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Ch. 18-Immune TodayCh. 18-Immune Today

What about this lab due date…What about this lab due date…

18 Immunology: Gene Expression and Natural

Defense Systems

18 Immunology: Gene Expression and Natural Defense Systems

• 18.1 What Are the Major Defense Systems of Animals?

• 18.2 What Are the Characteristics of the Nonspecific Defenses?

• 18.3 How Does Specific Immunity Develop?

• 18.4 What Is the Humoral Immune Response?

• 18.5 What Is the Cellular Immune Response?

• 18.6 How Do Animals Make So Many Different Antibodies?

• 18.7 What Happens When the Immune System Malfunctions?

18.1 What Are the Major Defense Systems of Animals?

Animals have various means of defense against pathogens—agents that cause disease.

Defense systems are based on the recognition of self (one’s own) and nonself (foreign) molecules.

Photo 18.1 Bacterial plaque in a human mouth. SEM.


Two general types of defense mechanisms:

Nonspecific defenses, or innate, act rapidly;

include skin, phagocytic cells, and molecules toxic to invaders.

Specific defenses, or adaptive, are aimed at specific pathogens,

e.g., antibodies. Slow to develop and long-lasting.

Photo 18.2 Human skin: Thick surface layer of keratin forms a barrier to pathogens. LM.


In animals that have both kinds of defense systems, they work together as a coordinated system.

Nonspecific defenses are the first line of defense, and are tremendously important.


Lymphoid tissues include thymus, bone marrow, spleen, and lymph nodes—essential parts of the defense system.

Blood plasma contains ions, small molecular solutes, soluble proteins. Red blood cells stay in the closed circulatory system. White blood cells and platelets are also in the lymph.


Lymph: fluid derived from blood and other tissues. From tissues, lymph moves into lymph system vessels.

Lymph vessels join and eventually form the thoracic duct, which joins the circulatory system at a vein near the heart.

Figure 18.1 The Human Lymphatic System

Photo 18.3 Normal human lymph node: pale germinal centers around the periphery. LM.


Lymph nodes are small, round structures at many sites along the lymph vessels.

Lymph nodes contain white blood cells.

As lymph passes through the nodes, it is filtered and “inspected” for nonself molecules.


Red and white blood cells originate from pluripotent stem cells in the bone marrow.

These cells constantly divide and can differentiate into a variety of blood cells.

Figure 18.2 Blood Cells (Part 1)


White blood cells, leukocytes,

have nuclei; they can leave closed circulatory system and enter extracellular spaces if nonself molecules or cells are present.

The number of white blood cells may increase in response to pathogens, providing a clue for detecting infections.


Two types of white blood cells:

• Granular includes histamine-producing signaling cells and phagocytes that engulf foreign cells and debris. Phagocytes include dendritic cells and macrophages.

• Lymphocytes participate in specific defenses—T cells and B cells.

Photo 18.4 Two white blood cells (monocyte, left; neutrophil, right) among red blood cells. LM.

Photo 18.5 Section through a macrophage. TEM.

Photo 18.6 Polymorphonuclear neutrophil ingesting bacteria by phagocytosis. TEM.


T cells: the immature cells migrate from the bone marrow to the thymus where they mature.

B cells leave bone marrow and circulate in blood and lymph; make antibodies.

Photo 18.7 Lymphocyte (T or B cell) in normal human blood. LM. Wright stain.


Many proteins are involved in the cell–cell interactions of the defense system:

• Antibodies are proteins that bind to substances identified as nonself. Secreted by B cells.

• T cell receptors are integral membrane proteins, recognize and bind nonself molecules on other cells.


Major histocompatibility complex (MHC): on the surface of most mammalian cells. They are self-identifying labels.

Cytokines: signal proteins released by T cells, macrophages, and other cells. Bind to target cells and alter their activity.

18.2 What Are the Characteristics of the Nonspecific Defenses?

Nonspecific defenses are general mechanisms; the first line of defense.

In humans, they include physical barriers, cellular, and chemical defenses.

Table 18.1 (Part 1)

Table 18.1 (Part 2)


Skin is a primary nonspecific defense.

Bacteria, fungi, and viruses can rarely penetrate healthy unbroken skin.

Normal flora—the bacteria and fungi that live on body surfaces without causing disease. Part of the defense system because they compete with pathogens for nutrients and space.


Tears, nasal mucus, and saliva have an enzyme, lysozyme, that attacks bacterial cell walls.

Mucus in the nose and respiratory tract traps microorganisms.

Cilia continuously move the mucus plus debris up towards nose and mouth.


Mucus membranes

produce defensins, peptides with hydrophobic domains that are toxic to many pathogens.


If pathogens reach digestive tract:

May be killed by gastric juices (hydrochloric acid and proteases), or by bile salts in the small intestine.

Small intestine lining is not normally penetrated by pathogens.


Vertebrate blood has antimicrobial proteins that make up the complement system.

The proteins act in a characteristic sequence or cascade—each protein activates the next.


The complement proteins provide three types of defense:

• They attach to microbes and mark them for phagocytes to engulf.

• Activate inflammation response and attract phagocytes to site of infection.

• Lyse invading cells.


Interferons are antimicrobial proteins produced by cells that are infected by a virus.

They increase resistance of neighboring cells to the same or other viruses.

Interferons are glycoproteins that bind to receptors on noninfected cell membranes; stimulate a signaling pathway that blocks viral reproduction.


Phagocytes travel freely in the lymph and circulatory systems, and also move into tissues.

Foreign cells, viruses, and fragments become attached to the phagocyte membrane, and are engulfed.

Defensins inside the phagocyte digest the foreign material.

Figure 18.3 A Phagocyte and Its Bacterial Prey


Natural killer cells: a type of lymphocyte, detect virus-infected cells, and some cancer cells, and initiate lysis.


Inflammation is a response to injury.

Cells adhering to skin and organ linings—mast cells—release histamine, a chemical signal.

Basophils also release histamine.


Symptoms of inflammation: redness, swelling, heat, pain.

Blood vessels in the area are dilated, induced by histamine.

The capillaries become “leaky” and plasma moves into tissues (causes swelling), along with complement proteins and phagocytes.

Figure 18.4 Interactions of Cells and Chemical Signals Results in Inflammation

Bloodcapillary

Skin

Bacteria introducedby splinter

Splinter

Mast cell

Damaged tissues attract mast cells which release histamine, which diffuses into the capillaries.


Histamine causes the capillaries to dilate and become leaky; complement proteins leave the capillaries and attract phagocytes.

Blood plasma and phagocytes move into infected tissue from the capillaries.

Complementproteins

Phagocyte


Deadphagocyte

Phagocytes engulf bacteria and dead cells.

Histamine and complement signaling cease; phagocytes are no longer attracted.

Signaling molecules stimulate endothelial cell division, healing the wound.


Phagocytes (neutrophils and macrophages) engulf invaders and dead cells.

They produce cytokines which signal the brain to produce fever. Increased temperature inhibits growth of pathogens.


Cytokines may also stimulate endothelial cells to make adhesion molecules—phagocytes bind to these and then pass through the vessel to the tissue.


The inflammation response may not remain local.

It can spread throughout the bloodstream—a condition called sepsis, which can be lethal.

Pus is a collection of dead cells and leaked fluids—it is gradually consumed by macrophages.


An invading pathogen is a signal, and a signal transduction pathway links the signal and the response.

The receptor is a membrane protein called toll.

Toll is part of a protein kinase cascade; results in transcription factors for 40 genes involved in specific and nonspecific defenses.


The cascade results in the phosphorylation of the transcription factor NF-κB, which can then enter the nucleus, and bind to gene promoters.

Figure 18.5 Cell Signaling and Defense

18.3 How Does Specific Immunity Develop?

The specific immune system has four key traits:

• Specificity

• Diversity—response to a wide variety of pathogens

• Ability to distinguish self from nonself

• Memory


Specificity: lymphocytes are crucial.

T cell receptors and antibodies bind to specific nonself molecules (antigens).

Specific sites on the antigens are called antigenic determinants or epitopes.

text art p. 407


A large antigen, such as a whole cell, may have many different antigenic determinants.

Some epitopes evoke a more powerful response—called immunodominant.

Each T cell and antibody is specific for a single antigenic determinant.


Distinguishing self from nonself: The immune system must be able to recognize all the body’s own antigenic determinants, and not attack them.


Diversity:

The immune system must respond to a wide variety of pathogens, and each pathogen may exist in many different varieties or strains.

Humans can respond specifically to about 10 million different antigenic determinants.


Immunological Memory:

After one response to a pathogen, the immune system “remembers” the pathogen and can respond more quickly and powerfully if that pathogen invades again.

Vaccination introduces an antigenic determinant, and the immune system remembers it.


Specific immune system has two types of responses:

• Humoral immune response

• Cellular immune response


Humoral immune response:

Antibodies react with antigenic determinants in blood, lymph, and tissue fluids.

Animals can produce a huge diversity of antibodies.


Some antibodies are soluble in blood and lymph; others are integral membrane proteins on B cells.

When a pathogen first invades, a B cell may recognize one of the pathogen’s antigenic determinants, and bind with it.

This stimulates the B cell to make multiple copies of the antibody.


Cellular immune response detects and destroys virus-infected cells and mutated cells.

Carried out by T cells in blood, lymph, and extracellular spaces in tissues.

T cell receptors bind to specific antigenic determinants, which initiates an immune response that results in destruction of the foreign cell.


Clonal selection:

Diversity is generated by DNA changes just after B and T cells are formed. Each B cell is able to produce only one kind of antibody.

Antigen binding selects a B or T cell for proliferation—divides to form a clone of cells.

Figure 18.6 Clonal Selection in B Cells


An activated lymphocyte produces two kinds of daughter cells:

• Effector cells carry out the attack. Effector B cells (plasma cells) secrete antibodies. Effector T cells secrete cytokines.

• Memory cells are long-lived cells that can divide on short notice to produce effector cells.


Primary immune response: When antigen is first encountered, “naïve” lymphocytes proliferate to produce clones of effector and memory cells.

Secondary immune response: When antigen is encountered again, memory cells proliferate and launch an army of plasma cells and effector T cells.


Because of immunological memory, natural immunity can occur after one exposure to diseases such as chicken pox.

Artificial immunity is conferred by inoculation with an antigen.


Immunization—inoculation with antigenic proteins, pathogen fragments, or other molecular antigens.

Vaccination—inoculation with whole pathogens that have been modified so they will not cause the disease.

Both initiate primary immune response, generating memory cells.

Table 18.2 (Part 1)

Table 18.2 (Part 2)


Pathogens used for vaccination may be altered by:

• Inactivation—treat with heat or chemicals to kill the pathogen.

• Attenuation—reduce virulence of a virus by repeatedly infecting cells with it.


• Recombinant DNA technology—produce peptide fragments that bind to lymphocytes, but don’t have the toxic portion of the protein.

• DNA vaccines—under development, inserting a gene that encodes an antigen.


Normally, the body is tolerant of its own molecules—immunological tolerance. Two mechanisms:

• Clonal deletion: certain immature B and T cells that show the potential to mount an immune response to self antigens undergo apoptosis.


• Clonal anergy: suppression of immune response if a mature lymphocyte recognizes self antigens.

Before a T cell sends out cytokines, it must also encounter a second molecule, CD28. Most body cells lack this signal.

CD28 is a co-stimulatory signal, expressed only on certain antigen-presenting cells.

Figure 18.7 Immunological Tolerance

18.4 What Is the Humoral Immune Response?

B cells are the basis of the humoral immune response.

First make an antibody that is expressed as a receptor protein on the cell surface.

If an antigen binds to the receptor, the B cell becomes a plasma cell, which makes antibodies secreted to the blood stream. Also gives rise to a clone of plasma and memory cells.


For B cell to develop into a plasma cell, a helper T cell (TH) with the same specificity must also bind to the antigen.

Division and differentiation of the B cell is stimulated by signals from the TH cell.

As plasma cell develops, ER and ribosomes increase—for synthesis of antibody proteins.

Figure 18.8 A Plasma Cell


Antibodies belong to protein group called immunoglobulins.

All contain a tetramer of four polypeptides—two light chains and two heavy chains, held together with disulfide bridges.

Each polypeptide chain has a variable region and a constant region.


Constant region determines the class of antibody—the function and destination.

Variable regions are specific for each immunoglobulin—responsible for antibody specificity.

Two antigen-binding sites are identical—bivalent.

Figure 18.9 The Structure of Immunoglobulins (Part 1)

Figure 18.9 The Structure of Immunoglobulins (Part 2)

Table 18.3 (Part 1)

Table 18.3 (Part 2)


Five classes of antibodies:

IgG—most abundant; soluble; greatest amounts made during secondary immune response.

Some IgG bind to antigens and then to macrophages, which engulfs the antigen.

Figure 18.10 IgG Antibodies Promote Phagocytosis


Monoclonal antibodies are from a clone of B cells; will have specificity for only one antigenic determinant.

Polyclonal are from different types of B cells; have specificity for many antigenic determinants.


A clone of B cells can be made by fusing a B cell with a tumor cell—the resulting cell is a hybridoma.

The hybridoma makes monoclonal antibodies and grows indefinitely in culture.

Figure 18.11 Creating Hybridomas for the Production of Monoclonal Antibodies


Monoclonal antibodies are used for:

• Immunoassays—detecting small amounts of molecules in tissue or fluids.

• Immunotherapy—monoclonal antibodies for antigenic determinants on cancer cells. Can be coupled with a radioactive or toxic ligands.


• Passive immunization—short-lived monoclonal antibodies are injected into life threatening situations, where there is not enough time to allow immune system to mount its own defense.

18.5 What Is the Cellular Immune Response?

Cellular immune response—mediated by T cells—directed against any factor that changes a normal cell into an abnormal cell.

T cell receptors are glycoproteins, with two polypeptide chains. The two chains have different amino acid sequences.

Figure 18.12 A T Cell Receptor


T cell receptors bind to a piece of an antigen displayed on the surface of an antigen-presenting cell.

When T cell is activated, it forms a clone and descendents differentiate into two types of effectors:

• Cytotoxic T cells (TC) recognize abnormal cells and kill them by lysis.

• Helper T cells (TH) assist both humoral and cellular responses.


Major histocompatibility complex (MHC) proteins: plasma membrane glycoproteins.

Main role is to present antigens to T cell receptors so that the T cell can distinguish between self and nonself.


Two classes of MHC proteins:

Class I—on surface of every nucleated cell. Bind to polypeptide fragments, travel to membrane and “present” the fragments to TC cells. TC cells have a surface protein CD8 that binds to MHC I.


Class II—on surfaces of B cells, macrophages, and other antigen-presenting cells.

When a nonself antigen is ingested, fragments bind to MHC II and are carried to the membrane and presented to TH cells. TH cells have a surface protein CD4 that binds to MHC II.

Figure 18.13 Macrophages Are Antigen-Presenting Cells


MHC I and MHC II proteins have an antigen binding site, which holds a polypeptide fragment.

T cell receptor recognizes not just the antigenic fragment, but the fragment bound to MHC I or II.

Figure 18.14 The Interaction between T Cells and Antigen-Presenting Cells (Part 1)


Humans have three gene loci each for MHC I and II, all six loci have hundreds of alleles.

Different people have very different genotypes for these proteins.

Genes for MHC, antibodies, and T cell receptors may have descended from one ancestor, and represent a gene “superfamily.”


Humoral immune response:

Activation phase occurs in lymphoid tissue. TH cell binds to antigen-presenting macrophage, produces a clone.

Effector phase—TH cells activate B cells with the same specificity, to produce antibodies.

HUMORAL IMMUNE RESPONSE

Figure 18.15 Phases of the Humoral and Cellular Immune Responses

HelperT cell (TH)

T cellreceptor

Macrophage

The antigen is taken up by phagocytosis and degraded in a lysosome.

Interleukin-1 (a cytokine)activates a TH cell.

Cytokines re-leased by the TH cell stimulate it to proliferate.

A T cell receptor recognizes an antigenic fragment bound to a class II MHC protein on the macrophage.

ACTIVATION PHASEClass II MHCprotein

Antigen



The TH cell proliferates and forms a clone.



EFFECTOR PHASE

B cell

The binding of antigen to a specific IgM receptor triggers endocytosis, degradation, and display of the processed antigen.

Cytokines activate B cell proliferation.

TH cell

A T cell receptor recognizes an antigenic fragment bound to a class II MHC protein on a B cell.



B cells proliferateand differentiate.

The plasma cellproduces antibodies.

Plasma cell

Memory cell

CELLULAR IMMUNE RESPONSE


ACTIVATION PHASE

Infected cell

CytotoxicT cell (TC)

T cellreceptor

Antigen

Class I MHCprotein

A viral protein made in aninfected cell is degraded into fragments and pickedup by a class I MHC protein.

A T cell receptor recognizesan antigenic fragment boundto a class I MHC protein onan infected cell.



The TC cell proliferates and forms a clone.



EFFECTOR PHASE

The T cell releases perforin…

A T cell receptor again recognizes an antigenic fragment bound to a class I MHC protein.

Infected cell(one of many)



…which lysesthe infected cell before the viruses can multiply.


B cells are also antigen-presenting cells.

They take up antigens bound to surface receptors by endocytosis, then display fragments on MHC II proteins.

A TH cell binds to the displayed complex, releases cytokines that cause B cell to produce a clone of plasma cells.


Cellular immune response:

Activation phase—a virus-infected or altered cell displays peptide fragments bound to MHC I. A TC cell binds and is activated to form a clone.

Effector phase—TC clones recognize other infected cells, bind to them and initiate lysis.


TC cells produce perforin, which lyses cells.

TC cells also bind to receptor (Fas) on target cells that initiates apoptosis.

TC cells recognize self MHC proteins complexed with foreign or altered fragments.


TC cells require a second signal for activation—co-stimulatory signal—when TC first binds to infected cell, there is additional interactions of TC proteins and CD28.

Also starts production of an inhibitor to ensure that response will end. Surface protein CTLA4 binds with the CD28, blocking the activation of TC cells.


MHC proteins are important in self-tolerance.

Developing T cells are “tested” in the thymus.

T cells unable to recognize self MHC proteins die quickly. If a T cell binds to self MHC proteins and the body’s own antigens, it dies.


In organ transplants, the tissue from another person has different MHC proteins and is recognized as nonself—it is destroyed or “rejected” by the immune system.

Drugs are used to overcome rejection—cyclosporin blocks a transcription factor necessary for T cell development.

18.6 How Do Animals Make So Many Different Antibodies?

As B cells develop, their genomes become modified so that each mature B cell can produce only one specific antibody.

Each gene encoding an immunoglobulin is actually a supergene assembled from a cluster of smaller genes.

Every cell has hundreds of genes that could participate in synthesis of antibodies.

Figure 18.16 Heavy-Chain Genes


During B cell development, the genes are cut out and rearranged. One gene is chosen randomly for joining, others are deleted.

A unique supergene is assembled. Result: enormous diversity of specific antibodies.

Figure 18.17 Heavy-Chain Gene Rearrangement and Splicing (Part 1)

Figure 18.17 Heavy-Chain Gene Rearrangement and Splicing (Part 2)


Genes for the light chains are on separate chromosomes; they are made in a similar way, with an equally large amount of diversity possible.

Light and heavy chain diversity together yield about 21 billion possibilities.


Other mechanisms for diversity:

• When DNA is rearranged, errors can occur during recombination, creating new codons—imprecise recombination.

• Before DNA is rejoined, terminal transferase adds nucleotides, creating insertion mutations.

• High spontaneous mutation rate


Class switching:

B cells can make only one type of antibody at a time, but it can change the class of antibody it makes.

Early B cells produce IgM—receptors that recognize specific antigenic determinants.


If B cell becomes a plasma cell, a deletion occurs in the DNA, resulting in an antibody with a different constant region of the heavy chain.

The antibody still has the same variable regions, and thus the same specificity; but a different function.

TH cells induce class switching through cytokine signals.

Figure 18.18 Class Switching

18.7 What Happens When the Immune System Malfunctions?

Allergic reactions occur when the immune system overreacts or is hypersensitive to an antigen.

The antigen may not be a danger, but the immune system produces inflammation and other symptoms.

Two types: immediate and delayed hypersensitivity.

Photo 18.11 Eczema, an allergic reaction.


Immediate hypersensitivity:

When exposed to an allergen, large amounts of IgE are produced. IgE constant end binds to mast cells and basophils—large amounts of histamine are released.

Histamines produce symptoms such as inflammation, blood vessel dilation, difficulty in breathing.

Figure 18.19 An Allergic Reaction (Part 1)

Figure 18.19 An Allergic Reaction (Part 2)


These reactions can be treated with antihistamines.

Severe allergic reactions can lead to death.

Allergy to pollen can be treated by desensitization—small amounts of allergen are injected under the skin, stimulates IgG production, but not IgE production.


Delayed hypersensitivity:

Begins hours after exposure to the allergen.

The antigen is taken up by antigen-presenting cells and a T cell response is initiated.

Example: poison ivy rash


Autoimmunity: clones of B and T cells are produced that are directed against self antigens. Possible causes:

• Failure of clonal deletion

• Viral infection—if virus has an antigenic determinant that resembles a self antigen

• Molecular mimicry—self has antigens that resemble nonself and are recognized by T cells


Autoimmune diseases tend to “run in families”—indicating a genetic component.

Genome scans indicate a transcription factor for B cells, RUNX1, may be involved.

Some alleles for MHC II are strongly associated with autoimmune diseases.


Some autoimmune diseases:

• Systemic lupus erythematosis (SLE)—antibodies to cellular components result in large circulating antibody-antigen complexes that become stuck in tissues, causing inflammation.


• Rheumatoid arthritis—T cell response can not be shut down, possibly due to low CTLA4 activity. Results in joint inflammation because of influx of white blood cells.

• Hashimoto’s thyroiditis—immune cells attack thyroid secretions.

Photo 18.12 Hands of 50-year-old man with 20-year history of rheumatoid arthritis. X-ray.


• Insulin-dependent diabetes mellitus (type I)—occurs most often in children. Caused by an immune reaction against cells in the pancreas that make insulin.


Immune deficiency disorders can be inherited or acquired.

T or B cells never form, or B cells lose their ability to become plasma cells.

TH cells (crucial to both humoral and cellular responses), are the targets of HIV retrovirus that results in AIDS—acquired immune deficiency syndrome.


HIV can be transmitted by:

• Blood—e.g., needle contamination

• Exposure through broken skin, wounds, mucus membranes

• Through blood of infected mother to baby during birth


HIV initially infects TH cells, macrophages, and dendritic cells. These cells carry the virus to the lymph nodes and spleen.

HIV preferentially infects activated TH cells in the lymph nodes and spleen.

Up to 10 billion viruses are made per day in the initial phase of infection.


Symptoms abate as T cells mount an immune response.

But antibody-complexed viruses can still infect TH cells—secondary infection.

The rate of secondary infection reaches a low, steady state level—the set point.

Set point level varies in individuals, and determines rate of progress of the disease.

Figure 18.20 The Course of an HIV Infection


Gradually, TH cells are destroyed, and the person is susceptible to many infections.

Opportunistic infections:

• Kaposi’s sarcoma, a rare skin cancer caused by a herpesvirus

• Pneumonia caused by fungus Pneumocystis carinii

• Lymphoma tumors caused by Epstein-Barr virus

Figure 18.21 Relationship between TH Cell Count and Opportunistic Infections


HIV is an enveloped retrovirus; the genome is RNA.

Virally encoded proteins necessary for infection and replication:

• Membrane glycoproteins gp120 and gp41 attach to host cell proteins CD4 and a co-receptor.

Figure 18.22 Two Receptors for HIV


• Reverse transcriptase—catalyzes synthesis of cDNA from viral RNA. Lacks proofreading function, which leads to a pool of mutant viruses.

• Integrase—catalyzes insertion of cDNA into host chromosome

• Protease—to complete viral proteins


Treating HIV: develop agents that block steps in viral life cycle without harming host cells.

Highly active antiretroviral therapy (HAART) is a combination of drugs—a protease inhibitor and two reverse transcriptase inhibitors.

Many people on HAART develop mutant strains of HIV.


New drug combinations are constantly being developed to combat mutating strains of HIV.

Researchers are trying to develop vaccines.

Photo 18.8 Human thymus tissue: lymphocyte lobules; blood vessels in septae. LM, H & E stain.

Photo 18.9 Lymphocytes in cortex of human lymph node tissue. LM, H&E stain.

Photo 18.10 Plasma cell in rat lymph node: extensive RER and large Golgi apparatus. TEM.

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