Immune System Physiology

Gian Carlo Delante, PhB PTRP RPT

Functions of the Immune System

• DestroypathogensDetect and kill abnormal cells such as cancerous cellsRemove dead cells and other debris from the body

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Pathogens

Two Intrinsic DefenseInnate Defense SystemNon-specificResponds quickly

Systems• (1)

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• External defenses– First lines of defense– Surface barriers: skin & mucous membranes

Internal defenses•––

Second lines of defenseAntimicrobial proteins, phagocytes, cells &chemicals in body fluids•

•Inhibit spread of invaders throughout bodyHallmark: Inflammation

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Adaptive Defense SystemSpecificTakes longer time to react

Mounts attack against particular foreign substances

• Lymphocytes: T cells and B cells

Adaptive Immunity

Adaptive defenses differ from innate

• defensesin–

4 key ways:Specific

• Directed against an identified enemy

Involve B and T lymphocytesHave memorySystemic

• Can act anywhere in the body

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Surface Barriers:Skin & Mucous

The first line of defense prevents pathogens from entering the body and includes physical barriers such as:– Intact skin– Mucous membranes

Membranes•

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Respiratory tract

Gastrointestinal tractGenitourinary tract

Surface Barriers: Skin

Properties of skin that help it resist invasion:Keratin– A tough protein in skin cells, forms an abrasion-

resistant and water-resistant outermost layerIntercellular junctions– hold skin cells tightly togetherSkin secretions– acidic and contain chemicals that make the skin

inhospitable for pathogens• Lysozyme: a skin secretion which can digest cell walls

of certain bacteria

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Surface Barriers: Mucous Membranes

• Mucous membrane secretions–––

Skin acidity (pH of 3 to 5) inhibits bacterial growthSebum contains chemicals toxic to bacteria Stomach mucosae secrete concentrated HCl and protein-digesting enzymesSaliva and lacrimal fluid contain lysozymeMucus traps microorganisms that enter the digestive and respiratory systemsCilia of upper respiratory tract sweep dust- and bacteria-laden mucus away from lower respiratory passages

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Five Lines of InnateInnate internal defenses

Internal Defense•

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fast-actingnonspecific

provide crude protection against any and all pathogens the enter the body•

•The 5 Lines(1) Phagocytic cells– Neutrophils and macrophages

(2) Natural killer (NK) cells– Kill body cells that have become

virus-infected or cancerous(3) Antimicrobial proteins– Compliment and interferon

(4) Inflammation(5) Fever

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Phagocytes:

Neutrophils vs. Macrophages These phagocytes perform essential functions for both

innate and adaptive immunityNeutrophils

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The most abundant of the leukocytes (50-70% of white blood cells)Normally not found in healthy tissues

The first cells to leave the blood and enter tissue at sites of infection or traumaRecruited by chemicals released by tissue macrophages and injured tissuesShort-lived cells that can only phagocytize a few pathogens before they die

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• Macrophages– Monocytes follow the influx of neutrophils into the affected tissue; these

monocytes transform into macrophages, reinforcing the resident macrophages that are already presentNormally present in tissuesChief phagocytic cells: phagocytize more cells than neutrophils in their lifetimeEither free macrophages: macrophages that wander in tissuesOr fixed macrophages: such as liver Kupffer cells and brain microglia

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Phagocytes:Neutrophils

vs. Macrophages

Phagocytes: Recognizing

Phagocytes use special cell membrane receptors to recognize and bind molecules (markers of non-self) that are found on pathogens and not on normal body cells– Mannose receptor– Toll-like receptors (TLR’s)

When a phagocyte recognizes a pathogen it triggers:– Ingestion of the pathogen– Release of chemicals alarm signals that mobilize other cells of innate and adaptive immunity

the Enemy

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Phagocytes: Killing Mechanisms

• Phagosome– The vesicle wherein the

engulfed pathogen is containedKilling mechanisms•– H+ is pumped into the phagosome

making it acidicEnzymes convert O2 into toxic reactive oxygen intermediates Phagosome fuses with lysosometo form a phagolysosome

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• Indigestible and residual materialis removed by exocytosis

NK Cells: Characteristics

Make up 10-15% of blood lymphocytesIdentification of target cells– Look for the absence of normally occurring self- proteins– Act in complimentary fashion to T cells which look for presence of abnormal antigens

Killing mechanism– Release cytolytic chemicals that enhance inflammatory response– React non-specifically and eliminate cancerous and virus- infected cells

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Antimicrobial Proteins:Interferons

Interferons (IFN) are cytokines

(IFN)•

– Cytokines: small proteins that act as chemical messengers between various parts of the immune systemBasic functions:

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Interfere with viral replicationModulate inflammationActivate immune cells

– Genes that synthesize IFN are activated when a host cell is invaded by a virusInterferon molecules (chemicals) leave the infected cell and enter neighboring cells Interferon stimulates the neighboring cells toactivate genes for Protein Kinase RNA-activated(PKR) (an antiviral protein)

• PKR nonspecifically blocks viral reproduction in the neighboring cell

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• 3 types of interferon–––

Alpha interferonBeta interferonGamma interferon

Antimicrobial Proteins:Interferons

Interferons are a family of related proteins each with slightly different physiological effectsLymphocytes– secrete gamma () interferon,

but most other WBCs secrete alpha () interferon

Fibroblasts– secrete beta () interferon

Interferons also activate macrophages and mobilize NK’s FDA-approved alpha IFN is used:– As an antiviral drug against

hepatitis C virus

– To treat genital warts caused by

the herpes virus

(IFN)•

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Antimicrobial Proteins:Compliment

Compliment gets its name from the fact that it compliments or enhances other components of both innate and adaptive defensesWhen activated, these proteins can:

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– Opsonization: Mark cells forphagocytosis

Chemotaxis: attracts macrophages and neutrophils Cell lysis: Kill some bacteria allby themselves by the formationof a Membrane Attack Complex(MAC)

Agglutination: clustering and binding of pathogens together Amplify aspects of theinflammatory response

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Antimicrobial Proteins:Compliment

Inflammation:The 5 cardinal signs

Cardinal Signs•

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DolorTumorRuborCalorFunctio laesa

• Functions– Prevents the spread of injurious

agentsDisposes off pathogens and dead cellsSets the stage for repair

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–• Inflammatory mediators are central

to the process of inflammation– Released by macrophages and other

tissue cells

Cause vasodilation and increase in vascular permeabilityAct as chemotaxins in chemotaxis

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Inflammatory Response:Phagocytic Mobilization

• Leukocytosis– neutrophils and monocytes are released from the bone marrow in response to leukocytosis-inducing factors released by injured cells

Margination: The binding of monocytes and neutrophils to blood vessel walls in the injure area– In response to inflammatory mediators, endothelial cells produce cell adhesion molecules which cause margination

Diapedesis– neutrophils squeeze through capillary walls and begin phagocytosis

Chemotaxis– The process whereby neutrophils and macrophages find their way to the site of injury by following the trail of chemical mediators

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Inflammation:Inflammatory

Histamine– One of the most powerful

inflammatory mediator

– Released by basophils (found in blood) and mast cells (found in connective tissue)

Prostaglandins and Kinins– Activate pain receptors– Ex: bradykinin & kallidinCytokines– Principally involved in regulating leukocyte behavior and function

Mediators•

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Fever

• Fever is a useful part of our defense systemRole in the immune system:

•– Most pathogens do not

grow as well at higher temperaturesDuring fever liver and spleen sequester iron and zinc making them less available to bacteriaHigher temperatures enhance phagocytosis and a variety of enzymatic processes used by the immune system

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Adaptive Immunity

A functional system that:•––––

3rdIs considered the line of defenseRecognizes specific foreign substances

Acts to immobilize, neutralize, or destroy foreign

substancesAmplifies inflammatory response and activates compliment

• Characteristics–––

Antigen-specificSystemicHas memory

• Has 2 separate but overlapping arms:– Humoral immunity or antibody-mediated immunity (B cell)– Cellular immunity or cell-mediated immunity (T cell)

AntigensAntigens (ANtibody GENerator)– Usually molecules of proteins, but can also be large carbohydrates or nucleic acids NOT normally found in the body (non-self)

– Substance that provokes an adaptiveimmune response

Antigenic determinant– the special shape formed by an antigen that a particular lymphocyte recognizes

Surface of any given pathogen is studded with many different antigens, each usually having many different antigenic determinantsB & T cells or antibodies recognize pathogens by binding to the them– Antibodies are secreted by the clonal descendants of B cells, called plasma cells

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Antigenic Determinants

Self-Antigens: MHCOur cells are dotted with protein molecules (self-antigens) that are not antigenic to us but are strongly antigenic to othersOne type of these mark a cell as self: Major Histocompatibility Complex (MHC) proteins– Unique to an individual

The two classes of MHC proteins are:– Class I MHC proteins – found on virtually all body cells– Class II MHC proteins – found on certain cells in the immune response (macrophages, dendritic cells, B cells)

Proteins•

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Cells of AdaptiveTwo types of lymphocytes– B lymphocytes (B cells) – oversee humoral immunity

Immunity•

• Mature in the bone marrow

– T lymphocytes (T cells) – non- antibody-producing cells that constitute the cell-mediated arm of immunity• Mature in the thymus

• Antigen-Presenting Cells (APC’s)– Process and present antigens to T

cells• Dendritic cells – capture antigens in

the periphery, migrate to lymph nodes, and present these antigens to T cellsMacrophagesB cells

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– Play essential auxiliary roles in immunityClass II MHC proteins–

Adaptive Immunity:Humoral and Cellular

Immunity

Humoral Immunity

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The branch of adaptive immunity that can be transferred via body fluids

Involves B cells and the antibodies they ultimately produce: anitbody- mediatedDirected against extracellular pathogensExample:

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• A bacterium has invaded the extracellular fluid

• Cellular Immunity– The branch of adaptive immunity which cannot be transferred

by transferring body fluidsInvolves the T cells which directly attack other cells: cell-mediatedDirected against cells of our own bodyExample:

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A cell has become cancerousA cell has been invaded by a virusA cell has been transplanted from another individual

Adaptive Immunity:Humoral and Cellular

Immunity

Humoral Immunity:

Antibodies:

Antibodies

•– Secreted by the clonal

descendants of B cells, called plasma cellsCan be found on the plasma membrane of B lymphocytes where they act as B cell antigen receptorsCan be secreted into extracellular fluids, where they are also known as immunoglobulins or gamma globulins

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Humoral Immunity: Antibodies

• Each antibodyhas two identicalantigen-bindingsites (at thevariable regions)

Shape ofantigen-bindingsite and shape ofantigenicdeterminantmust match inorder to bind

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Humoral Immunity: Antibodies

• The stem (constant region) determines whether an antibody:––––

Remains bound to the B cell as the B cell antigen receptorCan activate complimentCan act as opsonin to promote phagocytosis

Can be joined with another to form a pair called a dimer, or a complex of five antibodies called a pentamerIs secreted into blood plasma, or is transported into the lumen of the gut, across the placenta, or into other secretions such as saliva

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• Antibodies themselves do not destroy antigen – theyinactivate and tag antigens for destructionAll antibodies form an antigen-antibody (immune) complexThere are five classes of antibodies: IgG, IgA, IgM, IgE, andIgD

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Antibodies: Immunoglobulin G (IgG)

Antibodies:IgA is principally secreted into the mucosa of the:

Immunoglobulin A (IgA)•

– Gastrointestinal systemRespiratory systemGenitourinary system

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• Also found in:– Saliva– Sweat and tears

Breast milk allows passive transfer of immunity from mother to baby after birth

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Antibodies: Immunoglobulin M (IgM)

Antibodies: Immunoglobulin E (IgE)

• Parasitic worms in the body initiate a series of interactions within the immune system that results in the production of IgEKey to the production of IgE are:– Helper T cells– Interleukin-4

IgE antibodies coat the worm to mark it for attack– Eosinophils attack the parasite

– When receptors on eosinophils bind to IgE on the worm, eosinophils release toxic agents from their granules

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Antibodies: ImmunoglobulinAllergies

E (IgE)•

– Individuals who are prone to allergies make IgE antibodies directed against environmental antigens called allergensCommon allergens include chemicals found on pollen and dust mite feces

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• Allergic Response––

Sensitization – first exposure to an allergenIgE antibodies attach onto surface ofbasophils and mast cells

When exposed again to allergen, it binds to IgE on mast cells and basophils that degranulate releasing granules which contain histamine & other inflammatory mediatorsThese cause vasodilation (runny nose) and bronchoconstriction (difficulty breathing) When effect is systemic becomes anmedical emergency situation - anaphylaxis

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• Antihistamine– Block histamine receptors on bronchioles

and blood vessels

Antibodies: Immunoglobulin D (IgD)

• The role of IgD is notentirely clear– Is located in the

surface of naïve B cells(along with IgM)

Acts as B cell antigen receptor and participates in activating the B cell

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Antibodies – Summary of ActionsP: Antibodies, acting as opsonins, mark pathogens for destruction byphagocytosis

L: Antibodies attached to the surface of bacteria initiate the classical pathway of complement activation, which can result in lysis via the membrane attack complex (MAC – large pore formed in a target cell by compliment system causing cell lysis by creating osmotic imbalances)A: Antibodies clump molecules or entire cells (agglutination)– Clumping enhances phagocytosis (because IgM pantamers have 10 binding sites they are particularly good at forming clumps)

N: Antibodies can prevent viruses and toxic molecules, such as tetanus toxin, from interacting with the body’s cells– This process is called neutralization and is the process by which

antivenoms work

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Cellular Immunity

Since antibodies are useless against intracellular antigens, cell- mediated immunity is neededTwo major populations of T cells mediate cellular immunity (based on the presence of certain cell surface proteins – CD proteins)– CD4 cells (T4 cells) are primarily helper T cells (TH) which

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orchestrate immune response• 2/3 of all T cells

– CD8 cells (T8 cells) are cytotoxic T cells (TC) that destroy cellsharboring foreign antigens or that have become cancerous

• 1/3 of all T cellsOther types of T cells are:– Suppressor or Regulatory T cells (TS)

• shut down T cell-mediated immunity toward the end of an immune reaction

– Memory T cells• recognize foreign invaders, such as bacteria or viruses, as well as cancer cells• can reproduce to mount a faster and stronger immune response

than the first time the immune system responded to the invader

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CD4 and CD8 Cells

Antigen Presentation

Antigen Presentation:Class I MHC Protein

Class I MHC proteins – found on virtually all body cells

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Antigen Presentation:Class II MHC Protein

Class II MHC proteins – found on certain cells in the immune response (macrophages, dendritic cells, B cells)

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HIV/AIDS• Normal CD4 count: 500-1,500 cells per

mm³HIV positive: < 200 cells per mm³HIV targets CD4 cells by:

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Binding to the surface of CD4 cells

Entering CD4 cells and becoming a part of them

• As CD4 cells multiply to fight infection, they

also make more copies of HIVContinuing to replicate, leading to a gradual decline of CD4 cells

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• HIV can destroy entire "families" of CD4 cells. Then the diseases these "families" were designed to fight can easily take over. That's when opportunistic infections are likely to develop.

Types of Acquired Immunity

Hypersensitivity Reactions