Chapter 21: Lymphatic System

B Lymphocytes

(B Cells) Humoral Immunity in Red Bone

Interleukin 1

(IL-1) released by macrophages co-stimulates bound T cells to: • Release interleukin 2 (IL-2) • Synthesize more IL-2 receptors

T Lymphocytes

(T Cells) Cell-Mediated Immunity in Thymus

Bacterial Infection

Increase in Neutrophil

Passive Artificially Acquired

Injection of serum, such as gamma globulin and protection is immediate but ends when antibodies naturally degrade in the body.

Adaptive Immune Response

Is specific, systemic, and has memory.

Natural Killer (NK) Cells

Large granular lymphocytes, target cells that lack "self" cell-surface receptors, induce apoptosis in cancer cells and virus- infected cells, and secrete potent chemicals that enhance the inflammatory response.

3 Liters

Lost to tissues every 24 hours returned to the bloodstream.

Gamma (γ)

Lymphocyte produce this.

Antigen Receptor Diversity

Lymphocytes make up to a billion different types of antigen receptors is coded for by ~25,000 genes, gene segments are shuffled by somatic recombination, genes determine which foreign substances the immune system will recognize and resist.

Toll-Like Receptors (TLR)

Macrophages and epithelial cells of boundary tissues bear this and recognize specific classes of infecting microbes by activated this trigger the release of cytokines that promote inflammation.

Present Antigen and Activate T Cells

Macrophages mostly remain fixed in the lymphoid organs dendritic cells internalize pathogens and enter lymphatics to present the antigens to T cells in lymphoid organs.

Complement Fixation and Activation

Main antibody defense against cellular antigens, several antibodies bind close together on a cellular antigen, their complement-binding sites trigger complement fixation into the cell's surface, complement triggers cell lysis, activated complement functions, amplifies the inflammatory response, opsonization, and enlists more and more defensive elements.

B Cells

Mature in red bone marrow, Self-reactive B cells, are eliminated by apoptosis (clonal deletion) or undergo receptor editing - rearrangement of their receptors are inactivated (anergy) if they escape from the bone marrow, involved in adaptive immunity.

T Cells

Mature in the thymus under negative and positive selection pressures, positive selection, selects T cells capable of binding to self-MHC proteins (MHC restriction), negative selection, prompts apoptosis of T cells that bind to self-antigens displayed by self-MHC, ensures self-tolerance.

Cytokines

Mediate cell development, differentiation, and responses in the immune system plus include interleukins and interferons.

IgE

Monomer active in some allergies and parasitic infections and causes mast cells and basophils to release histamine.

IgD

Monomer attached to the surface of B cells and functions as a B cell receptor, and pump plus antigen receptor found on B cells.

IgA

Monomer or dimer; in mucus and other secretions, helps prevent entry of pathogens, and in all body fluids.

IgG

Monomer; 75-85% of antibodies in plasma, from secondary and late primary responses, crosses the placental barrier, abundant, and cross placenta barrier plus most abundant class of antibodies.

Fate of Clone Cells

Most clone cells become plasma cells that secrete specific antibodies at the rate of 2,000 molecules per second for four to five days. Secreted antibodies by: circulate in blood or lymph, bind to free antigens, and mark the antigens for destruction.

Alpha (α) Interferon

Most other WBC's produce this.

Edema

Moves foreign material into lymphatic vessels and delivers clotting proteins to form a scaffold for repair and to isolate the area.

Respiratory System Modifications

Mucus-coated hairs in the nose and cilia of upper respiratory tract sweep dust- and bacteria-laden mucus from lower respiratory passages.

Internal Defenses: Cells and Chemicals

Necessary if microorganisms invade deeper tissues by: • Phagocytes • Natural killer (NK) cells • Inflammatory response (macrophages, mast cells, WBCs, and inflammatory chemicals) • Antimicrobial proteins (interferons and complement proteins) • Fever

Margination

Neutrophils cling to capillary wall, clinging of phagocytic cells to inner wall of capillaries.

Leukocytes

Neutrophils enter blood from bone marrow.

Diapedesis

Neutrophils flatten and squeeze out of capillaries, phagocytes squeeze through the capillary endothelium.

Chemotaxis

Neutrophils follow chemical trail, white blood cells migrate to the site of tissue damage.

Phagocyte Mobilization

Neutrophils, then phagocytes flood to inflamed sites.

Secondary Immune Response

Occurs on re-exposure to the same antigen, sensitized memory cells respond within hours, antibody levels peak in two to three days at much higher levels, antibodies bind with greater affinity, antibody level can remain high for weeks to months plus last longer than a primary immune response.

Primary Immune Response

Occurs on the first exposure to a specific antigen, lag period: three to six days, peak levels of plasma antibody are reached in 10 days, antibody levels then decline.

Active Humoral Immunity

Occurs when B cells encounter antigens and produce specific antibodies against them.

T or Y Shaped Monomer

Of 4 looping linked polypeptide chains, two identical heavy chains and two identical light chains and variable regions of each arm combine to form two identical antigen-binding sites.

Constant Region

Of stem determines: the antibody class, cells and chemical that the antibody can bind to, and how the antibody class functions in antigen elimination.

Surface Barriers

Part of internal defense by the Skin, mucous membranes, and their secretions by physical barrier to most microorganisms, keratin is resistant to weak acids and bases, bacterial enzymes, and toxins and mucosae provide similar mechanical barriers plus Protective chemicals inhibit or destroy microorganisms • Skin acidity • Lipids in sebum and dermcidin in sweat • HCl and protein-digesting enzymes of stomach mucosae • Lysozyme of saliva and lacrimal fluid • Mucus

Adaptive Immune System

Protects against infectious agents and abnormal body cells, amplifies the inflammatory response, activates complement, and specific defense.

Self-Antigens: MHC Proteins

Protein molecules (self-antigens) on the surface of cells, antigenic to others in transfusions or grafts (example: MHC proteins) coded for by genes of the major histocompatibility complex (MHC) and are unique to an individual.

Humoral Immunity

Provided by antibodies

T Cells of the Cell-Mediated Response

Recognize and respond only to processed fragments of antigen displayed on the surface of body cells Targets • Body cells infected by viruses or bacteria • Abnormal or cancerous cells • Cells of infused or transplanted foreign tissue

Natural Killer Cells

Recognize other signs of abnormality: • Lack of class I MHC • Antibody coating a target cell • Different surface marker on stressed cells • Use the same key mechanisms as Tc cells for killing their target cells

Other Type of T Cells

Regulatory T cells (TREG) and memory T cells.

Activated T Cells

Release chemicals that: Prod macrophages to become insatiable phagocytes and to secrete bactericidal chemicals.

T Cell Activation: Co-Stimulation

Requires T cell binding to other surface receptors on an APC, dendritic cells and macrophages produce surface B7 proteins when innate defenses are mobilized, and B7 binding with a CD28 receptor on a T cell is a crucial co-stimulatory signal.

Lymphatic System

Resistance to disease and has two intrinsic systems: • Innate (nonspecific) defense system • Adaptive (specific) defense system

Primary T Cells

Response peaks within a week, T cell apoptosis occurs between days 7 and 30, effector activity wanes as the amount of antigen declines, benefit of apoptosis: activated T cells are a hazard, memory T cells remain and mediate secondary responses.

Active Naturally Acquired

Response to a bacterial or viral infection.

Active Artificially Acquired

Response to a vaccine of dead or attenuated pathogens.

Neutralization

Simplest mechanism, antibodies block specific sites on viruses or bacterial exotoxins, prevent these antigens from binding to receptors on tissue cells, and antigen-antibody complexes undergo phagocytosis.

Peyer's Patches

Small intestine (end part of ilium).

Haptens (Incomplete Antigens)

Small molecules (peptides, nucleotides, and hormones), not immunogenic by themselves, are immunogenic when attached to body proteins, cause the immune system to mount a harmful attack. Ex: Poison ivy, animal dander, detergents, and cosmetics.

Precipitation

Soluble molecules are cross-linked and complexes precipitate and are subject to phagocytosis.

Vaccines

Spare us the symptoms of the primary response, provide antigenic determinants that are immunogenic and reactive, target only one type of helper T cell, so fail to fully establish cellular immunological memory.

Complement

~20 blood proteins that circulate in an inactive form, include C1-C9, factors B, D, and P, and regulatory proteins, major mechanism for destroying foreign substances, amplifies all aspects of the inflammatory response, kills bacteria and certain other cell types by cell lysis, and enhances both nonspecific and specific defenses.

Antigens

Substances that can mobilize the adaptive defenses and provoke an immune response and most are large, complex molecules not normally found in the body (nonself).

Hodgkin's Disease

• An acquired immunodeficiency • Cancer of the B cells • Leads to immunodeficiency by depressing lymph node cells

Both Types of MHC Proteins

Synthesized at the ER and bind to peptide fragments.

Fever

Systemic response to invading microorganisms, leukocytes and macrophages exposed to foreign substances secrete pyrogens, reset the body's thermostat upward, high fevers are dangerous because heat denatures enzymes, benefits of moderate fever, causes the liver and spleen to sequester iron and zinc (needed by microorganisms) plus increases metabolic rate, which speeds up repair and not a sign of inflammation.

Immune Complex (Type III) Hypersensitivity

• Antigens are widely distributed through the body or blood • Insoluble antigen-antibody complexes form • Complexes cannot be cleared from a particular area of the body • Intense inflammation, local cell lysis, and death may result • Example: systemic lupus erythematosus (SLE)

Cell-Mediated Immune Response

T cells provide defense against intracellular antigens, two types of surface receptors of T cells, T cell antigen receptors: • Cell differentiation glycoproteins • CD4 or CD8 • Play a role in T cell interactions with other cells

Lymphocyte is a B Cell

The antigen provokes a humoral immune response and antibodies are produced.

Antibodies of the Humoral Response

The simplest ammunition of the immune response Targets: Bacteria and molecules in extracellular environments (body secretions, tissue fluid, blood, and lymph).

Adaptive Defense System

Third line of defense attacks particular foreign substances by: Takes longer to react than the innate system and innate and adaptive defenses are deeply intertwined.

Inflammatory Chemicals

This cause: • Dilation of arterioles, resulting in hyperemia • Increased permeability of local capillaries and edema (leakage of exudate) Exudate contains proteins, clotting factors, and antibodies.

Alternate Pathway

Triggered when activated C3, B, D, and P interact on the surface of microorganisms.

Inflammatory Response

Triggered whenever body tissues are injured or infected, prevents the spread of damaging agents, disposes of cell debris and pathogens, sets the stage for repair, Cardinal signs of acute inflammation: 1. Redness 2. Heat 3. Swelling 4. Pain (And sometimes 5. Impairment of function)

Innate Defense System

Two lines of defense • First line of defense is external body membranes (skin and mucosae) • Second line of defense is antimicrobial proteins, phagocytes, and other cells by: Inhibit spread of invaders Inflammation is its most important mechanism

Self-Tolerance

Unresponsive to self antigens and property of lymphocytes that prevents them from attacking the body's own cells.

Bone Marrow

Where self-reactive B cells are eliminated at.

Acquired Immune Deficiency Syndrome (AIDS)

• Cripples the immune system by interfering with the activity of helper T cells • Characterized by severe weight loss, night sweats, and swollen lymph nodes • Opportunistic infections occur, including pneumocystis pneumonia and Kaposi's sarcoma

Prevention of Rejection

• Depends on the similarity of the tissues • Patient is treated with immunosuppressive therapy • Corticosteroid drugs to suppress inflammation • Antiproliferative drugs • Immunosuppressant drugs • Many of these have severe side effects

Roles of Cytotoxic T(TC) Cells

• Directly attack and kill other cells • Activated TC cells circulate in blood and lymph and lymphoid organs in search of body cells displaying antigen they recognize Targets: • Virus-infected cells • Cells with intracellular bacteria or parasites • Cancer cells • Foreign cells (transfusions or transplants) Carry out cellular immune responses

Severe Combined Immunodeficiency (SCID) Syndrome

• Genetic defect • Marked deficit in B and T cells • Abnormalities in interleukin receptors • Defective adenosine deaminase (ADA) enzyme • Metabolites lethal to T cells accumulate • This is fatal if untreated; treatment is with bone marrow transplants

Making of AIDS

• HIV multiplies in lymph nodes throughout the asymptomatic period • Symptoms appear in a few months to 10 years • HIV-coated glycoprotein complex attaches to the CD4 receptor • HIV enters the cell and uses reverse transcriptase to produce DNA from viral RNA • The DNA copy (a provirus) directs the host cell to make viral RNA and proteins, enabling the virus to reproduce • HIV reverse transcriptase produces frequent transcription errors; high mutation rate and resistance to drugs • Treatment with antiviral drugs • Reverse transcriptase inhibitors (AZT) • Protease inhibitors (saquinavir and ritonavir) • New Fusion inhibitors that block HIV's entry to helper T cells

Inflammatory Mediators

• Histamine (from mast cells) • Blood proteins • Kinins, prostaglandins (PGs), leukotrienes, and complement Released by injured tissue, phagocytes, lymphocytes, basophils, and mast cells.

Acute (Type I) Reactions

• Hypersensitivities (allergies) begin in seconds after contact with allergen • Initial contact is asymptomatic but sensitizes the person • Reaction may be local or systemic • The mechanism involves IL-4 secreted by T cells • IL-4 stimulates B cells to produce IgE • IgE binds to mast cells and basophils, resulting in a flood of histamine release and inducing the inflammatory response • Systemic response to allergen that directly enters the blood • Basophils and mast cells are enlisted throughout the body • Systemic histamine releases may cause • Constrict ion of bronchioles • Sudden vasodilation and fluid loss from the bloodstream • Hypotensive shock and death • Treatment: epinephrine

Hypersensitivities

• Immune responses to a perceived (otherwise harmless) threat • Causes tissue damage • Different types are distinguished by • Their time course • Whether antibodies or T cells are involved • Antibodies cause immediate and subacute hypersensitivities • T cells cause delayed hypersensitivity

Autoimmune Diseases

• Immune system loses the ability to distinguish self from foreign • Production of autoantibodies and sensitized TC cells that destroy body tissues • Examples include multiple sclerosis, myasthenia gravis, Graves' disease, type I diabetes mellitus, systemic lupus erythematosus (SLE), glomerulonephritis, and rheumatoid arthritis

Helper T Cells

• Interact directly with B cells displaying antigen fragments bound to MHC II receptors • Stimulate B cells to divide more rapidly and begin antibody formation • B cells may be activated without TH cells by binding to T cell-independent antigens • Most antigens require TH co-stimulation to activate B cells • Cause dendritic cells to express co- stimulatory molecules required for CD8 cell activation

Clonal Selection

1. B cell is activated when antigens bind to its surface receptors and cross-link them 2. Receptor-mediated endocytosis of cross- linked antigen-receptor complexes occurs 3. Stimulated B cell grows to form a clone of identical cells bearing the same antigen- specific receptors (T cells are usually required to help B cells achieve full activation)

Mechanisms of Autoimmune Diseases

1. Foreign antigens may resemble self-antigens and antibodies against the foreign antigen may cross- react with self-antigen. 2. New self-antigens may appear, generated by Gene mutations Changes in self-antigens by hapten attachment or as a result of infectious damage. 3. Release of novel self-antigens by trauma of a barrier (e.g., the blood-brain barrier)

IgM

A pentamer; first antibody released, potent agglutinating agent, readily fixes and activates complement, largest, medics of the first responders.

Antigen-Binding Site

A.

Red Bone Marrow and place where T and B Cells are born at

A.

Human Immunodeficiency Virus (HIV)

AIDS is caused by this transmitted via body fluids—blood, semen, and vaginal secretions • HIV enters the body via • Blood transfusions • Blood-contaminated needles • Sexual intercourse and oral sex • HIV • Destroys TH cells • Depresses cell-mediated immunity

T Cell Activation

APCs (most often a dendritic cell) migrate to lymph nodes and other lymphoid tissues to present their antigens to T cells T cell activation is a two-step process: 1. Antigen binding 2. Co-stimulation

Reactivity

Ability to react with products of activated lymphocytes and antibodies released.

Immunogenicity

Ability to stimulate proliferation of specific lymphocytes and antibodies.

Immunocompetence

Able to recognize and bind to a specific antigen.

Destruction of Pathogens

Acidification and digestion by lysosomal enzymes by: • Respiratory burst • Release of cell-killing free radicals • Activation of additional enzymes • Oxidizing chemicals (e.g. H2O2) • Defensins (in neutrophils)

Immediate Hypersensitivity

Allergy

Leukocytosis

An increase in the number of white blood cells that are in circulation.

Without Co-Stimulation

Anergy occurs by T cells because: • Become tolerant to that antigen • Are unable to divide • Do not secrete cytokines

Agglutination

Antibodies bind the same determinant on more than one cell-bound antigen and cross-linked antigen-antibody complexes agglutinate. Example: clumping of mismatched blood cells

Classical Pathway

Antibodies bind to invading organisms and C1 binds to the antigen-antibody complexes (complement fixation).

Passive Naturally Acquired

Antibodies delivered to a fetus via the placenta or to infant through milk.

Antibody Targets

Antibodies inactivate and tag antigens, form antigen-antibody (immune) complexes, defensive mechanisms used by antibodies, neutralization and agglutination (the two most important), and precipitation and complement fixation.

Dendritic Cells

Are able to obtain other cells' endogenous antigens by • Engulfing dying virus-infected or tumor cells • Importing antigens through temporary gap junctions with infected cells They then display the endogenous antigens on both class I and class II MHCs.

Immunocompetent T Cells

Are activated when their surface receptors bind to a recognized antigen (nonself) T cells must simultaneously recognize, nonself (the antigen), self (an MHC protein of a body cell).

Rheumatoid Arthritis

Autoimmune Disorder

Naive (Unexposed)

B and T cells are exported to lymph nodes, spleen, and other lymphoid organs.

Heavy Chain

B.

Thymus and is immunocompetent with T Cells

B.

Clone Cells that do not become plasma cells

Become memory cells that provide immunological memory and mount an immediate response to future exposures of the same antigen.

Neutrophils

Become phagocytic on encountering infectious material in tissues.

Isografts

Between identical twins.

Allografts

Between individuals who are not identical twins.

Generating Antibody Diversity

Billions of antibodies result from somatic recombination of gene segments, hypervariable regions of some genes increase antibody variation through somatic mutations, and each plasma cell can switch the type of H chain produced, making an antibody of a different class.

Cytotoxic T Cells

Bind to a self-nonself complex and can destroy all infected or abnormal cells. Lethal Hit- Tc cell releases perforins and granzymes by exocytosis, perforins create pores through which granzymes enter the target cell, granzymes stimulate apoptosis • In some cases, TC cell binds with a Fas receptor on the target cell, and stimulates apoptosis

Bone Marrow and is immunocompetent with B Cells

C.

Light Chain

C.

T Cell Activation: Antigen Binding

CD4 and CD8 cells bind to different classes of MHC proteins (MHC restriction), CD4 cells bind to antigen linked to class II MHC proteins of APCs, CD8 cells are activated by antigen fragments linked to class I MHC of APCs, TCR that recognizes the nonself-self complex is linked to multiple intracellular signaling pathways, other T cell surface proteins are involved in antigen binding (e.g., CD4 and CD8 help maintain coupling during antigen recognition), antigen binding stimulates the T cell, but co- stimulation is required before proliferation can occur.

Subacute Hypersensitivities

Caused by IgM and IgG transferred via blood plasma or serum and slow onset (1-3 hours) and long duration (10-15 hours).

CD8

Cells become cytotoxic T cells (TC) that destroy cells harboring foreign antigens.

CD4

Cells become helper T cells (TH) when activated.

Antigenic Determinants

Certain parts of an entire antigen that are immunogenic and antibodies and lymphocyte receptors bind to them. Most naturally occurring antigens have numerous antigenic determinants that: Mobilize several different lymphocyte populations, form different kinds of antibodies against it, and large, chemically simple molecules (e.g.,plastics) have little or no immunogenicity.

Monoclonal Antibodies

Commercially prepared pure antibody, produced by hybridomas, cell hybrids: fusion of a tumor cell and a B cell, proliferate indefinitely and have the ability to produce a single type of antibody; used in research, clinical testing, and cancer treatment.

Interferons (IFNs)

Complement proteins that attack microorganisms directly and hinder microorganisms' ability to reproduce, Viral-infected cells are activated to secrete this by enter neighboring cells, neighboring cells produce antiviral proteins that block viral reproduction and also activates macrophages and mobilizes NKs. Functions • Anti-viral • Reduce inflammation • Activate macrophages and mobilize NK cells • Genetically engineered IFNs for • Antiviral agents against hepatitis and genital warts virus • Multiple sclerosis treatment *They do not stimulate B cells to produce antibodies.*

Immunodeficiencies

Congenital and acquired conditions that cause immune cells, phagocytes, or complement to behave abnormally.

Hinge Region

D.

Lymph Nodes and help with clone selection and with both B and T cells

D.

Regulatory T (TReg) Cells

Dampen the immune response by direct contact or by inhibitory cytokines and important in preventing autoimmune reactions.

Chyle

Delivered to blood via lymphatic system.

Phagocytes: Macrophages

Develop from monocytes to become the chief phagocytic cells Free macrophages wander through tissue spaces • E.g., alveolar macrophages Fixed macrophages are permanent residents of some organs • E.g., Kupffer cells (liver) and microglia (brain)

Class I MHC Proteins

Displayed by all cells except RBCs, bind with fragment of a protein synthesized in the cell (endogenous antigen), endogenous antigen is a self-antigen in a normal cell; a nonself antigen in an infected or abnormal cell, informs cytotoxic T cells of the presence of microorganisms hiding in cells (cytotoxic T cells ignore displayed self-antigens).

Antigen-Presenting Cells (APCs)

Do not respond to specific antigens and play essential auxiliary roles in immunity.

Class II MHC Proteins

Dsplayed by APCs (dendritic cells, macrophages and B cells), bind with fragments of exogenous antigens that have been engulfed and broken down in a phagolysosome, and recognized by helper T cells.

Capillaries and Recirculate

E.

Stem Region

E.

Complement Activation

Each pathway involves activation of proteins in an orderly sequence, each step catalyzes the next, both pathways converge on C3, which cleaves into C3a and C3b, enhances inflammation, promotes phagocytosis, causes cell lysis, C3b initiates formation of a membrane attack complex (MAC), MAC causes cell lysis by inducing a massive influx of water, C3b also causes opsonization, and C3a causes inflammation.

Antigen-Presenting Cells (APCs)

Engulf antigens, present fragments of antigens to be recognized by T cells. Major types: Dendritic cells in connective tissues and epidermis, macrophages in connective tissues and lymphoid, organs, and B cells.

T Cells that are Activated

Enlarge, proliferate, and form clones plus differentiate and perform functions according to their T cell class.

Adherence of Phagocyte to Pathogen

Facilitated by opsonization—coating of pathogen by complement proteins or antibodies.

Lacteal

Fats absorbed in lymph capillaries.

Beta (β) Interferon

Fibroblasts produce this.

Tissue Injury

First Step in Inflammation

Antigen Challenge

First encounter between an antigen and a naive immunocompetent lymphocyte plus usually occurs in the spleen or a lymph node.

Class II MHC Proteins

Found on certain cells in the immune response, antigen-presenting cells.

Class I MHC Proteins

Found on virtually all body cells (except RBC)

Xenografts

From another animal species.

Autografts

From one body site to another in the same person.

Immunoglobulins

Gamma globulin portion of blood, protein secreted by plasma cells and capable of binding specifically with antigen detected by B cells.

Interleukin 2

IL-2 is a key growth factor, acting on cells that release it and other T cells: Encourages activated T cells to divide rapidly, used therapeutically to treat melanoma and kidney cancers, and other cytokines amplify and regulate innate and adaptive responses.

Roles of Helper T(TH) Cells

• Play a central role in the adaptive immune response, once primed by APC presentation of antigen, they: • Help activate T and B cells • Induce T and B cell proliferation •Activate macrophages and recruit other immune cells • Without TH, there is no immune response

Delayed Hypersensitivities

• Slow onset (one to three days) • Mechanism depends on helper T cells • Cytokine-activated macrophages and cytotoxic T cells cause damage • Example: allergic contact dermatitis (e.g., poison ivy)

Cytoxic (Type II) Reactions

•Antibodies bind to antigens on specific body cells, stimulating phagocytosis and complement-mediated lysis of the cellular antigens •Example:mismatched blood transfusion reaction