in a cut

or scratch and migrate towards them. Once arrived, they ingest bacteria and kill them. For killing,

neutrophils use proteolytic enzymes and reactive oxygen species as part of the respiratory burst (see

Chapter 9).

Macrophages are derived from circulating monocytes. Macrophages, like neutrophils, kill by using

the respiratory burst and proteolytic enzymes. Macrophages secrete various cytokines that attract

leukocytes to the infection site and initiate the acute phase inflammatory response. Finally, macrophages

act as antigen-presenting cells to T cells and are hence an important bridge to the adaptive immune

response.

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Macrophages can circulate in lymph vessels (wandering, non-fixed macrophages), or they can reside

in connective tissue, lymph nodules, along the digestive tract, in the lungs, in the spleen and other places

(mature, fixed macrophages). Fixed macrophages are part of the reticuloendothelial system (RES),

which, in addition to removing pathogens, also remove old cells and cellular debris from the

bloodstream. Some of these macrophages have their own names. For instance, the macrophages along

certain blood vessels in the liver are called Kupffer cells, while the macrophages of the joints are called

synovial A-cells. Microglial cells are macrophages located in the brain.

Dendritic cells are, similar to macrophages, a critical link between the innate and adaptive immune

systems. They exist in an immature form throughout the epithelium of the skin (Langerhans’ cells), the

respiratory tract and the gastrointestinal tract. After phagocytosis of pathogens, the cells mature and

travel to regional lymph nodes, where they activate T cells, which then activate B cells to produce

antibodies against the pathogen.

Natural killer (NK) cells attack aberrant body cells such as virus-infected cells and malignant cells.

They release the cytolytic protein perforin, which forms a pore in the plasma membrane of the target

cell. Proteolytic enzymes such as granzyme enter through the pore and induce apoptosis. Upon

exposure to lymphocyte secretions such as interleukin-2 and interferon-gamma, NK cells become

lymphokine-activated killer (LAK) cells, which are even more efficient in killing than NK cells.

Eosinophils are best known as participants in allergic reactions where they might detoxify some of the

inflammation-inducing substances. But they are also able to secrete factors that punch small holes in

worms and certain other parasites causing them to die.

Mast cells are present in most tissues in the vicinity of blood vessels. They are especially prominent

under coverings, lining the body surfaces such as skin, mouth, nose, lung mucosa and digestive tract.

Although best known for their roles in allergy and anaphylaxis of the adaptive immune system, mast

cells play an important role in the innate system as well. They release factors that increase blood flow

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and vascular permeability bringing components of immunity to the site of infection. In combination with

IgE antibody from B cells, mast cells can also target parasites which are too large to be phagocytosed,

such as intestinal worms.

<h1>THE ADAPTIVE IMMUNE SYSTEM:

Microbes that escape the onslaught of cells and molecules of the innate immune system face attack by

T cells and B cell products of the adaptive immune system (Table 10.1), also called the acquired

immune system. Adaptive immunity is a relatively recent evolutionary development and characteristic

of jawed vertebrates. The adaptive immune system is induced by hundreds of thousands of diverse

antigens, which are presented as glycoproteins on the surface of bacteria, as coat proteins of viruses, as

microbial toxins, or as membranes of infected cells. It responds with the generation of antibodies and

cells that specifically assault the invading pathogen. The adaptive immune response is slow, being fullly

activated about four days after the immunological threat. Adaptive immune responses exhibit

immunological memory, so that repeated exposure to the same infectious agent results in improved

resistance against it (anamnestic response).

Although innate and adaptive immune system are characterized by contrasting functions and timing

(Table 10.1), they work together in ways that obscure their differences. For instance, the initiation and

the adequate functioning of the innate system often depends on the presence of elements of the adaptive

immune system such as small amounts of specific antibody in blood plasma. The reverse is true as well.

Antibodies and other mediators of the adaptive immune system depend on elements that are typically

associated with the innate immune system such as neutrophils. Only when working together can the

innate and adaptive immune system provide a considerable obstacle to the establishment and long-term

survival of infectious agents.

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<h2>The Three Most Important Features of Adaptive Immune Responses Are Specificity,

Diversity and Memory

The specificity of the adaptive immune system is created by antigen-recognition molecules which are

synthesized prior to the exposure to antigen and are then modified during the immune response to make

them more specific to the antigen. Three types of molecules participate in this anticipatory defense

system: Specific receptors on T and B lymphocytes, molecules encoded in the major histocompatibility

complex (MHC), and antibodies. All three types of molecules show an extreme diversity so that each

molecule can specifically detect a particular antigen.

The T cell receptor (TCR) resembles the Fab fragment of an immunoglobulin (Fig. 10. 4). There are

two forms of TCRs known. Over 90 percent of peripheral T cells express one of them, the alpha/beta

form. TCRs are antigen-specific. In an individual, there are about 1018 different TCRs, but each T cell

has only one type of it. The B cell receptor (BCR) is a membrane-bound form of immunoglobulin.

There are about 1014 BCRs, again one type of immunoglobulin per B cell. There is a similarly high

number of antigen-specific MHC molecules per individual. The molecule diversity is achieved by

multiple genes encoding for the molecules (polygeny) as well as variable recombination and mutation of

the molecules during cell differentiation (polymorphy). The MHC genes are known as the most

polymorphic genes of the human genome.

The binding of an antigen to the lymphocyte with the best fitting receptor occurs mainly in the local

lymph node and induces the proliferation of the responsive cell, a process known as clonal selection

(Fig. 10.2). However, in the case of T cells, T cell proliferation is only induced if a co-stimulatory

signal, secondary to TCR binding, occurs. Clonal selection amplifies the number of T or B lymphocytes

that are programmed to specifically respond to the inciting stimulus. While all of the cells that were

generated after a single clone has expanded, are specific for the inducing antigen (and hence have the

same TCR or BCR), they may not all possess the same functional characteristics. For instance, clonal

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proliferation of T cells leads to the generation of more antigen-specific T cells and to the production of

effector T cells, such as T helper (TH) cells and cytotoxic T cells (CTL).

Antigen-binding to the BCR of B cells induces their development into plasma cells, which are capable

of generating antibodies, first IgM antibodies and later IgG, IgA and/or IgE antibodies. The antibody can

be found in a variety of body fluids, including saliva, other secretions, and plasma. Other progeny in the

expanded B cell clone may function as memory cells, which account for one of the primary tenets of

immunity. These cells mimic the reactive specificity of the original lymphocytes that responded to the

antigen and accelerate the responsiveness of the immune system when the antigen is encountered again.

It leads to increased resistance after initial exposure to the infectious agent and is the basis for

vaccination (see Clinical Box 3).

<h2>T Cell Mediated Immunity is One of the Two Fundamental Mechanisms of Adaptive

Immunity

Cell-mediated immunity (or cellular immunity) is accomplished by activated T cells (Fig. 10.3). T

cells continuously patrol the body and check the virulence of antigen in a process called immune

surveillance. T cells are activated by binding of antigen to the specific TCR plus a co-stimulatory event.

Antigen can only bind to the TCR when presented by antigen presenting cells (APC) in combination

with MHC. The complex interaction between the T cell and the APC is called immunological synapse.

Almost every cell in the body can present antigen to the TCR of CD8+ cytotoxic T cells. In this case,

the antigen is a cytosolic pathogen, which was degraded in the cytosol and associated with MHC class I

molecules (Table 10.3). In the case that the antigen stems from intra- or extracellular bacteria or toxins,

it is associated with MHC class II molecules and presented to the TCR of CD4+ T helper cells. Only

macrophages, dendritic cells, and B cells can do that. Macrophages become APCs when they upregulate

their MHC-II molecules in response to infection and stimulation of specific lipopolysaccharide (LPS)

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receptors by bacterial ligand. Dendritic cells are mostly found in peripheral tissue where they ingest,

accumulate and process antigens. B cells are the least efficient APCs. They become activated by ligand

binding to the BCR and ingest soluble proteins by pinocytosis.

The CD4+ and CD8+ cells develop in the thymus. CD stands for Cluster of Differentiation. There are

more than one hundred and sixty clusters that coat the lymphocyte surface. CD4 and CD8 are two that

are used to identify T cell subsets. When the cells coming from the bone marrow reach the thymus they

have neither CD4 nor CD8 (double negative T cells), but they then start expressing both markers

(double positive T cells). During development in the thymus they differentiate into either CD4 or CD8

cells. At the same time, they develop their ability to distinguish self from non-self peptides as explained

in the following.

First, cells that do not bind MHC/antigen complexes within 3-4 days will die. This happens to over 95

percent of the cells. The rest of the cells undergo positive selection. This means that T cells that bind

antigen (self or non-self) complexed with MHC, class I or II, proliferate. This happens in the cortex of

the thymus. At this time, cells with TCRs specific for MHC II retain CD4 and lose CD8 and become T

helper cells. T cells that are specific for MHC I retain CD8 and lose CD4 and become cytotoxic T cells.

After positive selection, cells undergo negative selection in the medulla of the thymus. During this

process cells that bind with high affinity to MHC/self antigen complexes will die by apoptosis. This is

important since these cells would later react with self peptides and cause autoimmune diseases. Cells

that bind with low affinity to MHC/ self antigen are allowed to leave the thymus. They will later only be

activated by high affinity binding to MHC/ foreign antigen complex, the adequate signal for immune

activation.

Cytotoxic CD8+ T cells release lymphotoxins which cause cell apoptosis of virus-infected cells (Fig.

10.3). Suppressor T cells inhibit the production of cytotoxic T cells when they are no longer needed.

Helper CD4+ T cells direct the immune response by secreting lymphokines. They stimulate proliferation

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of cytotoxic T cells and B cells, attract neutrophils, and activate macrophages. The differentiation of

CD4+ T helper cells into helper 1 and helper 2 cells occurs only after they have been activated during an

immune response in the peripheral lymphoid system. Each type of effector T cell produces a distinct set

of effector molecules. For instance, T helper 1 cells release the macrophage-activating effector

molecules interferon-gamma and tumor necrosis factor-alpha, while T helper 2 cells produce B cell

activating effector molecules such as interleukin 4, 5, and 15, among numerous other cytokines.

Research shows that the dual T helper cell model, although still widely be used, is too simple and might

soon need to be expanded. For instance, many T cells express cytokines from both profiles. They are

often named T helper zero cells. Additionally, many T cell cytokines are expressed by other immune

cells as well. Lastly, memory T cells recognize a previously encountered pathogen.

T cells and their products may act directly or exert their effects in concert with other effector cells,

such as neutrophils and macrophages. The secretion of T cell factors that recruit and activate other cells

takes time, and thus, the consequences of T cell activation are not noticeable until 24 to 48 hours after

antigen challenge. An example illustrating this time delay is the delayed-type hypersensitivity reaction

(see also Immune Diseases below) to purified protein derivative (PPD), a response used to assess prior

exposure to the bacteria that cause tuberculosis. Injected under the skin of sensitive individuals, PPD

elicits the familiar inflammatory reaction characterized by local erythema and edema 1 to 2 days later.

Cell-mediated immune responses, while slow to develop, are potent and versatile. These delayed

responses provide the main defense against many pathogens. T cells are also responsible for the

rejection of transplanted tissue grafts (see Organ Transplantation below) and containment of the growth

of neoplastic cells (see Immune Disorders below). A deficiency in T cell immunity, such as that

associated with AIDS, predisposes the affected patient to a wide array of serious, life-threatening

infections.

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<h2>Humoral Immunity is the Second Fundamental Mechanism of Adaptive Immunity

Humoral immunity consists of defense mechanisms carried out by soluble mediators in the blood

plasma (Fig. 10.3). Binding of antigen to the BCR activates B lymphocytes, which then start

proliferating and maturing in the presence of T helper cytokines. Most new cells become plasma cells

which produce antibodies for four to five days, resulting in a high level of antibodies in plasma and

other body fluids. These antibodies can specifically bind to the antigenic determinant that induced their

secretion. Other B cell clones become long-lived memory B cells. In general, antibodies are known to

induce immediate responses to antigens and, thereby, provoke immediate hypersensitivity reactions (see

Immune Disorders below).

<h2>Antibodies Consist of Four Protein Chains Arranged Like the Letter Y

Antibodies, also called immunoglobulins or Igs, constitute the gamma globulin part of the blood

proteins. The primary structure of an antibody is illustrated in Figure 10.4. Each antibody molecule

consists of four polypeptide chains (two heavy chains and two light chains) held together as a Y-

shaped molecule by one or more disulfide bridges. There are two classes (isotypes) of the light chain

called kappa and lambda. Heavy chains have five different isotypes (gamma, alpha, mu, epsilon and

delta), which consitute five different classes of antibody, each with different effector functions (see

below). Each polypeptide chain possesses both a conserved constant region and a variable region,

where considerable amino acid sequence heterogeneity is found.

The amino terminal portions of the variable regions are known as the Fab regions. The hypervariable

regions at the end of the Fab region, known as antibody idiotypes, are the antigen-binding regions. Each

antibody unit possesses two identical antigen-binding sites, one at each end of the “Y.” The carboxy

terminal end of the heavy chain is termed the Fc region. Fc fragments can bind to cells such as

neutrophils, monocytes, and mast cells through their Fc receptors, which amplifies the biological

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activity of antigen-bound antibody. Antibodies are flexible in that the Fab arm can wave, bend and rotate

and even the Fc region has some degree of freedom. This freedom of movement allows it to more easily

conform to the shape of the antigen.

<h2>Antibodies Work in Three Ways to Destroy the Antigen

1. Neutralization. Antibodies can bind to toxins forming easily recognizable antibody-antigen

complexes, which are removed by phagocytosis. Antibodies can also immobilize and agglutinate

infectious agents with the effect that a virus cannot penetrate the host cell or a microbe cannot colonize

mucosal tissue. In some cases the complexes may also settle out of solution and precipitate.

2. Opsonization. IgG antibodies bind to bacteria or virus-infected cells via the Fab region. That way,

the pathogen is ‘tagged’ or ‘opsonized’ for phagocytosis or destruction by free radicals and enzymes.

Some complement components can also act as opsonins.

3. Complement Fixation. Complement is a group of at least nine distinct proteins that circulate in

plasma (Fig. 10.5). A cascade of events occurs when the first protein recognizes preformed immune

complexes of antigen molecules bound to antibodies (classical pathway). These events include the

recruitment of inflammatory cells. In addition, complement can be activated when one of the proteins is

exposed to the cell wall of certain bacteria. Initiation of this system (alternate pathway) results in the

lysis of the target by formation of the membrane attack complex (MAC). Because of its tubular

structure and hydrophobic nature, the MAC inserts into the membrane of the cell and allows free

passage of small molecules, ions and water resulting in the cell’s death. Complement fixation is the basis

for various diagnostic tests to detect a specific antibody or a specific antigen in a patient’s serum

<h2>There Are Five Major Antibody Classes With Different Primary Functions

Figure 10.4 and Table 10.4 summarize the shape and functions of the five major classes of antibodies.

Figure 10.4 additionally shows the similarities of the TCR and the BCR with immunoglobulin.

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IgG is the major antibody produced in response to secondary and higher order antigen encounters.

Secondary immune responses are faster and longer, and produce more antibody with higher affinity to

the antigen compared to primary responses. Hence, IgG is the most prevalent antibody in serum and is

responsible for adaptive immunity to bacteria and other microorganisms. It has a half-life of 23 days, the

longest amongst the antibody classes. When bound to antigen, IgG can activate serum complement and

cause opsonization. IgG exists in serum as a monomer. It can cross the placenta and is secreted into

colostrum, protecting the fetus as well as the newborn from infection.

IgA usually exist as polymers of the fundamental Y-shaped antibody unit. In most IgA molecules, two

antibody units are held together by a secretory piece (J chain), a protein synthesized by epithelial cells.

In this conformation, IgA is actively secreted into saliva, tears, colostrum, and mucus and hence is

known as secretory immunoglobulin. IgA has a half-life of about 6 days.

IgM consists of five Y units. Its size and large number of antigen-binding sites provide the molecule

with an excellent capacity for agglutination of bacteria and blood cells. Such agglutinated antigens are

efficiently and quickly removed by fixed macrophages of the RES system. IgM is the first antibody

secreted after an initial immune challenge and provides resistance early in the course of infection. It has

a half-life of about 5 days.

IgE is a monomeric antibody that is slightly larger than IgG, but has a relatively short half-life of

about 3 days. IgE avidly binds via its Fc region to cells such as mast cells and basophils, which are

involved in allergic reactions (see Immune Diseases below).

IgD is found in plasma and on the surface of some immature B cells. It has a half-life of 3 days. An

exact function is not known. It is expressed early during B-cell differentiation and has been postulated to

be involved in the induction of immune tolerance. IgD serum concentration does increase during chronic

infection, but is not associated with any particular disease.

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<h1>INFLAMMATION

Inflammation is the initial response of the body to infection or trauma. Although microbial infection is

probably the most common cause for inflammation, many types of tissue injury can evoke inflammatory

reactions. These include mechanical injury, radiation, burns, frostbites, chemical irritants, and tissue

necrosis resulting from lack of oxygen or nutrients. The body instigates a non-specific cascade of

physiological processes involving elements of the innate immune system, with the goal to repair cellular

damage in vascularized tissues and to restore the tissue to its normal function.

Inflammation is the response of a complex system that mobilizes immune, endocrine, and neurological

mediators (see Neuroendoimmunology below). In a normal response, it is self-initiating, temporally self-

propagating, and self-terminating. Inflammation is a necessary response to tissue injury, and human life

without inflammation is unthinkable. On the other hand, inflammation often overshoots in its reactions,

which leads to a vicious circle of repeated injury and persistent inflammation. In this respect,

inflammation is closely connected with all kinds of illnesses so that anti-inflammatory therapy is at the

heart of a wide variety of therapies.

<h2>Inflamed Tissue is Swollen, Red, Hot and Painful, Resembling an “Internal Fire”

The clinical aspects of inflammation have been known for over two thousand years and gave

inflammation its name as resembling an internal fire. These include four signs: first, rubor (redness),

generated by increased blood flow due to dilation of small blood vessels, and second, calor (heat)

generated by the metabolism of leukocytes and macrophages recruited to the site of damage. While the

increased blood flow contributes to a small temperature increase in the skin, systemic fever occurs as a

result of the chemical mediators of inflammation, especially IL-1 acting at hypothalamic neurons. The

third and fourth signs are tumor (swelling) due to edema, and dolor (pain) caused by the production of

prostaglandins, bradykinin, and serotonin. With increasing knowledge of the complexity of

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inflammation, many models have been put forward to expand on and to categorize the great variety of

inflammatory responses. However, they are not yet commonly used in clinics beyond the addition of a

fifth sign, functio laesa (the loss of function), which is a common, well-known consequence of

inflammation.

Laboratory investigation of inflammation usually reveals an increased number of neutrophils in

peripheral blood, an increased erythrocyte sedimentation rate (see Chapter 9), and increased

concentration of acute-phase blood proteins. The latter are produced by the liver in response to

circulating pro-inflammatory cytokines such as IL-1, IL-6, and tumor necrosis factor alpha (TNF-). An

important member of the blood protein profile is C-reactive protein, a pro-inflammatory marker which

is used to monitor the severity and progression of some cardiovascular diseases. A high serum level of

the amino acid homocysteine has been associated with increased risk of atherosclerosis and other

conditions involving inflammation.

<h2>Acute Inflammation Involves Vasodilation, Vascular Leakage and Leukocyte Emigration

The immediate response of acute inflammation includes local dilation of blood vessels, which

increases blood flow to the injured area, sometimes up to ten-fold. The vessel walls become leaky, on the

one hand due to the injury-related necrosis of endothelial cells, and on the other hand due to chemically

directed retraction of endothelial cells. Next, water, salts and small proteins, such as fibrinogen, exit

from the plasma into the damaged area in a process called exudation. The leaking fluid is called

exudate, or pus in the case of an infected wound. Fibrinogen forms fibrin, which impedes the

movement of microorganisms and makes them easier to phagocytose. Acute inflammation is initially

mediated by histamine, followed by factors derived from local cells (e.g. bradykinin), and recruited

neutrophils (Table 10.5).

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Recruited neutrophils adhere to the endothelial cells via selectins. Loose bridges are established

between P-selectin and E-selectin on endothelial cells and L-selectins on neutrophils (margination).

Thus slowed down, the neutrophils move along the endothelium like tumbleweed (rolling). A more firm

connection is built between integrins on neutrophils, and Intracellular and Vascular Adhesion Molecules

(ICAM, VCAM) on the endothelial side. This allows neutrophils to actively migrate through the blood

vessel basement membranes into the tissue (transmigration or diapedesis) without damaging the

endothelial cells. Eventually, monocytes are attracted and differentiate into macrophages when leaving

the blood. Lymphocytes follow as well. The appearance of these non-granular cells marks the entry into

chronic inflammation.

<h2>Inflammatory Mediators Are Small Secreted Substances Which Regulate Inflammation

Inflammatory mediators are soluble molecules that act locally at the site of damage and coordinate the

development of inflammatory responses. Exogenous mediators include endotoxin, bacterial toxin

associated with the LPS complex of gram-negative bacteria. It is released when bacteria are lysed and

binds to receptors on monocytes and macrophages thus activating them. Endogenous mediators are

released from injured or activated cells at the inflammation site. There is a long list of substances that

are known to regulate inflammation, many of them with seemingly redundant functions. Table 10.5 lists

a few of them.

An important class of mediators is cytokines, which are cell products synthesized de novo in response

to immune stimuli. They generally act over short distances and short time spans. They include

lymphokines (cytokines made by lymphocytes), monokines (made by monocytes), chemokines

(chemoattractants made by various cells), and interleukins (made by one leukocyte and acting on other

leukocytes). Many mediators can interact with multiple receptors, often exerting very diverse functions.

For instance, histamine interacts with three receptors. The H1 receptors mediate acute pro-inflammatory

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vascular effects, while activation of H2 receptors results in anti-inflammatory actions. H3 receptors are

involved in the control of histamine release.

From a structural standpoint, inflammatory mediators belong to many different categories, such as

proteins (e.g. complement, antibodies, acute phase reactants), lipids (e.g. prostaglandins, platelet-

activating factor), amines (e.g. histamine), gases (e.g. NO, O2-), kinins (e.g. bradykinin) and

neuropeptides (e.g. substance P). Many plasma-derived mediators are present as precursors and need

enzymatic cleavage to become active. Cell-derived mediators can be preformed (e.g. histamine) or

synthesized as needed (e.g. prostaglandin).

<h2>Acute Inflammation Is Considered to Be a Stereotypic but Highly Complex Process That Self

Terminates

Modern molecular biology superimposes many additional layers of complexity onto the presented

model of inflammation, and our current understanding of acute inflammation as a stereotypic response

might soon need to be revised. For instance, it has been shown that aspects of both inflammation and

repair can be triggered and modulated by factors independent of the vasculature. Vibration and hypoxia

can lead to degranulation of mast cells and release of histamine, hence initiating inflammatory events.

Similarly, increased mechanical load on tendon fibroblasts can modulate their inflammatory response.

In addition, pro-inflammatory molecules can be upregulated without any stimulation by inflammatory

cell invasions.

Under normal circumstances acute inflammation terminates itself. Chemical mediators disappear due

to a short half-life or are enzymatically inactivated (e.g. kininases inactivate kinins). Substrates are

consumed, and the lymph flow carries the mediators away faster than they can be produced. Repair of

damaged tissue is induced by anti-inflammatory cytokines such as IL-4, IL-10, and transforming growth

factor beta (TGF-). Pools of lymph fluid (blisters) may form in response to burns, infections, or

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irritating agents. If an infected area is further liquefied and shielded from surrounding tissue as a

response of the body, it is called an abscess. Some abscesses are acutely cleared (e.g. pimples), but other

lesions might become chronic and then require natural or surgical drainage for healing. Following

inflammation, tissue that is capable of regeneration will be almost completely restored, while, otherwise,

scar formation occurs.

<h2>Chronic Inflammation Is the Failure to Resolve Inflammation and Usually Causes Serious

Body Harm

Chronic inflammation develops when neither agent nor host is strong enough to overwhelm the other

(e.g in the case of osteomyelitis, the staphylococcus infection of bone), when there is prolonged

exposure to the toxic agent (e.g. silicosis from inhalation of crystalline silica dust), or as part of

autoimmune diseases (e.g. rheumatoid arthritis). It can also develop without being preceded by acute

inflammation (e.g. in tuberculosis). Chronic inflammation may last weeks, months, or years and leads to

chronic wounds. They are composed of loosely arranged connective tissue (granulation tissue),

infiltrated fibroblast, and inflammatory cells. The vastly dominant inflammatory cell type, and the only

cell type present in the case of chronic inflammation due to a non-antigenic agent (e.g. suture thread), is

monocytes/ macrophages. In the case that the injurious agents are also antigenic, other cell types appear

such as lymphocytes, plasma cells, and eosinophils.

Chronic inflammation leads to ongoing tissue damage and clinical symptoms found in typical

inflammatory diseases such as rheumatoid arthritis, atherosclerosis, or psoriasis. Inflammatory cells

secrete products such as reactive oxygen species and proteases that cause additional cell damage. Other

products, such as arachidonic acid and pro-inflammatory cytokines, amplify, as well as propagate, the

responses. This is a vicious cycle that weakens the body and makes it more susceptible to infection.

Overwhelming inflammation combined with immune suppression can lead to Systemic Inflammatory

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Response Syndrome (SIRS), which is called sepsis when the inflammation is due to infection. This can

lead in the worst case to organ failure and death.

Inflammation can happen everywhere in the body. Inflammatory conditions are usually indicated by

adding the suffix “itis”. Myocarditis is the inflammation of the heart, nephritis is the inflammation of the

kidney. Some inflammatory conditions don’t follow the conventional terminology. The most common

one is Asthma (see Clinical Focus Box 1). Another example is pneumonia, which is more commonly

used than pneumonitis to name chronic infection of the lung, characterized by inflamed and fluid-filled

alveoli.

<h2>Novel Solutions to Resolve Chronic Inflammation Are a Core Topic of 21st Century Medical

Research

In recent years, the role of inflammation in diseases that were traditionally not recognized as

inflammatory diseases is viewed with considerable interest. In fact, inflammation is now recognized to

be a critical pathologic component underlying a wide variety of diseases ranging from Alzheimer’s and

Parkinson’s disease to diabetes and certain types of cancer (e.g. colon cancer). While the association

between inflammation and disease has been recognized for a long time, inflammation was mainly

considered as being a result of the illness, instead of being a cause of it. Recent studies clearly show that

the destructive self-promoting cycle between oxidative stress and resulting inflammation that causes

more oxidative stress, contributes to the development of chronic illnesses. These chain of events may

initially occur at a low, unnoticeable level, which leads to the speculation that subacute chronic

inflammation is part of, and may be even the source of, all illnesses. This is a provocative, but

interesting thought that is worth pursuing in light of the increasing occurrence of chronic diseases in our

aging population.

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Glucocorticoid steroid hormones are the most powerful anti-inflammatory drugs currently available.

Corticosteroids inhibit the accumulation of neutrophils at sites of inflammation, (see

Neuroendoimmunology below) but also have widespread effects on other inflammatory cells and

processes. Non-steroidal anti-inflammatory drugs (NSAIDs) inhibit cyclooxygenase (Cox) involved in

prostaglandin production. There are at least two isoforms of the enzyme. Cox-1 is found in platelets, and

catalyzes the production of thromboxane A2. Cox-1 inhibition leads to diminished blood clotting, thus

drugs that block Cox-1 can be used as blood thinners. Cox-2 is expressed in blood vessels and

macrophages in response to inflammation, and leads to production of prostaglandin I2. Drugs that

specifically block Cox-2 can decrease inflammatory pain. However, both Cox-1 and Cox-2 are present

at many more sites, a reason for the abundant pharmacological side effects of the drugs. Alternative

medical therapies include nutrients (e.g. vitamin E), herbs (e.g. chamomile) and supplements (e.g.

glucosamines) with anti-oxidative and anti-inflammatory abilities.

Since the side effects of many available anti-inflammatory drugs outweigh their benefits, a main focus

of 21st century medical research is to develop novel anti-inflammatory strategies. New drugs generally

aim to target specific pathways instead of general inflammatory processes. For instance, leukotriene

modifiers are a relatively new class of anti-inflammatory medications for asthma patients (see Clinical

Focus Box 1) that specifically block the products of arachidonic acid metabolism to prevent an asthma

episode before it even starts. Another example is the use of molecularly engineered antibodies that are

directed against specific inflammatory cytokines or cytokine receptors by using gene recombinant

techniques. Novel non-pharmacological anti-inflammatory therapies may be developed from research

that shows that vibration or low energy radiation suppresses inflammation.

<h1>ORGAN TRANSPLANTATION

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Organ transplantation is indicated when irreversible damage has occurred and alternative treatments

are not applicable. The first human kidney was transplanted in the early 1950’s to the donor’s identical

twin brother. Such a transplant is called an isograft since donor and recipient are genetically identical.

Today, over 10,000 kidneys and many other organs are transplanted in the US per year, most often as

allografts between genetically different, but immunogenically matched people. Kidneys, lungs and

livers come from living donors since a person can live with one kidney and one lung and since liver

tissue regenerates. Transplants of heart, whole lung, pancreas, or cornea come from deceased donors.

So-called non-vital transplants of body parts such as hands, knees, uterus, trachea and the larynx have

also been achieved. Tissue that is transplanted in the same individual from one place to another place is

called an autograft. Skin and blood vessels are common tissue for such transplantation.

While transplantation is nowadays a viable therapeutic option, it is mainly limited by the immensely

larger demand for transplantation organs compared to their availability (see Clinical Box 2). An attempt

to overcome the donor organ shortage is xenograft transplantation, where animal tissue is used to

replace human organs. Two other avenues for replacement of necrotic tissue are the development of

artificial organs and the transplantation of stem cells that may be able to regenerate full functioning

organs. The latter is the holy grail of organ replacement since the new tissue would not be recognized as

foreign, if the stem cells come from the recipient. However, as of today, these alternatives don’t work

nearly as well as allografted organs. Additionally, there are major ethical problems involved.

Xenotransplantation may introduce new diseases to humans and disrespectfully treat animals. The use of

animal and artificial organs may raise problems of self esteem, and stem cell therapy may require the

destruction of human embryos.

<h2>Histocompatibility is the Most Important Criterion for Match in Organ Donation

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The major reason for the donor organ shortage is that the blood and tissue of the donor and recipient

need to have similar immunogenic markers to avoid rejection. For instance, virtually all kidneys with

unmatched ABO blood group between donor and recipient will be rejected within minutes. It is critical

that the recipient does not have, or develop, antibodies against the donor’s human leukocyte antigen

(HLA). HLA are the human antigens of the MHC complex (see T Cell Mediated Immunity above).

These antigens are present on the surface of most body cells, but were first discovered on leukocytes.

For minimum requirements, transplant doctors look at only six of the many HLA antigens (two A, two

B, and two DRB1 antigens) for matching donors to patients. However, research has shown that a match

in more HLA antigens and additional factors such as race, age and sex, improves the patient’s chances

for success.

Although tissue typing decreases the risk of transplant rejection, the match between donor and

recipient is never perfect (except for identical twins). The reality of clinical practice results in organ

transfer from less well-matched donors. So, clinical symptoms resulting from immune attacks on the

transplant are fairly common. Table 10.6 summarizes the different types of rejections.

Immunosuppressive drugs greatly decrease the risk of rejection. There are a wide variety of drugs

available that inhibit different immune processes. Many of them aim to downregulate the unwanted T

cell responses. Total destruction of T cells and other leukocytes by whole body irradiation is used before

bone marrow transplanation (see Clinical Focus Box 2).

<h1>IMMUNE SYSTEM DISORDERS

Many things can go wrong in the complex world of the immune system. First, the immune system may

overreact. It is important for proper functioning that the immune system be very sensitive to pathogens

and use enough power to definitely defeat the pathogen since even small numbers of residual

microorganisms may soon endanger the body again. But this principle comes at the risk of overdoing it.

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Asthma, familial Mediterranean fever (recurrent episodes of peritonitis, pleuritis and arthritis) and

Crohn's disease (inflammatory bowel disease) are examples of an over-reacting immune system.

The most common overreactions of the immune system are known as allergies, or anaphylaxis in the

case of severe forms. Allergies are categorized into four classes (see Table 10.7). Dependent on the

sensitivity of the affected person, they can cause localized or systemic symptoms. Localized reactions

are usually biphasic, with an immediate response mainly due to histamine (erythema, wheal and flare)

and a delayed response that may last several hours. Systemic reactions might be life-threatening due to

the sudden loss of blood pressure as a result of general vasodilation and due to airway obstruction as a

result of smooth muscle contraction.

Second, the immune system may not respond. Immunodeficiencies occur when a part of the immune

system is not present or not working properly. A large variety of disorders falls into this category,

although the number of patients with congenital immunodeficiency diseases is low. The study of these

diseases reveal important insights into cellular and molecular immunology. For instance, Severe

Combined Immuno Deficiency (SCID), commonly known as “bubble boy disease”, represents a group

of congenital disorders characterized by little or no immune response. Research showed that in the x-

linked form of SCID, T cells are disfunctioning due to a mutation of the IL-2 receptor gamma chain. The

immunological consequences are severe and may lead to the patient’s death within the first year of life.

Third, the immune system may respond inappropriately. Autoimmune disorders are the attack on the

body’s own cells, with minimal to devastating consequences. What triggers autoimmune reactions is still

poorly understood and involves genetic, hormonal, and environmental factors. An example is Systemic

lupus erythematosus (SLE), a chronic autoimmune disease with largely unknown etiology that affects

multiple organs, possibly as a result of unregulated apoptosis. Autoimmune phenomena may also occur

secondarily to another disease.

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The examples presented in Table 10.7 are not intended to be comprehensive, but to provide a

framework, which can be expanded in pathology courses. Many diseases involve mechanisms that fit

into several of the categories. Rheumatoid arthritis (RA) is a good example. It is thought to be initiated

by an unknown antigen that stimulates antibody formation, characteristic of type III hypersensitivity.

This leads to joint damage, and as a result, auto-antigens are released, which perpetuate the disease in

the typical fashion of an autoimmune disease. T cells are recruited and activate macrophages which

leads to chronic inflammation. The disease is maintained by immune responses dominated by T helper 1

cells, characteristic of type IV hypersensitivity reactions.

<h2>The Adaptive Immune System Can Cause Malignant Tumors, But Also Recognize Tumors

From Other Tissues

Like any cell, cells of the immune system can grow out of control. Leukemia, the abnormal growth of

leukocytes, is the most common childhood cancer. Lymphomas encompass a diverse group of cancers

which present as solid masses specific to the lymphatic system. At least two viral infections have been

associated with immune system malignancies. The human T cell leukemia virus type 1 (HTLV-1) can

cause acute T cell leukemia and lymphoma (ATLL), and the Epstein-Barr virus of the herpes family is

linked to Burkitt’s lymphoma and possibly Hodgkin’s lymphoma. In both cases, most people remain

healthy when infected. However, people who are immuno-compromised due to previous infections,

other diseases, or age, may develop cancer. For instance, Burkitt’s lymphoma is the most common

childhood cancer in central Africa, where malaria and malnutrition lead to immune weakness.

Some leukemias and lymphomas are easy to differentiate histologically from healthy tissue, others are

not. For instance, lymphoblasts in acute lymphoblastic leukemia (ALL) look very different from normal

lymphocytes. However, the cells in chronic lymphocytic leukemia (CLL) are hard to distinguish from

normal cells and the disease might resemble a physiological high lymphocyte count. In this case,

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identification of specific cell markers, which are not present in healthy cells, will aid the diagnosis. If

these tumor markers are antigenic, the immune system might recognize them as well. The resulting

combat of the immune system against cancer that has already developed is not well understood. It has

led, however, to the rapidly advancing field of cancer immunotherapy, which aims to enhance the

body’s natural defense against malignant tumors.

<h1>NEURO-ENDO-IMMUNOLOGY:

The actions of the immune system are interconnected with the actions of the endocrine and the

neuronal systems (Fig. 10.6). For instance, it is well known that the physiological stress response

downregulates the immune system. As a consequence, individuals, stressed from losing a relative, or

stressed by examinations, become sick more easily. From the fast growing knowledge of the

mechanisms that underlie such phenomena the picture emerges that there is far more information

exchange among the three systems through hormones, neurotransmitters and cytokines than previously

thought. Immune, endocrine, and neuronal systems share a number of the same receptors and synthesize

and secrete some of the same molecules. Accordingly, the strength of a person’s immune response

depends not only on the type of antigen or the person’s age and genetic makeup, but also on the

individual’s lifestyle choices, emotional character, and ability to cope with stress.

<h2>Neuronal Components of the Central and Autonomic Nervous System Modulate Immune

Functions

During an immune response cytokines such as IL-1 stimulate the activity of paraventricular

hypothalamic neurons to release corticotropin-releasing factor (CRF). This starts the physiological stress

response aimed at bringing an individual back to physiological homeostasis. In the pituitary gland CRF

stimulates the expression of POMC, which is converted to beta-endorphin and ACTH. ACTH stimulates

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the release of corticosteroids from the adrenal gland. All these molecules can bind directly to receptors

on immune cells. The resulting actions are generally inhibitory to the immune system, but can also be

immunosupportive, especially during acute stress.

Activating the stress response via CRF also leads to activation of the sympathetic nervous system and

the release of its neurotransmitter norepinephrine. This autonomic path of the stress response can also be

activated by cytokines that are released by immune cells, or by cells of the central nervous system

(CNS) such as microglia and astrocytes. A network of autonomic nerve fibers send information from the

CNS to the spleen and lymph nodes, where the fibers end in close proximity to T lymphocytes and

macrophages. These immune cells, as well as B cells, express beta-adrenergic receptors of the beta 2

subtype and their activation generally leads to inhibition of cell function. For instance, adrenergic

activation of T cells decreases their expression of integrins, so that they cannot migrate out of the blood

vessel into the tissue, which explains the high T cell counts seen soon after a stressful event.

Sympathetic nerve endings and the adrenal medulla also release endorphins and enkephalins. These

opioid peptides oppose the body’s stress response and help maintain homeostasis during times of

physical and psychological stress. The immune responses to opioids vary, dependent on the subtype and

concentration of the neuropeptide. Melatonin, a hormone of the pineal gland, seems to regulate the

opioid network and consequently the immune system. Melatonin therapy is under consideration to

support the immune system of aged people to avoid immunosenescence.

<h2>Immune Cells and Their Secretions Affect the Central Nervous System, Modulated by

Hormones

The information flow from the peripheral immune system to the CNS is carried by lymphokines and

and thymokines (produced by the thymus). For instance, IL-1 is a potent mitogen for astroglial cells. In

addition, it acts at hypothalamic cells causing fever. IL-2 promotes the division and maturation of

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oligodendrocytes, and IL-3 supports the survival of cholinergic neurons. Additionally, CD4+ T cells and

macrophages manufacture neuropeptides such as Vasoactive Intestinal Peptide (VIP) and Pituitary

Adenylate Cyclase Activating Polypeptide (PACAP) which was previously thought to be products solely

of non-immunological cells.

Until recently, it was also believed that the brain is devoid of peripheral immune cells. It is now

known that immune cells can pass the blood brain barrier and enter the central nervous system, where

they may trigger autoimmune disorders. For instance, autoimmune T cells that recognize myelin basic

protein of myelin sheaths might be associated with the development of the demyelinating disease

multiple sclerosis. However, it seems that neuronal autoimmune cells are present in the CNS in the first

place to regulate physiological neuronal events. For instance, it is discussed that they contribute to

maintaining the brain’s ability for cognitive functions.

A large number of hormones have been linked to immune functions. For instance, thyroid stimulating

hormone (TSH), best known as a regulator of metabolic functions, is also produced and used by cells of

the immune system. Growth hormone, prolactin, female and male sex hormones, and leptin are

additional examples of hormones that unequivocally modulate the immune system. In the typical fashion

of hormones, they exert multiple actions in a variety of target cells, dependent on the hormone

concentration, the target tissue, and the environment. This makes hormones optimal regulators of the

body’s homeostasis, but usually causes unwanted side effects when used clinically.

Currently available immune therapies using hormones or neuropeptides are still limited. The adrenal

hormone epinephrine is given to reverse some effects of allergy, and immunocompromised people are

counseled to find ways for dealing with stress. However, many new applications are being developed

and it is safe to say that in the near future distinct enhancement or suppression of immune cell functions

will play a more important role in our approaches to help the body to maintain homeostasis.

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CHAPTER SUMMARY

The immune system encompasses key immunological organs such as thymus, spleen, bone marrow,

lymph system. It additionally includes cells and non-cellular elements that are part of every tissue

throughout the body.

Leukocytes traffick between lymphoid organs, lymphatics and blood vessels.

A substance that elicits an immune response is called immunogen. Haptens and antigens are

substances that bind to T cells or antibodies, but only antigens elicit an immune response.

The overall goal of the immune system is to distinguish between self and foreign molecules inside

our body tolerating normal body substances and eliminating any invasion by foreign substances.

To battle foreign invaders, the immune system has two systems: the innate system as the immediate

response to common immunogens, and the adaptive system, which changes throughout life and

which has memory to respond to an encounter more strongly the second time compared to the first

time.

Innate immunity includes physical, chemical, and mechanical barriers to entry of pathogens. It also

includes phagocytes, killer cells, eosinophils and mast cells.

Phagocytes encompass neutrophils, macrophages, and dendritic cells. They have receptors for

pathogens and for complement-coated and antibody-coated antigens. They can engulf and destroy

pathogens, influence immune responses via immune mediators. Macrophages and dendritic cells can

act as antigen-presenting cells to T cells.

Acute inflammation is the body’s initial response to infectious microorganisms and injuries. It is

characterized by the dilation and leaking of blood vessels and subsequent attraction of circulating

leukocytes to the inflammatory site, where innate immune responses occur.

Adaptive immunity is a delayed, but highly effective, immune response against specific antigens.

The adaptive immune system is divided into cell-mediated immunity, which targets infected cells

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and is managed by T cells, and humoral immunity, which deals with infectious agents in blood and

tissues, and is mediated by B cells and their antibodies.

B and T cells have antigen-specific receptors, which bind pure antigen in the case of B cells, or

antigen presented on MHC in the case of T cells.

Stimulation by antigen plus other signals causes T lymphocytes to proliferate into clones of effector

cells and memory cells.

Cytotoxic CD8+ T cells recognize and kill cells that are infected with endogenous pathogen

presented on class I MHC. CD4+ T helper 1 cells activate macrophages that present antigen on class

II MHC. CD4+ T helper 2 cells activate B cells that present exogenous antigen on Class II MHC.

Activated B cells become antibody-producing plasma cells and memory cells.

Antibodies are antigen-specific binding proteins that neutralize and opsonize antigen and activate

complement to promote various immune reactions. Antibodies occur in five isotpyes with special

functions.

Graft rejection is the major complication of organ transplantation and mainly depends on the

allogeneic differences in the human leukocyte antigens (HLAs) between organ donor and recipient.

Every acute illness evokes an immunological response, and nearly every prolonged serious illness

interferes with the immune system.

Chronic inflammation leads to tissue damage and clinical symptoms. It is associated with the

predisposition to a multitude of diseases.

Immune system diseases are caused by abnormal or absent immunologic mechanisms, whether

humoral, cell-mediated, or both.

The actions of the immune system are closely interrelated with the actions of the endocrine and the

neuronal systems to keep body homeostasis.

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REVIEW QUESTIONS

1. After the nurse covers a patient’s wound with an adhesive bandage, he rapidly develops a red rash

with small blisters. The called clinician diagnoses acute dermatitis. He explains to the nurse that the

patient’s T lymphocytes are overreacting, while in most other acute inflammatory conditions another

cell type dominates. To which other cells is the doctor referring?

A. B cells

B. Dendritic cells

C. Eosinophils

D. Mast cells

E. Neutrophils

2. Penicillin is a small antibiotic molecule with a molecular weight of 300 Dalton. It binds to an enzyme

in the wall of many bacteria, which leads to the weakening of the cell wall. As an unwanted side effect,

penicillin can also bind to serum or tissue proteins, and the resulting complexes can cause allergic

reactions mediated through IgE antibodies. Which of the following describes the parent penicillin

molecule?

A. Antigen

B. Hapten

C. Immunogen

D. Opsonin

E. Pathogen

3. A 40-year old woman is determined to run a marathon once in her life. For the last 4 months, she

trained almost every day, ate high protein meals, and lost 10 kg, while still keeping up with her job and

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motherly duties. Her husband recognizes that she more frequently blows her nose, rubs her eyes and

clears her throat in the evening. Which of the following best characterizes her condition?

A. Acquired immunodeficiency

B. Anaphylaxis

C. Atopic disease

D. Food allergy

E. Non-allergic asthma

4. A scientific article announces a breakthrough for organ transplantation in an article entitled “Specific

suppression of CD4+ T cell alloreactivity by allo-MHC class I- restricted CD8+ T cells.” Which of the

following bests describes the finding?

A. Cytotoxic T cells were suppressed by MHC antigen-presenting cells

B. Cytotoxic T cells were suppressed by T helper cells

C. MHC antigen-presenting cells were suppressed by T helper cells

D. T helper cells were suppressed by cytotoxic T cells

E. T helper cells were suppressed by MHC antigen-presenting cells

5. Herpes simplex viruses tend to infect cells of skin or mucous membranes. As part of the immune

response against the infection, the virus is presented by a host cell (1), with antigen-presenting

molecules (2), to target cells (3). Which of the following are correct for 1, 2 and 3?

A. 1: Any cell 2: MHC class I 3: Cytotoxic T cell

B. 1: Any cell 2: MHC class II 3: T helper cell

C. 1: Any cell 2: MHC class I 3: T helper 1 cell

D. 1: B cell 2: MHC class II 3: Cytotoxic T cell

E. 1: Dendritic cell 3: MHC class II 3: Cytotoxic T cell

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ANSWERS AND RATIONALES

1. The answer is E. Neutrophils are the main cells to mediate the effects of acute inflammation. They

remove the irritating agents by phagocytosis and destroy microorganisms by lysosomal enzymes and

reactive oxygen radicals. The presence of lymphocytes and monocytes/macrophages is usually an

indication that the inflammation has reached the chronic state. However, in most inflammatory disorders

of the skin, such as dermatitis, lymphocytes are the common reacting cells. This is even the case, with

rare exceptions, for immune-mediated skin reactions.

2. The answer is B. Penicillin is a chemical hapten that needs to bind to a macromolecule, usually a

protein, to become immunogenic.

3. The answer is E. Non-allergic asthma can be triggered by strenuous exercise or stress. It leads to the

same symptoms as allergic asthma, also called atopic asthma. Anaphylaxis, or severe allergy, is not the

best answer since her husband is the one that recognizes the symptoms. Food allergy is a possibility due

to the altered diet, but there is no mentioning of any relation between the symptoms and meals. Acquired

immunodeficiencies may develop after a disease or due to malnutrition.

4. The answer is D. CD4+ cells are T helper cells. CD8+ cells are cytotoxic T cells. Cytotoxic T cells

were raised that could recognize MHC class I antigens on target antigen-presenting cells and

consequently suppress the response of T helper cells to MHC class II antigen of the same antigen

presenting cell. This would support the goal to suppress the host’s immune response to donor MHC

antigens for organ transplantation.

5. The answer is A. Endogenous antigens such as viruses replicating within a host cell are digested by

enzymes of the host cell and presented, coupled to MHC class I molecules, to CD8+ cytotoxic T cells,

which destroy the infected cell. Class I MHC is expressed by almost all host cells.

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CLINICAL FOCUS BOXES

<box>10.1 Allergies and Asthma

Epidemiological data confirm what many parents suspected. Allergies amongst children are more

common compared to the incidence rate during their childhood. In the past 30 years, the prevalence of

allergies has been greatly increasing in the US and in the world, proportionally more so in wealthy

countries compared to poorer countries and more so in urban areas compared to rural areas. One

hypothesis to explain this phenomenon proposes that the children that are not exposed to enough

antigens or innocuous microorganisms from soil or water early in their childhood don’t adequately

develop their T helper 1 cell response. This leads to an imbalance towards T helper 2 cell responses

which are present since birth. Even though this hypothesis is disputed as being desperately

oversimplified, it is undisputed that the various manifestations of allergic inflammation are the result of

wrongly activated T helper 2 cells.

Asthma is one common allergic disorder, which affects about 5% of the US population. It belongs to the

category of type I hypersensitivity reaction, and is characterized by airways that narrow excessively in

response to a wide variety of provoking stimuli. Typical allergens causing atopic (also called extrinsic or

allergic) asthma are animal dander, dust mites, grass pollen and cockroach antigen. Non-atopic asthma

might be triggered by strenuous exercise or worry. The symptoms of both asthma types are similar and

include wheezing, breathlessness, chest tightness, and coughing. They are caused by chronic

inflammation of the airways which leads to their swelling. The restriction of the airflow to and from the

lungs is further exacerbated by bronchoconstriction, excess production of mucus, and increased collagen

deposition.

The development of asthmatic symptoms ultimately depends on the presence of T helper 2 cells, which

secrete a characteristic cytokine repertoire. Interleukin-4 activates B cells to produce IgE antibodies,

which bind to mast cells, eosinophils and other airway cells via receptors that are specific for the Fc

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portions of IgE antibodies. Upon subsequent encounter with the antigen, IgE-crosslinking on mast cells

and eosinophils occurs and leads to the cells’ activation and their release of histamine and leukotrienes.

These and other inflammatory factors recruit inflammatory cells including additional T helper 2 cells to

the lung resulting in a damaging immunological positive feedback cycle. IL-4, together with IL-9, is also

necessary for mast cell maturation, and along with IL-5, for eosinophil recruitment.

Several treatments are available that interfere with the different allergic processes. Antihistamine drugs

for treatment of atopic asthma are targeting H1 receptors or prevent the release of histamine from mast

cells. Epinephrine and beta-2 selective agonists for treatment of systemic anaphylaxis modulate the

sympathetic nervous system (see Neuroendoimmunology). Corticosteroids and leukotriene receptor

antagonists aim at suppression of inflammation. Immunotherapy (also called hypo- or desensitization)

involves subcutaneous injections that contain gradually increasing doses of an allergen extract. The

immune system responds with gradually increasing levels of IgG antibodies, which seems to avoid

dramatic reactions when the allergen is then encountered naturally.

<box>10.2 Bone Marrow Transplantation

When a patient has a terminal bone marrow disease, such as leukemia or aplastic anemia, often the only

possibility for a cure is a bone marrow transplant. In this procedure, healthy bone marrow cells are

used to replace the patient’s diseased hematopoietic system. To identify a suitable donor, blood

leukocytes of prospective donors, usually a close relative, are screened to determine whether their

antigenic pattern matches that of the patient. The antigenic composition of leukocytes in bone marrow

and peripheral blood are identical, so analysis of blood leukocytes usually provides enough information

to determine whether the transplanted cells will engraft successfully. If significantly different from the

recipient’s tissue type, transplanted leukocytes may be recognized as foreign by the patient’s immune

system and, therefore, be rejected, a phenomenon called host-versus-graft response.

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More commonly, sufficient differences between the engrafted cells and the host’s own tissue lead to

debilitating consequences as a result of graft-versus-host disease (GVHD). In GVHD, functional T

cells in the proliferating graft recognize host tissue as foreign and mount an immune response. The

disease often begins with a skin rash, as transplanted lymphocytes invade the dermis, and ends in death

as lymphocytes destroy every organ system in the marrow recipient.

Recent advances have decreased the morbidity of marrow transplants and have substantially increased

the potential pool of bone marrow donors for a given patient. Immunosuppressive agents, including

steroids, cyclosporine, and anti-T cell antiserum, effectively decrease the immune function of the

transplanted lymphocytes. Another useful approach involves “purging”—the physical removal of T cells

from bone marrow prior to transplantation. T cell-depleted bone marrow is much less capable of causing

acute GVHD than untreated marrow. These techniques have enabled the successful transplantation of

bone marrow obtained from unrelated donors.

Many problems remain, however. One of the most serious is donor identification. An unrelated

transplant is successful only if the donor’s human leukocyte antigens (HLA) closely match those of the

recipient. Since there are several antigenic determinants and each can be occupied by any one of several

genes, there are thousands of possible combinations of leukocyte antigens. The chance that any

individual’s cells will randomly match those of another is less than one in a million. Finding a suitable

donor is a formidable problem that often generates intense frustration. In conjunction with continued

development of methods to reduce or eliminate GVHD, the expanding bone marrow transplant registries

may someday allow identification of a donor for anyone who needs a bone marrow transplant.

<box>10.3 Vaccination and DNA vaccines against AIDS (From Bench to Bedside)

According to a 2006 estimate, about 1.2 million people in the US and over 60 million worldwide are

infected with HIV, the human immunodeficiency virus causing acquired immunodeficiency syndrome

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(AIDS). Since its first diagnosis in 1981, more than 20 million people have died of AIDS. One

preventative measure against the spreading of pandemic infectious diseases such as AIDS is

vaccination. For instance, vaccination has eradicated the polio virus from the Western hemisphere.

Great effort is currently being undertaken to develop an AIDS vaccine.

The principle of vaccination, also called immunization, is to stimulate the acquired immune system of

the body to fight diseases. Passive immunization refers to the administration of antibodies and

lymphocytes. These last only a few days and hence provide only transient protection. Nevertheless, it

might be a life saving measure in emergencies as in the case of a person bitten by an animal with the

rabies virus. Active immunization is necessary to provide long-term protection, because it generates

immunological memory. To immunize against viral diseases, the vaccine generally contains an

attenuated (weakened) or killed virus. The vaccine for immunization against bacterial diseases often

contains only a portion of the bacteria. These vaccines might be generated by recombinant technology,

where the gene coding for the pathogenic epitope of the bacteria is isolated and expressed in an

appropriate host cell.

In the fight against AIDS, several clinical trials are underway using another type of vaccine, DNA

plasmid vaccine. In this case, genes that encode proteins of pathogens are injected into a person, rather

than the pathogens themselves. The gene of interest is grown in bacteria and hence called plasmid DNA.

When injected in humans, it is taken up by mainly antigen-presenting cells, which then produce the

encoded protein. This antigenic protein elicits an immune response just like a conventional vaccine.

DNA vaccines are attractive for protection against HIV, where inoculation with a dead or attenuated

virus is very risky. It has been proven, at least in animal models, that DNA vaccines activate both

cellular and humoral immune responses. This is advantageous since live viral vaccines only induce the

cellular response, while vaccines containing killed microorganisms, or subunits of them, only induce the

humoral response. Another advantage is the stability of DNA vaccines at ambient temperatures, which

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makes them useable in areas where constant refrigeration of the vaccine is not possible. Finally, DNA

vaccines are cheaper and easier to produce than conventional vaccines and can be manipulated by the

tools of recombinant technology.

The potential that the vaccine plasmid DNA might become integrated into human chromosomal DNA

raises concern. This could induce cancer due to the disruption of a cell division gene or the activation of

an oncogene. Another problem of DNA vaccines includes the question of how to terminate their actions.

Continuous antigenic stimulation may lead to immune tolerance or autoimmunity. Another safety

consideration involves the potential induction of antibodies against the plasmid DNA, which again

might lead to autoimmune diseases. These concerns are currently being addressed, for instance, by

improving the delivery of the plasmid DNA only to antigen-presenting cells, and at the correct time for

immune cells to respond. While the ultimate clinical effectiveness of DNA vaccines is unclear, they

have shown promising results in preclinical trials against diseases such as AIDS.

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Table 10.1 Characteristics of the Innate and Adaptive Immune Systems

Innate Adaptive

System Old, present in all animals

Evolved in early vertebrates

Present at birth Transferable to other individualsHighly reliable Frequently malfunctioning

Stimulation Not required RequiredSpecificity Minimal Highly specific

Self vs non-self discrimination Receptor mediated

Response Within minutes Develops over daysNo change in quality and quantity over time

Improved by previous infection

Memory No YesSoluble factors Lysozyme, complement,

acute phase proteins, interferon, cytokines

Antibodies

Cells Phagocytic leukocytes, NK Cells

T cells, B cells

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Table 10.2 Cellular Elements of the Innate Immune System

Effector Cells Main function Phagocytosis

Neutrophils Kill microorganisms intracellularly

+

Macrophages Kill microorganisms intra- and extracellularly

+

Dendritic cells Destroy microorganisms +

NK and LAK cells

Destroy virus infected and tumor cells

-

Eosinophils Secrete factors that kill certain parasites and worms

-

Mast Cells Release factors which increase blood flow and vascular permeability

-

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Table 10.3 T cell mediated immunity response

Source of antigen : Viruses, some bacteria Bacteria, phagocytosed or living in phagosomes

Extracellular proteins (vaccines, toxins)

Location of antigen : Cytosol Phagosomes Endosomes

Antigen Presenting Cell (APC) : Any cell Macrophages, dendritic cells

B cells

Location of APC : Anywhere Lymphoid and Connective tissue, Body cavities, Epithelium

Lymphoid tissues, Blood

Molecules of display : MHC class I MHC class II MHC class II

Antigen recognition cells : CD8+ CTL cells CD4+ TH1 cells CD4+ TH2 cells

Response : Release of cytotoxic effector molecules

Release of macrophage-activating effector molecules

B cell activation

Effect : Death of infected cell Killing of bacteria and parasites

Secretion of antibody to eliminate bacteria and toxins

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Table 10.4 Characteristics of Different Antibody Classes

IgG IgA IgM IgD IgE

Molecular weight (x 10-3 Daltons) 150 150, 400 900 180 190Y units/molecule 1 1–2 5 1 1Serum concentration (mg/dL) 600–1500 85–300 50–400 <15 0.01–0.03Serum concentration (% of Ig) ~76 ~15 8 1 0.002Crosses placenta + - - - -Enters secretions + + + - - -Agglutinates particles + + + + + - -Allergic reactions + - - - + + + +Complement fixation + - + + - -Fc receptor binding to monocytes and neutrophils

+ + - + - -

Dominant in secondary immune response +Main antibody in external secretions +Dominant in primary immune responses +Responsible for hypersensitivity +

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Table 10.5 Endogenous Inflammatory Mediators

Released By Some ActionsChemical mediators

Histamine Mast cells, basophils, eosinophils, leukocytes, platelets

VasodilationVascular permeability

Lysosomal compounds Neutrophils, macrophages

Vascular permeabilityComplement activation

Eicosanoids Prostaglandins Thromboxanes Leukotrienes

Many cellsNeutrophils

Vasoactive properties, platelet aggregation, prolong edema

Platelet activating factor Neutrophils, monocytes, mast cells, eosinophils

Vascular permeabilityNeutrophil migrationBronchoconstriction

Serotonin Mast cells, platelets VasoconstrictionCytokines Lymphocytes,

monocytesVasoactive and chemotactic properties

Chemokines Tissues cells, endothelial cells, leukocytes

Chemotaxis of inflammatory effector cells

Gases Nitric oxide Endothelial cells, macrophages

Vascular smooth muscle relaxation and vasodilation, kills microbes, counteracts platelet actions

Neuropeptides TachykininsKinins

Mainly sensory neurons Vasodilation, vascular permeability, smooth muscle contraction, mucus secretion, pain

Activated ByPlasma factors

Complement(most important C5a, C3a, but others also involved)

Enzymes from dying cells; antigen-antibody complexes (classical pathway); endotoxins (alternate pathway); products of kinin, coagulation and fibrinolytic system

Chemotaxis, phagocyte, mast cell and platelet degranulation, cytolytic activity, opsonization of bacteria (facilitates phagocytosis)

Kinins Coagulation factor XII Vascular permeabilityMediators of painNon-vascular smooth muscle contraction

Coagulation Factors Coagulation factor XII Conversion of fibrinogen to fibrinFibrinolytic system Plasmin lyses fibrin

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Table 10.6 Types of Graft Rejection

Type Time Reasons

Hyper-acute

Minutes - hours Pre-formed anti-donor antibodies trigger type II hypersensitivity reactions

Acute Days – weeks HLA incompatibility or inappropriate connection to blood supply trigger T cell activation and type IV hypersensitivity reactions. Complicated by antibody-mediated rejection.

Chronic Months - years Unclear. Cellular and humoral mechanisms involved. Reoccurance of disease possible.

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Table 10.7 Immune Disorders

Names Mechanisms Examples (common names of diseases)

Hypersensitivity Disorders: Damaging immune responses elicited by allergens

Immediate Hypersensitivity:

Type I(Immediate hypersensitivity)

Allergens cause cross-linking of IgE bound to mast cells, which release vasoactive mediators (e.g. histamine). Symptoms within minutes.

Atopic diseases: Hives, Asthma, Hay fever Food allergy Systemic anaphylaxis

Type II(Ag-Ab cytotoxicity)

Cytotoxicity mediated by antibody (primarily IgG) directed against epitopes on surface membrane of host cells. Symptoms within hours.

Newborn hemolytic anemia Autoimmune hemolytic anemia Blood transfusion reactions

Type III(Ag-Ab immune complex disease)

Circulating immune complexes (primarily IgG) escape phagocytosis and cause deposits in tissues or blood vessels. Symptoms within hours.

Serum sickness Glomerulonephritis Farmer's lung (allergic pneumonitis)

Delayed-type hypersensitivity:

Type IV(Cell-mediated hypersensitivity)

Memory TH1 cells cause cell-mediated immunity resulting in tissue damage by macrophages. Symptoms within day(s).

Contact dermatitis (e.g. poison ivy) Photoallergic dermatitis (e.g. sunscreen) Celiac disease (gluten)

Immunodeficiency Disorders: Diseases caused by deficiencies (primary) or being the result of it (secondary)

B cell Deficiency in antibody-mediated immunity Bruton’s agammaglobulinemia IgA deficiency

T cell Deficiency in cell-mediated immunity DiGeorge syndrome (thymic hypoplasia)

Combined Combined deficiency of cellular and humoral immunity

SCIDs

Non specific Mediated by deficient phagocytic and/or natural killer cells

Leukocyte adhesion deficiency Chronic granulomatous disease

Complement Defects of individual components or control proteins C1, C4, C2, C3, C5-9 deficiencies Hereditary angioedema (lack of C1 inhibitor)

Acquired Human immunodeficiency virus (HIV) infects and kills CD4

+ T helper cells, which leads to massive immunosuppression and increased risk of cancer.

AIDS Prolonged serious disorders (cancers, kidney

failure, diabetes, liver problems, etc)

Autoimmune Disorders: Immune responses against the body’s own tissue

Antibody mediated A specific antibody targets a particular antigen, which leads to its destruction and the signs of the disease

Autoimmune hemolytic anemia (erythrocytes) Myasthenia gravis (neuromuscular receptors) Graves’s disease (adrenal gland cells)

Immune complex mediated Antibodies complex with autoantigen into large molecules which circulate around the body and cause destruction

Systemic lupus erythematosus Rheumatoid arthritis

T cell mediated T cells recognize autoantigen, which leads to tissue destruction without requiring the production of autoantibody

Multiple sclerosis Type 1 Diabetes Hashimoto’s thyroiditis

Mediated by complement deficiency

Deficiencies in complement components often lead to, or predispose to the development of autoimmunity

Systemic lupus erythematosus

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Figure Legends

FIGURE 10.1

Organs and cells of the immune system. Thymus and bone marrow are primary lymphatic organs.

Lymph nodes, tonsils, spleen, and the lymphatic tissue of the gut are secondary lymphatic organs.

Leukocytes are immune cells which circulate in blood. Macrophages, dendritic cells and mast cells are

primarily found in tissues.

FIGURE 10.2

Clonal selection of lymphocytes. Only the clone of lymphocytes that has the unique ability to recognize

the antigen of interest proliferates and generates progenitor cells. These cells are specific to the inducing

antigen, but may have different functions. In the case of B cells, plasma cell clones produce antibodies,

and memory cell clones enhance subsequent immune responses to the specific antigen.

FIGURE 10.3

Cellular and humoral immune responses of the adaptive immune system. Cellular immune

responses are accomplished by activated T cells, humoral immune responses are mediated by B cells and

antibodies. Exogenous antigen activates B cells by binding to the B cell receptor (BCR) and T cells by

binding to the T cell receptor (TCR). However, TCR binding only occurs when antigen peptide is

presented by antigen-presenting cells (APC) in association with major histocompatibility complex

(MHC). The TCR is either associated with CD4 or CD8, dependent on the T cell type. Endogenous

antigens are presented via MHC to cytotoxic T cells, which destroy the host cell together with the

intracellular pathogen.

FIGURE 10.4

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Antibodies and antigen receptors. Antibodies are immunoglobulins (Ig) with five isotypes (IgA, IgD,

IgE, IgG, IgM). The basic unit of each isotype is a monomer that consists of two heavy chains and two

light chains held together in a Y configuration by disulfide bonds. The heavy chains differ in the various

isotypes. IgG and IgD consist of one monomer, IgA of two, and IgM of five monomers. Each end of the

“Y” is called Fab since it is the fragment that contains the antigen-binding site. A second, crystablizable

fragment is called Fc. The B cell receptor resembles a membrane-associated Ig monomer. The T cell

receptor contains a Fab-like structure.

FIGURE 10.5

Complement. Complement (C) proteins “complement” antibody activity in a cascade of events to

eliminate pathogens. The endpoint is formation of a membrane attack complex (MAC), which inserts

into membranes of cells and causes their lysis. The classical pathway is activated by antigen-antibody

complexes. The alternate pathway is activated by pathogen surface molecules. The lectin pathway is in

response to inflammation. Most proteins exist in an inactive form. Two important activation enzymes,

C3 convertase and C5 convertase, are shown.

FIGURE 10.6

Integration of the immune system with the nervous and endocrine systems. Immune, endocrine, and

neuronal systems synthesize some of the same hormones, neuropeptides, thymosins and lymphokines,

which act as communication molecules and regulate body homeostasis.

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GLOSSARY TERMS

(For blood cells, see chapter 9)

Active immunity: Immunity due to activation of lymphocytes (natural), or immunity due to vaccination

(artificially)

Acute phase blood proteins: Serum proteins elevated during acute inflammation

Adaptive immune system: Antigen-specific immune response

AIDS: Acquired immunodeficiency syndrome caused by the human immunodeficiency virus (HIV)

Allergy: Type I immediate hypersensitivity disorder

Allo: greek: other

Allograft: Transplant between genetically different people

Anamnestic response: Increased immune response to repeated antigen exposure

Antibody: Secreted proteins that can bind antigen

Antigen: Substance that binds to antigen receptors and antibody

APC: Antigen-presenting cell. Cell displaying antigen on its surface together with MHC class II

Antigen-recognition molecules: TCR, BCR, MHC

Apoptosis: Non-immunogenic cell death

Atopy: Predisposition to becoming allergic

Auto: Greek: self

Autograft: Transplant grafted into a new position on the same person

BCR: B cell receptor. Antigen-specific receptor on B cells

Calor: Heat associated with inflammation

Cancer immunotherapy: Therapeutic use of natural immune system to fight cancer

CD: Cluster of differentiation. Distinct plasma membrane molecules used as cell markers

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Cellular immunity: Immunity mediated by activated T cells

Chemokine: Cytokine that attract and activate leukocytes

Clonal selection: Proliferation of specific lymphocytes (positive selection) or inhibition of growth

(negative selection)

Complement: Serum proteins that can be activated as part of a cascade of events that may lead to cell

lysis, formation of opsonins and regulation of inflammation

Cross-reactivity: Antibody that react with antigen closely related to the one that induced its formation

Cytokine: Communication molecules synthesized in response to immune stimuli

Dendritic cell: APC of epithelia and blood

Diapedesis

DNA vaccine

Dolor

Effector cell

Endotoxin

Epitope

Exudate

Functio laesa

Gamma globulin

Graft versus host disease

Graft:

Granzyme: enzymes present in the granules of cytotoxic T cells and NK cells which induce apoptosis in

the target cells. now called fragmentins.

Hapten small molecule which is immunogenic only when covalently linked to a carrier molecule.

Histamine

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HLA

Host versus graft disease

Humoral immunity

Hypersensitivity

Idiotype: the antigenic specificity of the variable (antigen-binding) region of an antibody or TCR

molecule.

Immune deficiency

Immune surveillance

Immune tolerance

Immunogen

Immunoglobulin

Immunological synapse

Inflammation

Innate immune system: Nonspecific defense mechanisms.

Interleukin: Cytokine made by one leukocyte and acting on another

Leukemia

LPS

Lymph node

Lymphatic organs: primary and secondary

Lymphocyte

Lymphokine: Cytokine made by lymphocytes

Lymphokine-activated killer cells

Lymphoma

MAC

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Macrophages

Margination

Mast cells

Memory cell

MHC: Major histocompatibility complex

Monokine: Cytokine made by monocytes

Necrosis

Opsonin:

Passive immunity: Immunity passed from mother to child (natural), and immunity obtained by injection

of foreign antibodies (artificially)

Pathogen

Perforin molecule used by NK cells and cytotoxic T cells (CTL) to make pores in the membranes of

target cells.

Phagocyte

Rh: Rhesus antigen.

Rolling

Rubor

Self-tolerance

Sepsis

TCR: T cell receptor

Thymus

Toll-like receptor

Toxoid inactivated toxin, often used as a vaccine against the toxin.

Vaccine: include attenuated

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