Chapter 15

Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display.

Chapter 15

The ImmuneSystem

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Chapter 15 Outline Innate Immunity Adaptive Immunity Complement System T Cells Histocompatibility Antigens Interactions Between Antigen-Presenting Cells and

Lymphocytes Active Immunity Passive Immunity Immune System and Cancer Diseases Caused By Immune System

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Defense Mechanisms

Against pathogens constitute the immune system Can be grouped into 2 categories:

Innate (nonspecific) immunity is inherited as part of structure of each organism

Adaptive (specific) immunity is a function of lymphocytes and changes with exposure

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Innate Immunity

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Innate Immunity

Distinguishes between “self” and “non-self” Is 1st line of defense against invading pathogens Includes epithelial barriers, high acidity of gastric juice,

phagocytosis, and fever

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Phagocytosis

Is triggered in response to pathogen-associated molecular patterns (PAMPs) produced only by microorganisms Best known are lipopolysaccharide (LPS) from

gram-bacteria and peptidoglycan from gram+s Some immune cells have receptors for PAMPs

(called Toll receptors)

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Phagocytosis continued

Is performed by 3 classes of phagocytic cells: Neutrophils - 1st to arrive at infection sites Mononuclear phagocytes - macrophages and

monocytes Organ-specific phagocytes in liver, spleen, lymph

nodes, lungs, and brainFixed phagocytes line sinusoids of liver, spleen,

and lymph nodes and remove pathogens

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Connective tissue and blood contain mobile leukocytes (WBCs) These are attracted

to infection (chemotaxis) by chemokines

WBCs from blood exit capillaries by extravasation (diapedesis) and ingest pathogens


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Pseudopods from phagocyte surround pathogen Forming a

vacuole Vacuole

fuses with lysosomes which digest pathogen


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Fever

Appears to be component of innate immunity Occurs when hypothalamic thermostat is reset

upwards by IL1- and other cytokines (endogenous pyrogens) Pyrogens are released by WBCs in response to

endotoxin from gram– bacteria

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Interferons

Are polypeptides produced by cells infected with virus that provide short-acting, non-specific resistance to viral infection in nearby cells 3 types: a, b, g, interferon

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Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. 15-12


Adaptive Immunity

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Adaptive Immunity

Is acquired ability to defend against specific pathogens by prior exposure to those pathogens

Is mediated by production of specific antibodies by lymphocytes

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Antigens

Are molecules that elicit production of antibodies that specifically bind those antigens

Are usually large molecules that are foreign to the body

Immune system can distinguish “self” molecules from non-self antigens Normally makes antibodies only against non-self

antigens Large, complex molecules can have a number of

antigenic determinant sites (different sites that stimulate production of, and bind to, different antibodies)

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Haptens

Are small non-antigenic molecules that become antigens when bound to proteins (form an antigenic determinant site) Useful for creating antibodies for research and

diagnosis

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Immunoassays

Are tests that use specific antibodies to identify a particular antigen

The binding of antibody to antigen causes clumping (agglutination) which can be visualized

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Lymphocytes

Are derived from stem cells in bone marrow Which replace selves by cell division so are not

depleted Lymphocytes produced by this process seed

thymus, spleen, and lymph nodes with self-replacing colonies

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T Lymphocytes (T cells)

Develop from lymphocytes that seed thymus Do not secrete antibodies Attack infected host cells, cancer cells, and foreign

cells Thus they provide cell-mediated immunity

Supply 65 – 85% of lymphocytes for blood and most of lymphocytes in germinal centers of lymph nodes and spleen

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B Lymphocytes (B cells)

Fight bacterial infections by secreting antibodies into blood and lymph Thus provide humoral immunity

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Thymus

Is located below the thyroid gland Grows during childhood, gradually regresses after

puberty Contains T cells that supply other tissues

T cells can be depleted, e.g. by AIDs or chemotherapy

These can only be replenished up to late childhoodAfter that, repopulation is accomplished by

production in secondary lymphoid organs

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Secondary Lymphoid Organs

Consist of lymph nodes, spleen, tonsils, and Peyer’s patches Located in areas where antigens could gain entry to

blood or lymph Lymphocytes migrate constantly through blood and

lymph from one lymphoid organ to another Enhances chance that antibody will encounter its

antigen Spleen filters blood; other lymphoid organs filter

lymph

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Local Inflammation

Occurs when bacteria enter a break in the skin Inflammatory reaction is initiated by nonspecific

mechanisms of phagocytosis and complement activation Complement activation attracts phagocytes to area

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Local Inflammation continued

As inflammation progresses, B cells produce antibodies against bacterial antigens Attachment of antibodies to antigens amplifies

nonspecific responses because of complement activationAnd promotes phagocytic activity of neutrophils,

macrophages, and monocytes (= opsinization)

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In inflamed area, leukocytes attach to surface of endothelial cells Move by chemotaxis

to inflamed site Neutrophils arrive 1st,

then monocytes, then T cells

Undergo extravasation


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Mast cells secrete heparin, histamine, prostaglandins, leukotrienes, cytokines, and TNF-a These produce

redness, warmth, swelling, pus, and pain

Recruit more leukocytes

If infection continues, endogenous pyrogens are released

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B Lymphocytes (B cells)

Have antibodies on surface that are receptors for antigens When bound to

antigen, are stimulated to divide and secrete antibodies

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B Lymphocytes (B cells) continued

When B cells divide, some progeny become memory cells Others become

plasma cells that produce about 2000 antibodies/sec that are specific for original antigen This provides

active immunity

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B Lymphocytes (B cells) continued

Binding of B cells to antigen also triggers a cascade of reactions that activate complement proteins Complement proteins can kill antigen-bearing cells

and promote phagocytosis

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Antibodies

Are proteins called immunoglobulins Part of gamma globulin class of plasma proteins

Antibodies have same basic structure but their differences provide for antibody specificity

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Antibody Structure

Is in shape of “Y” 2 long heavy (H) chains are

joined to 2 shorter light (L) chains

When cleaved, stalk of Y becomes crystallizable fragment (Fc) Fc is constant among

different antibodies Arms of Y contain antigen-

binding fragment (Fab) Fab contains a variable

region that confers antibody specifity

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Antibody Diversity

Each person has about 1020 antibody molecules With a few million different specificities Likely there is an antibody specific for any antigen a

person might encounter

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Antibody Diversity continued

2 mechanisms might account for diversity If a few hundred genes code for Hs and a few

hundred for Ls, different combinations could lead to millions of different antibodiesRecombination of these in developing

lymphocytes of marrow produces antigen-independent diversity

Diversity further increases via somatic hypermutationOccurs as B cells undergo antigen dependent

proliferation in 2o lymphoid tissues in response to foreign antigens

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Complement System

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The Complement System

Is part of nonspecific defense system Activity is triggered by binding of antibodies to antigens

(classic pathway) and by bacterial coat polysaccharides (alternative pathway)

Binding of antibodies to antigens does not by itself destroy antigens or pathogens

Antibodies label targets for complement system attack and also stimulate opsonization

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Is a series of proteins whose activation forms a membrane attack complex which perforates a cell causing it to lyse

Complement proteins can be subdivided into 3 functional groups: C1 - recognition C4, C2, C3 - activation C5-C9 - attack (complement fixation)

These form the membrane attack complex

The Complement System continued

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In classic pathway, antibody-antigen binding activates C1 C1 hydrolyzes C4 into C4a and C4b

C4b binds to cell membrane and becomes active, splitting C2 into C2a and C2b

C2a attaches to C4b and cleaves C3 into C3a and C3b

Alternate pathway also cleaves C3 (and so converges with classic pathway at this step)

C3b converts C5 to C5a and C5b

The Complement System continued

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Fixation of Complement Proteins

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Membrane Attack Complex

C5b and C6 - C9 are inserted into bacterial cell membrane, forming membrane attack complex This creates large pore in membrane, causing osmotic

influx of H2O, lysis, and cell death

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Complement Fragments

That are liberated during activation have a number of effects, including

Attracting phagocytes (chemotaxis) Phagocytes have receptors for C3b which can serve as

bridge to victim cell C3a and C5a stimulate mast cells to secrete histamine

Which increases blood flow and capillary permeability, bringing in more phagocytes

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T Cells

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Killer or Cytotoxic T Cells

Carry CD8 cell surface marker Destroy body cells that possess foreign antigens

Usually from a pathogen, but can be from malignancy or self cells never seen by immune system

Kill by cell-mediated destruction That is, must be in contact with victim cell Kill by secreting perforins which create a pore in

victim's membrane and cause lysis Also secrete granzymes which cause destruction of

victim's DNA15-44


Helper and Suppressor T Cells

Helper Ts carry CD4 surface marker

Indirectly participate by enhancing responses of both killer T cells and B cells

Regulatory Ts decrease responses of killer Ts and B cells Carry CD25 surface

marker (and CD4) Help protect against

autoimmune responses

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Lymphokines

Are cytokines secreted by lymphocytes

Usually called interleukin-1, 2, 3 . . . or IL-1, IL-2 . . .

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T Cell Receptor Proteins

Only protein antigens are recognized by most T cells T cell receptors cannot bind to free antigens T cells respond to foreign antigens when they are

presented on surface of antigen-presenting cells Chief antigen presenting cells are macrophages and

dendritic cells

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Originate in marrow, then migrate to most tissues Prominent where pathogens might enter body

Engulf protein antigens, partially digest them, and display polypeptide fragments on surface for T cells to "see"

Dendritic Cells

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Dendritic Cells continued

Fragments are associated on surface with histocompatibility antigens which are necessary to activate Ts

To increase chance of interacting with correct T cells, dendritics migrate to secondary lymphoid organs Where secrete

chemokines to attract Ts

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Histocompatibility Antigens

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Histocompatibility Antigens

Are on surface of all body's cells except mature RBCs Also called human leukocyte antigens (HLAs)

Are coded for by group of 4 genes on chromosome 6 called the major histocompatibility complex (MHC) The 4 genes have multiple alleles creating many

possible MHC types

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MHC genes produce 2 types of cell surface molecules: class-1 and class-2 Class-1s are made by all cells except RBCs Class-2s are made only by antigen-presenting cells

and B cellsThese present class-2s, together with foreign

antigens, to helper Ts This is the only way to activate helper Ts so

they can promote B cell activity

MHC

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In order for killer and helper Ts to function they require co-presentation of antigen with a specific MHC marker

Killer Ts are activated to kill victim cell only by co-presentation of antigen and class-1 marker

Helper Ts require antigen and class-2 marker

MHC continued

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Co-presentation requirement comes from presence of different coreceptors on killer and helper T cells Killer T coreceptor CD8 interacts only with class-1s Helper T coreceptor CD4 interacts only with class-2s

MHC continued

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Interactions Between Antigen Presenting Cells and Lymphocytes

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T Cell Response to a Virus

When virus infects body it is phagocytized by macrophage or dendritic cell Its partially-digested polypeptide fragments are

antigens that are displayed on surfaceForm a complex with class-2 MHC molecules that

macrophages present to helper T cells Helper Ts bind and are activated

Can now promote B cell activity

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When macrophages and T cells form a complex, macros secrete IL-1 and TNF (which is good at killing cancer cells) IL-1 stimulates cell division and proliferation of

helper Ts Activated helpers secrete M-CSF and g-interferon and

IL-2 Promotes activity of macrophages Activated helpers activate B cells

Macrophage-T cell Interaction

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Killer T cell Activity

Killer Ts destroy infected cells if class-1 markers are present

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Helper T cell-B cell Interactions

Activated helper Ts promote humoral response of B cells by binding to their surface antigens and MHC class 2s

This stimulates proliferation of Bs, their conversion to plasma cells, and their secretion of antibodies

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Destruction of T cells

Activated Ts must be destroyed after infection is over Occurs because Ts produce a surface receptor called

FAS FAS production increases during infection After a few days, Ts begin to produce FAS ligand Binding of FAS to FAS ligand triggers apoptosis (cell

suicide)

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Active Immunity

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Primary and Secondary Responses On 1st exposure to

pathogen, there is latency of 5-10 days before specific antibodies are made (= primary response) Antibody levels plateau

after few days and decline after a few weeks

Subsequent exposure to same antigen causes secondary response Antibody production is

much more rapid and sustained

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Clonal Selection Theory

Is mechanism by which secondary immune responses are produced Each B cell produces only 1 kind of antibody and

related antigen receptor (on its surface) Exposure to its antigen stimulates a B cell to divide

until a large population of genetically identical cells (clones) is producedSome of these become plasma cells and secrete

antibodiesSome become memory cells that can be

stimulated to produce antibodies in the secondary response

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Germinal Centers

Develop in lymph nodes and spleen from a cloned and activated B cell Which proliferate and undergo hypermutation

Generating and secreting diverse antibodies for the 2o immune response

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Active Immunity

Development of a secondary response provides active immunity

Immunizations induce primary responses by inoculating people with pathogens whose virulence has been attenuated or destroyed (vaccinations) Cause development of B cell clones that can

provide 2o response

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Immunological Tolerance

Ability to produce antibodies against non-self antigens while tolerating self-antigens (immunological competence) occurs during 1st month of life Tolerance requires continuous exposure to an

antigen Some self-antigens, such as lens protein in eye, are

normally hidden from blood Exposure to such self-antigens results in production

of autoantibodies Killer T cells that attack self-antigens are called

autoreactive T cells

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Immunological Tolerance continued

2 possible mechanisms for tolerance: Clonal deletion theory: tolerance occurs because T

cells that recognize self-antigens are destroyedGood evidence this occurs in thymus

Clonal anergy: lymphocytes directed against self-antigens are present throughout life but don't attack self-antigensMechanism not understoodAppears to underlie tolerance in B cells

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Passive Immunity

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Passive Immunity

Is immune protection produced by transfer of antibodies to a recipient from a donor Donor was actively immunized

Person who receives these ready-made antibodies is passively immunized Used to treat snakebite, rabies, tetanus,

hepatitis

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Passive Immunity continued

Occurs naturally before and after birth Some antibodies from mother pass placenta to fetus

during pregnancy and provide passive immunity During 1st 2-3 days of nursing, mother produces

colostrum which is rich in her antibodies and gives her immunity to infant

Immunological competence (ability to mount a specific immune response) does not develop until 1 month after birth

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Monoclonal Antibodies

Commercially prepared for use in research and diagnostic tests

Exhibit specificity for only 1 antigenic determinant Animal (usually mouse) is injected with antigen, and its

B cells harvested from spleen Bs are hybridized with cancerous myeloma cells to

make them immortal Individual Bs are screened and the one that

produces right antibody is selected This one is allowed to multiply in culture and its

clones (= hybridoma) are source of large quantity of antibodies

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Immune System and Cancer

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Tumor Immunology

Believed that tumor cells arise often but are normally recognized and killed by immune system

When cancer develops, the immunological surveillance system of T and natural killer cells has failed

Tumor biology is similar to and interrelated with functions of immune system

Most tumors are clones of single cells whose mitosis is not controlled by normal inhibitory mechanisms

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Tumor Immunology continued

Tumor cells dedifferentiate (become less specialized like cells of an embryo) As dedifferentiate, produce surface antigens that are

normally recognized by immunological surveillance and destroyed

Because were absent at the time immunological competence was established

Body treats these antigens as foreign Presence of these antigens provides basis of

laboratory diagnostic tests for some cancers

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Natural Killer (NK) Cells

Are lymphocytes related to T cells Provide first line of cell-mediated defense Considered to be part of the innate immune system Possess an array of surface receptors that allow them

to fight viruses, bacteria, parasites and malignant cells NK cells destroy tumors in a non-specific fashion;

backed up by specific response of killer Ts NKs are stimulated by interferon from T cells NKs attack cells that lack class-1 MHC antigens

Kill with perforins and granzymes15-80


Immunotherapy for Cancer

Most strategies involve boosting, or directing, patients own immune responses

Interferons and interleukins have been useful in treatment of some forms of cancer E.g. interleukin-2, which activates both killer T and B

cells, has shown promise

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Effects of Aging and Stress

Little is known about why susceptibility to cancer is so variable

Cancer risk increases with age One factor may be that aging lymphocytes

accumulate genetic errors that decrease effectiveness

Thymus function declines with age Tumors grow faster in stressed animals Stress hormones (corticosteroids) cause decreased

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Diseases Caused By Immune System

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Diseases Caused by Immune System

Can be grouped into 3 categories: autoimmune diseases, immune complex diseases, and allergies All caused by abnormal functioning of immune

system

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Autoimmune Diseases

Are produced by failure of immune system to recognize and tolerate self-antigens Autoreactive T cells are formed and B cells produce

autoantibodies Afflicts women twice as often as men

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Autoimmune Diseases continued

Failure of self-tolerance may be due to: An antigen that does not normally circulate in blood

being presented to immune systemE.g. in Hashimoto's thyroiditis, antibodies are

stimulated to attack thyroglobulin (which is normally hidden from immune surveillance)

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Failure of self-tolerance may be due to: Combination of a self-antigen, that is otherwise

tolerated, with a foreign haptenE.g. in thrombocytopenia (low platelet count),

platelets are destroyed because they combine with victim's medications

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Failure of self-tolerance may be due to: Antibodies being produced that are directed against

other antibodiesHappens with rheumatoid arthritis

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Failure of self-tolerance may be due to: Antibodies against foreign antigens cross-reacting

with self-antigensThis can happen with rheumatic fever

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Failure of self-tolerance may be due to: Self-antigens being presented to helper T cells

together with class-2 MHC moleculesThis happens in Type I diabetes

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Immune Complex Diseases

Involve formation of immune complexes that are free and not attached to a cell These activate complement proteins and promote

inflammation Can result from infections by bacteria, parasites,

viruses Can result from formation of complexes between self-

antigens and autoantibodies This occurs in rheumatoid arthritis and lupus

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Allergy (Hypersensitivity)

Is an abnormal immune response to allergens Comes in 2 forms: immediate and delayed

hypersensitivity Immediate is due to abnormal B cell response to

allergen; causes effects in secs to minsCaused by foods, bee stings, pollen

Delayed is abnormal T cell response that causes symptoms 24-72 hrs after exposure

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Immediate Hypersensitivity

Dendritic cells stimulate a class of helper Ts to secrete interleukin-4 and -13 which cause B and plasma cells to secrete IgE antibodies IgEs do not circulate in blood; are attached to mast

cells and basophils When re-exposed to same allegen, antibodies on

mast cells and basophils bind it and stimulate secretion of histamine, leukotrienes, and prostaglandin DProducing allergy symptomsHistamine increases capillary permeability and

enhances immune response15-93


Immediate Hypersensitivity continued

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Delayed Hypersensitivity

Symptoms take longer to develop (hrs to days) Is a cell-mediated T cell response

Symptoms caused by secretion of lymphokines, not histamine Antihistamines provide little benefit

Examples include contact dermatitis caused by poison ivy, oak, or sumac

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Chapter 15