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Biology 221Anatomy & Physiology II

Chapter 21pp. 778-787

TOPIC 6TOPIC 6 Immune System Immune System

Resistance to DiseaseResistance to Disease

E. Lathrop-Davis / E. Gorski / S. Kabrhel

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Overview: Functions• Functional rather than anatomical system • Functions:

– Protects against pathogens° microbes° parasites

– Eliminates tissues and cells that have been damaged, infected or killed

– Distinguishes between self and non-self

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OverviewTwo types of resistance work together against disease• Innate = nonspecific

– general defense against wide range of pathogens– rapid response– in place at birth– mechanisms: intact membranes, phagocytes,

antimicrobial chemicals, inflammation• Adaptive = specific

– specific response to pathogens – slower than innate system– acquired as person is exposed– mechanisms: T cell lymphocytes, antibodies

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Nonspecific Resistance - Overview• A. Physical barriers• B. Cellular barriers• C. Fever

See Table 22.2, p. 801

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Physical Barriers: Intact Skin• Consists of keratinized stratified squamous

epithelium• Relatively dry (inhibits growth of some pathogens)• Sebaceous gland secretions include antibacterial

chemicals (lysozyme, fatty acids)• Normal bacterial flora compete with pathogens• Slightly acidic• Slightly salty (sweat)

Fig. 5.3, p. 152

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Physical Barriers: Intact Mucous Membranes

• Line body cavities open to outside (digestive, urinary, reproductive, respiratory tracts)

• Intact barrier – nonkeratinized stratified squamous epithelium lines openings (mouth, pharynx, esophagus, vagina, parts of rectum and urethra)

• Low pH in some areas – slightly acidic (mouth, vagina, urethra) to

highly acidic (stomach)• Antimicrobial proteins (lysozyme in saliva and

lacrimal fluid)• Normal bacterial flora compete with pathogens

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Physical Barriers: Mucus

• hairs help trap particles• cilia move particles

– ciliary escalator -- present in trachea and bronchi; moves mucus and particles up to throat

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Cellular Responses: Inflammation• Functions:

– prevents spread of pathogens or damaging chemicals to other tissues

– removes dead cells and pathogens– prepares tissue for repair

• Signs of inflammation– redness, heat, swelling, pain

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Main Inflammatory Chemicals• Histamine

– secreted by basophils and mast cells– vasodilation and increased capillary

permeability– antihistamines

• Kinins (proteins, e.g., bradykinin) – vasodilation, increased capillary permeability– induce chemotaxis (draw WBCs to area)– stimulate pain receptors

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Other Inflammatory Chemicals• Prostaglandins (lipid – fatty acid molecules)

– sensitize blood vessels to other inflammatory chemicals (enhance inflammation)

– stimulate pain receptors• Complement – enhances inflammation• Cytokines

– proteins released by various WBCs and tissue cells

– many enhance various aspects of inflammation

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Process of Inflammation• Release of inflammatory chemicals• Vascular changes: vasodilation and increased

capillary permeability, resulting in:– hyperemia (increased blood flow to area) and

exudate formation (loss of fluid containing plasma proteins to tissue)

– increased temperature increased cellular metabolism

See Fig. 22.2, p. 797

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Process of Inflammation– increased oxygen and nutrients to tissue and

cellular defenders– leakage of clotting proteins walls off

pathogen to limit spread; forms network for tissue repair

See Fig. 22.2, p. 797

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Process of Inflammation (con’t)• Phagocyte mobilization

– leukocytosis - increased number of leukocytes (especially neutrophils)

– chemotaxis draws leukocytes to injured area– margination (“pavementing”; leukocytes adhere

to capillary wall)– diapedesis (leukocytes pass through capillary

wall)– phagocytosis of pathogens and debris– pus formation - occurs with severe infection

(WBCs, dead and dying tissue cells, pathogens accumulate)

See Fig. 22.3, p. 798

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Phagocytes in Inflammation• Neutrophils respond most quickly (usually within

a few hours) – associated with acute, local infection

• Monocytes respond more slowly (usually within 8-12 hours)– enter tissue and become macrophages with

more lysosomes– associated with chronic infection

Think About It: What causes each of the signs of inflamamtion? - redness, heat, swelling, pain

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Cellular Responses: Major Phagocytes• Macrophages

– reside in tissues– derived from monocytes– free (wandering) macrophages - wander through

tissues– fixed macrophages - stay in particular organ

° e.g., Kuppfer cells (liver), microglia (brain)http://www.usc.edu/hsc/dental/ghisto/gi/c_90.html

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Cellular Responses: Major Phagocytes• Neutrophils = microphages

– respond quickly to localized infections– degranulation - release of chemicals stored in

granules destroys pathogens also kills neutrophilhttp://www.usc.edu/hsc/dental/ghisto/bld/c_1.html

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Cellular Responses: Other Phagocytes• Eosinophils

– respond most to parasitic worms (release chemicals to destroy worm)

http://www.usc.edu/hsc/dental/ghisto/bld/c_3.html

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Cellular Responses: Other Phagocytes• Mast cells

– reside in tissues– release histamine during inflammation– less common– respond to variety of bacteria (phagocytic role

uncertain)http://image.bloodline.net/stories/storyReader$1682

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Mechanism of PhagocytosisSteps:• Microbial adherence

– recognition of bacterium as “non-self”– more difficult with encapsulated bacteria– opsonization – enhanced phagocytosis due to

presence of complement proteins and antibodies• Formation of pseudopodia and engulfment of particle• Union of phagocytic vesicle with lysosome• Digestion of particle• Exocytosis of indigestible material

See Fig. 22.1, p. 795

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Mechanism of Phagocytosis (con’t)• Respiratory burst

– used against pathogens that resist lysosomal enzymes (e.g., tuberculosis bacteria)

– stimulated by chemicals released by immune system

– produces free radicals (e.g., NO)• Defensins – antimicrobial proteins produced by

neutrophils

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Cellular Responses: Natural Killer (NK) Cells

• Large, granular lymphocytes• Responsible for immunological surveillance –

respond to abnormal antigens• Kill cancer cells and virally-infected cells• Release perforins

– produce channels in target cell membrane– cause nucleus to degrade

• Produce other chemicals that enhance inflammation

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Antimicrobial Proteins: Complement• Group of 20+ plasma proteins (circulate in

inactive form) • Two pathways of activation:

– classical pathway ° linked to immune system° activation results from interaction of antigen-

antibody complex with key complement proteins

– alternative pathway – interactions of other complement proteins with polysaccharides on surface of certain microorganisms

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Fig. 22.5, p. 800

Antimicrobial Proteins: Complement• Both pathways start cascade resulting in

– enhanced actions of nonspecific and specific resistance mechanisms, including inflammation and opsonization

– lysis of bacterial cells

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Antimicrobial Proteins: IFNsInterferons• group of related proteins secreted by body cells

infected with virus • alpha () & beta () stimulate synthesis of PKR in

nearby uninfected cells– PKR is a protein that blocks protein synthesis at

ribosomes --> prevents viral replication• gamma stimulate (activate) macrophages and NK

cells• produced artificially and used clinically to treat

genital herpes (caused by herpes virus), also used in treatment of hepatitis C, and viral infections in organ transplant patients

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Antimicrobial Proteins: Lysozyme• In tears & saliva• Kills unencapsulated bacteria

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Fever• Increased body temperature in response to

pathogens• Involves resetting of “thermostat” in hypothalamus

– response to pyrogens secreted by leukocytes and macrophages in response to bacteria and other foreign particles

• Mild fever – enhances activity of phagocytes and tissue repair– causes liver and spleen to sequester iron and zinc

(needed by bacteria to multiply)• High fever (> 104 oF or 40 oC) - damages proteins

of sick person

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Specific (Adaptive) ResistanceAlso known as acquired resistanceCharacteristics:• antigen specific • systemic• differentiates between normal (self) antigens and

foreign (non-self) antigens• has memory (faster response second time around)

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Specific (Adaptive) ResistanceTypes• Humoral = antibody-mediated immunity

– result of specific antibodies (proteins) present in blood

• Cellular = cell-mediated immunity– result of specific group of cells = T cell

lymphocytes

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Antigens (Ags)• Substances that activate immune system and elicit

response– immunogenicity - cause production of antibody

by plasma cells– reactivity - reacts with antibody, if present

• Antigenic determinants = epitopes– parts of antigen that are recognized by T cells

and antibodies– usually protein- or sugar-based

Fig. 22.6, p. 803

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Antigens (con’t)• Complete antigen has both characteristics

– large molecules typically with more than one antigenic determinant

– most foreign proteins, nucleic acids, some lipids, some large polysaccharides

• Haptens = incomplete antigens – reactive but not immunogenic– generally small molecules– hapten can combine with other molecules to

become complete antigen° e.g., penicillin

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Antigens (con’t)• Self-antigens – major histocompatibility complex

(MHC) proteins– glycoproteins found on individual’s own cells – two types:

° Class I MHC proteins – found on all cells of body° Class II MHC proteins – found only on cells

involved in immune response

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Antigens (Ags): Terms• Agglutination – antibody binds to antigenic

determinants of cells and cross-links several together resulting in clumping– e.g., cross-reactions between blood types

• Precipitation – antibody binds to antigenic determinants of soluble antigen (e.g., toxin) and causes clumping

• Neutralization – antibody covers active site(s) on antigen

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Cells of the Immune SystemLymphocytes• become immunocompetent in primary lymphoid

organs (bone marrow or thymus), where they learn self-tolerance (recognition of body’s own protein antigens)

• move to secondary lymphoid tissue to become exposed to antigens, then return to blood and lymph circulation

• types: – B cells = B lymphocytes– T cells = T lymphocytes– Antigen-presenting cells (APCs)

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Cells of the Immune System

• B cells = B lymphocytes– become immunocompetent in bone marrow– develop into plasma cells after exposure to antigen

and produce specific antibodies• T cells = T lymphocytes

– become immunocompetent in thymus– active in cellular immunity

Fig. 22.8, p. 805

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Cells of the Immune System: APCsAntigen-presenting cells (APCs)• types:

– dendritic cells– Langerhan’s cells of epidermis– macrophages– activated B cell lymphocytes

• engulf foreign particles and present fragments on own surface to T cells so that the latter can recognize and respond to them

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Fig. 22.9, p. 807

Humoral Immunity• Relies on B cells• Primary response – to first exposure

– antigen binds to B cell with appropriate receptor B cell engulfs antigen divides into daughter cells that secrete antibodies or become memory cells

• Secondary response – much faster due to presence of memory B cells

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Passive Versus ActiveHumoral Immunity

Active

Naturally Acquired

Artificially Acquired

Infection

Vaccine (dead or attenuated pathogens)

Passive

Antibodies passed from mother to fetus or infant

Injection of gamma globulin

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Antibodies• Immunoglobulins (Igs) = gamma globulins• General structure: (See Table 22.3, p. 811)

– consist of 4 polypeptide chains held together by disulfide bonds = antibody monomer

– each chain has a variable and a constant region

Fig. 22.12, p. 810

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Antibodies• variable region

– give specificity to antibody– includes antigen-binding sites

• constant region – includes stem region of heavy chains and proximal

parts of both heavy and light chains– stem region determines actions and classes of

antibodiesFig. 22.12, p. 810

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Most Common Antibody Classes• IgG

– most abundant and diverse plasma antibody in both primary and secondary responses

– protects against circulating bacteria, viruses, toxins

– activates complement– crosses placenta to protect fetus

• IgM– actgs as antigen receptor on B cell membrane– important to primary response– causes agglutination and activates complement

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Less Common Antibody Classes• IgA

– found primarily in mucus and other secretions (e.g, saliva, sweat, intestinal juice, milk)

– prevents attachment of antigens to epithelium• IgD

– acts as antigen receptor• IgE

– present in skin, gastrointestinal and respiratory tract mucosae, tonsils

– binds to mast cells and basophils– increases during allergy and chronic parasitic

infection of GI tract

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Fig. 22.13, p. 812

Mechanisms of Antibody Action• Enhance phagocytosis by:

– Neutralization– Agglutination– Precipitation

• Activate complement,which: – Enhances inflammation– Causes cell lysis– Enhances phagocytosis

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Cell-Mediated Immunity• Involves T cells• Types of T cells (see Table 22.4, p. 818)

– Cytotoxic T cells (TC)– Helper T cells (TH)– Suppressor T cells (TS) – Delayed hypersensitivity T cells (TDH)

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Cytotoxic T Cells (TC)• Destroy body cells that are infected by antigen

(viruses, bacteria, internal parasites) or have non-self antigens (e.g., cancer cells)

• Mechanism seems to involve release of perforin onto membrane of affected cell

Fig. 22.17, p. 820

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Cytotoxic T Cells (TC)• Other mechanisms include:

– lymphotoxin (causes fragmentation of target cell DNA)

– tumor necrosis factor (TNF; triggers cell death = apoptosis)

– gamma interferon (stimulates macrophages)

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Helper T Cells (TH)

• stimulate production of B cells and cytotoxic T cells

Fig. 22.16, p. 817

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Other Types of T Cells

• Suppressor T cells (TS) – limit activity of T and B cells after infection has been beaten

• Delayed hypersensitivity T cells (TDH) – – involved in delayed allergic reactions by

secreting interferon and other cytokines– enhance nonspecific phagocytosis by

macrophages

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T Cell Activation• Step 1 – Antigen binding

– T cell antigen receptor (TCR) binds to antigen-MHC protein complex on cell

• Step 2 – Costimulation– recognition of costimulatory signals stimulates

clonal division of T cells into various types• Cytokines

– released by macrophages and T cells– some act as costimulators

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Organ TransplantsTypes:• Autograft – from one site to another in same

person (e.g., skin graft)• Isograft – between identical twins (or members of

same clone)• Allograft – between nonidentical individuals of

same species • Xenograft – between different species (e.g., pig

valves in heart; baboon heart in infant)

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Organ Transplant: Rejection• Occurs when antigens on donor tissue are attacked

by recipient’s immune system• Immunosuppressive therapy

– corticosteroids – suppress inflammation– cytotoxic drugs– radiation (X ray) therapy– antilymphocyte globulins– immunosuppressant drugs (e.g., cyclosporine)

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Disorders: Immunodeficiencies• Severe combined immunodeficiency syndromes

(SCID) – genetic deficiencies of immune system• Acquired immunodeficiencies

– may result from anticancer drugs– Hodgkin’s disease - blocks lymph nodes– acquired immune deficiency syndrome (AIDS)

° caused by HIV virus transmitted in secretions (especially blood, semen, vaginal secretions)

° changes ratio of helper to suppressor T cells (decreases number of TH)

° allows opportunistic infections to proliferate

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Autoimmune Disorders• Multiple sclerosis – destroys myelin sheaths in

CNS• Myasthenia gravis – blocks/destroys ACh

receptors of skeletal muscle• Type I diabetes mellitus – destroys beta cells in

pancreas• Grave’s disease – abnormal antibodies resembling

TSH stimulate thyroid• Systemic lupus erythematosis (SLE) – systemic

disease affecting heart, kidneys, lungs, skin• Rheumatoid arthritis (RA) – destroys joints

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Hypersensitivity Disorders: AllergiesTwo kinds:• Immediate = acute or type I

– begin within seconds of subsequent contact with antigen

• Delayed = type IV– takes hours to days to see response

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Immediate Hypersenstivities• occur in person after initial exposure (response to

1st exposure normally not seen) • most common type of acute hypersensitivity is

anaphylaxis– Mediated by interleukin 4 (IL-4)

° stimulates B cells to mature into IgE-secreting plasma cells

- which stimulate release of histamine from basophils and mast cells (see inflammatory response)

– Local or systemic

Fig. 22.19, p. 826

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Anaphylaxis (con’t)• Local – e.g., hives in skin; asthma, hay fever; GI

reactions• Systemic

– caused by introduction of allergen into blood (e.g., venom in bee sting; penicillin injection)

– causes widespread release of histamine widespread vasodilation widespread loss of fluid to tissues

radical drop in BP anaphylactic shock

– also causes bronchoconstriction– treated with epinephrine

What does epinephrine do?

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Delayed Hypersensitivity (Type IV) Reactions

• Cell-mediated response• Involves cytotoxic and delayed hypersensitivity T cells• Most familiar are contact dermatitis, responses to some

heavy metals, cosmetics and deodorants• Effects appear hours or even days after exposure