Download The Immune System

The Immune System
Defense Mechanisms
• The Immune system
• All structures and processes that provide a defense
against pathogens.
• Pathogen: a disease-causing agent
• Is a functional system
• Includes cells that carry out immune defense
• Trillions of cells
• Inhabit lymphatic tissue
• Circulate in body fluid
• Most important
• Lymphocytes
• macrophages
Defense Mechanisms
• Immune defenses identify self from non-self
• Protect against microbes
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Viruses
Bacteria
Fungi
Parasites
• Isolate or remove nonmicrobial foreign substances
• Destroy cancer cells
• Function is called Immune surveillance
Defense Mechanisms
• Immunology
• Study of physiological defenses by which the host
destroys or neutralizes foreign matter
• Both dead and living foreign matter
• Immunity: also called immune defenses
• Nonspecific or innate:
• Inherited defense mechanisms.
• Specific or acquired:
• Prior exposure (lymphocytes).
Immunity
• Nonspecific immunity
• Characteristics
• Can respond immediately to protect against any foreign
substance or cell
• Does not have to recognize specific identity
• Is genetic
• Specific Immunity
• Characteristics:
• Depends upon specific recognition
• By lymphocytes
• Attack is unique to the substance or cell
• Work together:
• Nonspecific sets the stage for specific
The Players
• Cells
• All leukocytes
• Notable derivatives or relations
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Plasma cells
Macrophages
Macrophage-like cells (not descended from macrophages)
Mast cells
The Players
• Chemicals
• Cytokines
• Protein messengers released from cells
• Regulate cell growth and development in both nonspecific and specific defenses
• Act as paracrine agents mostly
• Sometimes have hormone effects
• Circulate in blood
• Physiology is complex
First Line of Defense:
Skin and Mucous Membranes
• Nonspecific resistance refers to a wide variety of body responses against a wide
range of pathogens (disease producing organisms) and their toxins.
• Mechanical protection includes the intact epidermis layer of the skin, mucous
membranes, the lacrimal apparatus, saliva, mucus, cilia, the epiglottis, and the flow
of urine. Defecation and vomiting also may be considered mechanical processes that
expel microbes.
• Chemical protection is localized on the skin, in loose connective tissue, stomach, and
vagina.
• The skin produces sebum, which has a low pH due to the presence of unsaturated
fatty acids and lactic acid.
• Lysozyme is an enzyme component of sweat that also has antimicrobial properties.
• Gastric juice renders the stomach nearly sterile because its low pH (1.5-3.0) kills
many bacteria and destroys most of their toxins; vaginal secretions also are slightly
acidic.
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Skin & Mucous Membranes
• Mechanical protection
• skin (epidermis) closely packed, keratinized cells
• shedding helps remove microbes
• mucous membrane secretes viscous mucous
• cilia & mucus trap move microbes toward throat
• washing action of tears, urine and saliva
• Chemical protection
• sebum inhibits growth bacteria & fungus
• perspiration lysozymes breakdown bacterial cells
• acidic pH of gastric juice and vaginal secretions destroys
bacteria
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Second Line of Defense: Internal
Defenses
• The second line of defense involves internal antimicrobial proteins,
phagocytic and natural killer cells, inflammation, and fever.
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Internal Defenses
• Antimicrobial proteins discourage microbial growth
• interferons
• complement proteins
• transferrins
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Antimicrobial Proteins
• Body cells infected with viruses produce proteins called
interferons (IFNs).
• Once produced and released from virus-infected cells,
IFN diffuses to uninfected neighboring cells and binds to
surface receptors, inducing uninfected cells to synthesize
antiviral proteins that interfere with or inhibit viral
replication.
• INFs also enhance the activity of phagocytes and natural
killer (NK) cells, inhibit cell growth, and suppress tumor
formation; they may hold promise as clinical tools in AIDS
and cancer treatment once they are more fully
understood.
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Antimicrobial Proteins
• A group of about 20 proteins present in blood plasma and on cell
membranes comprises the complement system
• when activated, these proteins “complement” or enhance certain immune,
allergic, and inflammatory reactions.
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Natural Killer Cells & Phagocytes
• NK cells kill a variety of microbes & tumor cells
• found in blood, spleen, lymph nodes & red marrow
• attack cells displaying abnormal MHC antigens
• Phagocytes (neutrophils & macrophages)
• ingest microbes or particulate matter
• macrophages developed from monocytes
• fixed macrophages stand guard in specific tissues
• histiocytes in the skin, Kupffer cells in the liver, alveolar
macrophages in the lungs, microglia in the brain &
macrophages in spleen, red marrow & lymph nodes
• wandering macrophages in most tissue
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Phagocytosis
• Phagocytes are cells specialized to perform phagocytosis and include
neutrophils and macrophages.
• The four phases of phagocytosis include chemotaxis, adherence,
ingestion, digestion and killing.
• After phagocytosis has been accomplished, a phagolysosome is
formed.
• The lysosome in the phagolysosome, along with lethal oxidants
produced by the phagocyte, quickly kills many types of microbes.
• Some of the reasons why a microbe may evade phagocytosis include:
capsule formation, toxin production, interference with lysozyme
secretion, and the microbe’s ability to counter oxidants produced by
the phagocytes.
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Phagocytosis
• Chemotaxis
• attraction to chemicals from
damaged tissues, complement
proteins, or microbial products
• Adherence
• attachment to plasma membrane of
phagocyte
• Ingestion
• engulf by pseudopods to form
phagosome
• Digestion & killing
• merge with lysosome containing
digestive enzymes & form lethal
oxidants
• exocytosis residual body
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Inflammation
• Damaged cell initiates
• Signs of inflammation
• redness
• heat
• swelling
• pain
• Loss of function may be a fifth symptom,
depending on the site and extent of the
injury.
• Function is to trap microbes, toxins or
foreign material & begin tissue repair
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Stages of Inflammation
• The three basic stages of inflammation are vasodilation and increased
permeability of blood vessels, phagocyte migration, and tissue repair.
• Vasodilation & increased permeability of vessels
• caused by histamine from mast cells, kinins from precursors in the blood,
prostaglandins from damaged cells, and leukotrienes from basophils &
mast cells
• occurs within minutes producing heat, redness & edema
• pain can result from injury, pressure from edema or irritation by toxic
chemicals from organisms
• blood-clotting factors leak into tissues trapping microbes
• Phagocyte emigration
• within an hour, neutrophils and then monocytes arrive and leave blood
stream (emigration)
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• Tissue repair
Fever
• Abnormally high body temperature that occurs
because the hypothalamic thermostat is reset
• Occurs during infection & inflammation
• bacterial toxins trigger release of fever-causing cytokines
such as interleukin-1
• Benefits
• A fever intensifies the effects of interferons, inhibits
bacterial growth, and speeds up tissue repair
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SPECIFIC RESISTANCE: IMMUNITY
• Immunity is the ability of the body to defend itself against
specific invading agents.
• bacteria, toxins, viruses, cat dander, etc.
• Differs from nonspecific defense mechanisms
• specificity----recognize self & non-self
• memory----2nd encounter produces even more vigorous
response
• Antigens are substances recognized as foreign by the immune
responses.
• The branch of science that deals with the responses of the
body when challenged by antigens is called immunology.
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Maturation of T Cells and B Cells
• Both T cells and B cells derive from stem cells in bone
marrow.
• B cells complete their development in bone marrow.
• T cells develop from pre-T cells that migrate to the
thymus.
• Before T cells leave the thymus or B cells leave bone
marrow, they acquire several distinctive surface
proteins; some function as antigen receptors,
molecules capable of recognizing specific antigens.
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Maturation of T and B
Cells
• T cell mature in thymus
• cell-mediated response
• killer cells attack antigens
• helper cells costimulate T
and B cells
• effective against fungi,
viruses, parasites, cancer, and
tissue transplants
• B cells in bone marrow
• antibody-mediated response
• plasma cells form
antibodies
• effective against bacteria
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Types of Immune Response
• Cell-mediated immunity (CMI) refers to destruction of antigens by T cells.
• particularly effective against intracellular pathogens, such as fungi,
parasites, and viruses; some cancer cells; and foreign tissue transplants.
• CMI always involves cells attacking cells.
• Antibody-mediated (humoral) immunity (AMI) refers to destruction of
antigens by antibodies.
• works mainly against antigens dissolved in body fluids and extracellular
pathogens, primarily bacteria, that multiply in body fluids but rarely
enter body cells.
• Often a pathogen provokes both types of immune response.
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APC’s and MHC-II
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Antigens
• Molecules or bits of foreign material
• entire microbes, parts of microbes, bacterial toxins, pollen,
transplanted organs, incompatible blood cells
• Required characteristics to be considered an antigen
• immunogenicity = ability to provoke immune response
• reactivity = ability to react to cells or antibodies it caused to be
formed
• Get past the bodies nonspecific defenses
• enter the bloodstream to be deposited in spleen
• penetrate the skin & end up in lymph nodes
• penetrate mucous membrane & lodge in associated lymphoid tissue
Chemical Nature of Antigens/Epitopes
• Large, complex molecules, usually proteins
• if have simple repeating subunits are not usually
antigenic (plastics in joint replacements)
• small part of antigen that triggers
the immune response is epitope
• antigenic determinant
• Hapten is smaller substance that
can not trigger an immune
response unless attached to
body protein
• lipid of poison ivy
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Diversity of Antigen Receptors
• Immune system can recognize and respond
to a billion different epitopes -- even
artificially made molecules
• Explanation for great diversity of receptors
is genetic recombination of few hundred
small gene segments
• Each B or T cell has its own unique set of
gene segments that codes its unique
antigen receptor in the cell membrane
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Major Histocompatibility Complex Antigens
• All our cells have unique surface markers (1000s molecules)
• integral membrane proteins called HLA antigens
• MHC-I molecules are built into cell membrane of all cells except red blood cells
• Function
• if cell is infected with virus MHC-I contain bits of virus marking cell so T cells
recognize is problem
• Some cells also display MHC class II antigens.
• MHC-II markers seen only on membrane of antigen presenting cells
(macrophages, B cells, thymus cells)
• Function
• if antigen presenting cells (macrophages or B cells) ingest foreign proteins,
they will display as part of their MHC-II
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Pathways of Antigen Processing
• B and T cells must recognize a foreign antigen before
beginning their immune response
• B cells can bind to antigen in extracellular fluid
• T cells can only recognize fragments of antigens
that have been processed and presented to them as
part of a MHC molecule
• Helper T cells “see” antigens if part of MHC-II
molecules on surface of antigen presenting cell
• Cytotoxic T cells “see” antigens if part of MHC-I
molecules on surface of body cells
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Processing of Exogenous
Antigens
• Cells called antigen-presenting cells (APCs) process
exogenous antigens (antigens formed outside the
body) and present them together with MHC class II
molecules to T cells.
• APCs include macrophages, B cells, and dendritic
cells.
• The presentation of exogenous antigens together
with MHCII molecules on antigen presenting cells
alerts T cells that “intruders are present”.
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Processing of Exogenous Antigens
• Foreign antigen in body fluid is phagocytized by APC
• macrophage, B cell, dendritic cell (Langerhans cell in skin)
• Antigen is digested and fragments are bound to MHC-II molecules stuck
into antigen presenting cell membrane
• APC migrates to lymphatic tissue to find T cells
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Processing of Endogenous Antigens
• Endogenous antigens are synthesized within the body and include
viral proteins or proteins produced by cancer cells
• Most of the cells of the body can process endogenous antigens
• Fragments of endogenous antigen are associated with MHCI
molecules inside the cell.
• The antigen MHCI complex moves to the cell’s surface where it alerts
T cells.
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Cytokines & Cytokine Therapy
• Small protein hormones involved in immune responses
• secreted by lymphocytes and antigen presenting
cells
• Cytokine therapy uses cytokines (interferon)
• alpha-interferon used to treat Kaposi’s sarcoma (in
AIDS patients), genital herpes, hepatitis B and C &
some of the leukemias
• beta-interferon used to treat multiple sclerosis
• interleukin-2 used to treat cancer (side effects)
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CELL-MEDIATED IMMUNITY
• Begins with activation of T cell by a specific antigen
• Result is T cell capable of an immune attack
• elimination of the intruder by a direct attack
• In a cell-mediated immune response, an antigen is
recognized (bound), a small number of specific T cells
proliferate and differentiate into a clone of effector cells (a
population of identical cells that can recognize the same
antigen and carry out some aspect of the immune attack),
and the antigen (intruder) is eliminated.
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Activation, Proliferation, and
Differentiation of T Cells
• T cell receptors recognize antigen fragments
associated with MHC molecules on the
surface of a body cell.
• Proliferation of T cells requires costimulation,
by cytokines such as interleukin-1 (IL-1) and
interleukin-2 (IL-2), or by pairs of plasma
membrane molecules, one on the surface of
the T cell and a second on the surface of an
APC.
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Overview of Mature T Cells
1. Helper T (TH) cells, or T4 cells, display CD4 protein, recognize
antigen fragments associated with MHC-II molecules, and secrete
several cytokines, most important, interleukin-2, which acts as a
costimulator for other helper T cells, cytotoxic T cells, and B cells.
2. Cytotoxic T (TC) cells, or T8 cells, develop from T cells that display
CD8 protein and recognize antigen fragments associated with
MHC-I molecules.
3. Memory T cells are programmed to recognize the original invading
antigen, allowing initiation of a much swifter reaction should the
pathogen invade the body at a later date.
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Helper T Cells
• Display CD4 on surface so also known as T4 cells or
TH cells
• Recognize antigen fragments associated with MHC-II
molecules & activated by APCs
• Function is to costimulate all other lymphocytes
• secrete cytokines (interleukin-2)
• autocrine function in that it costimulates itself
to proliferate and secrete more interleukin
(positive feedback effect causes formation of
many more helper T cells)
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Cytotoxic T Cells
• Display CD8 on surface
• Known as T8 or Tc or killer T cells
• Recognize antigen fragments associated with MHC-I
molecules
• cells infected with virus
• tumor cells
• tissue transplants
• Costimulation required by cytokine from helper T
cell
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Memory T Cells
• T cells from a clone that did not turn into cytotoxic T cells during a
cell-mediated response
• Available for swift response if a 2nd exposure should occur
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Details: Cytotoxic T Cells
• Cytotoxic T cells fight foreign invaders by killing the target cell (the cell
that bears the same antigen that stimulated activation or proliferation of
their progenitor cells) without damaging the cytotoxic T cell itself.
• When cytotoxic T cells encounter a cell displaying a microbial antigen,
they can release granzymes which trigger apoptosis. The microbe is
then destroyed by phagocytes.
• Cytotoxic T cells can also bind to infected cells and release perforin and
granulysin. Perforin causes cytolysis while granulysin destroys the
microbe.
• Cytotoxic T cells can also release lymphotoxin which activates
damaging enzymes within the target cell.
• When the cytotoxic T cell detaches from a target cell, it can destroy
another cell.
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Immunological Surveillance
• Immunological surveillance is carried out by cytotoxic T cells.
• They recognize tumor antigens and destroy the tumor cell.
• The immune system can recognize proteins in transplanted
organs as foreign and mount a graft rejection.
• Success of a proposed organ or tissue transplant depends on
histocompatibility. Tissue typing (histocompatibility testing) is
done before any organ transplant.
• Organ transplant recipients also receive immunosuppresive
drugs such as corticosteroids.
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Immunological Surveillance
• Cancerous cell displays unusual surface antigens (tumor
antigens)
• Surveillance = immune system finds, recognizes & destroys cells
with tumor antigens
• done by cytotoxic T cells, macrophages & natural killer cells
• most effective in finding tumors caused by viruses
• Transplant patients taking immunosuppressive drugs suffer most
from viral-induced cancers
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Graft Rejection
• After organ transplant, immune system has
both cell-mediated and antibody-mediated
immune response = graft rejection
• Close match of histocompatibility complex
antigens has weaker graft rejection response
• immunosuppressive drugs (cyclosporine)
• inhibits secretion of interleukin-2 by
helper T cells
• little effect on B cells so maintains some
resistance
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Antibody-Mediated Immunity
• The body contains not only millions of different T cells but
also millions of different B cells, each capable of responding
to a specific antigen.
• B cells sit still and let antigens be brought to them
• stay put in lymph nodes, spleen or peyer’s patches
• Once activated, differentiate into plasma cells that secrete
antibodies
• Antibodies circulate in lymph and blood
• combines with epitope on antigen similarly to key fits a
specific lock
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Activation, Proliferation, and
Differentiation of B Cells
• During activation of a B cell, an antigen binds to antigen receptors on
the cell surface.
• B cell antigen receptors are chemically similar to the antibodies that
will eventually be secreted by their progeny.
• Some antigen is taken into the B cell, broken down into peptide
fragments and combined with the MHC-II self-antigen, and moved to
the B cell surface.
• Helper T cells recognize the antigen-MHC-II combination and deliver
the costimulation needed for B cell proliferation and differentiation.
• Some activated B cells become antibody-secretion plasma cells.
Others become memory B cells.
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Antibodies
• An antibody is a protein that can combine specifically with the
antigenic determinant on the antigen that triggered its production.
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Antibody Structure
• Antibodies consist of heavy and light chains
and variable and constant portions.
• Based on chemistry and structure, antibodies
are grouped into five principal classes each
with specific biological roles (IgG, IgA, IgM,
IgD, and IgE).
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Antibody Structure
• Glycoproteins called immunoglobulins
• 4 polypeptide chains -- 2 heavy & 2 light chains
• hinged midregion lets assume T or Y shape
• tips are variable regions -- rest is constant region
• 5 different classes based on constant region
• IgG, IgA, IgM, IgD and IgE
• tips form antigen binding sites
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Antibody Structures
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Antibody Actions
• Neutralization of antigen by blocking effects of toxins or
preventing its attachment to body cells
• Immobilize bacteria by attacking cilia/flagella
• Agglutinate & precipitate antigens by cross-linking them
causing clumping & precipitation
• Complement activation
• Enhancing phagocytosis through precipitation,
complement activation or opsonization (coating with
special substance)
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Monoclonal Antibodies
• Antibodies against a particular antigen can be
harvested from blood
• different antibodies will exist for the
different epitopes on that antigen
• Growing a clone of plasma cells to produce
identical antibodies difficult
• fused B cells with tumor cells that will grow
in culture producing a hybridoma
• antibodies produced called monoclonal
antibodies
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Antibodies: Clinical Applications
• Monoclonal antibodies are important in
measuring levels of a drug in a patient’s blood
• Diagnosis of pregnancy, allergies, and diseases
such as hepatitis, rabies, and some sexually
transmitted diseases.
• They have also been used in early detection of
cancer and assessment of extent of metastasis.
• They may be useful in preparing vaccines to
counteract transplant rejection, to treat
autoimmune diseases, and perhaps to treat AIDS.
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Role of the Complement
System in Immunity
• Complement system is made up of over 30 proteins.
• Many complement proteins are inactive and must be activated.
• Activated complement acts in a cascade that causes
• inflammation: dilation of arterioles, release of histamine &
increased permeability of capillaries
• opsonization/phagocytosis: protein binds to microbe making it
easier to phagocytize
• cytolysis: a complex of several proteins can form holes in microbe
membranes causing leakiness and cell rupture
• Complement may be activated by the classical pathway, alternative
pathway, and the lectin pathway
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Pathways of the
Complement System
• Classical
pathway
begins with
activation of
C1
• Alternate
pathway
begins with
activation of
C3
• Lead to
inflammation,
enhanced
phagocytosis
or microbe
bursting
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Immunological Memory
• Immunological memory is due to the presence of long-lived
antibodies and very long-lived lymphocytes that arise during
proliferation and differentiation of antigen-stimulated B and T cells.
• Immunization against certain microbes is possible because
memory B cells and memory T cells remain after the primary
response to an antigen.
• The secondary response (immunological memory) provides
protection should the same microbe enter the body again. There
is rapid proliferation of memory cells, resulting in a far greater
antibody titer (amount of antibody in serum) than during a
primary response.
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Immunological Memory
• Primary immune response
• first exposure to antigen
response is steady, slow
• memory cells may remain for
decades
• Secondary immune response
with 2nd exposure
• 1000’s of memory cells proliferate & differentiate into
plasma cells & cytotoxic T cells
• antibody titer is measure of memory (amount
serum antibody)
• recognition & removal occurs so quickly not even sick
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SELF-RECOGNIZITON AND SELF-TOLERANCE
• T cells undergo both positive and negative selection to
ensure that they can recognize self-MHC antigens (selfrecognition) and that they do not react to other selfproteins (tolerance).
• Negative selection involves both deletion and anergy.
• B cells develop tolerance
• Much research has centered on cancer immunology, the
study of ways to use the immune system for detecting,
monitoring, and treating cancer.
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Self-Recognition & Immunological
Tolerance
• T cells must learn to recognize self (its own MHC molecules ) & lack
reactivity to own proteins
• self-recognition & immunological tolerance
• T cells mature in thymus
• those can’t recognize self or react to it…
• destroyed by programmed cell death (apoptosis or deletion)
• inactivated (anergy) -- alive but unresponsive
• only 1 in 100 emerges immunocompetent T cell
• B cells similarly develop in bone marrow
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Development of
Self-Recognition &
Immunological
Tolerance
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