Study of the Immune System

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Study of the Immune System
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Defense Mechanisms of the Host

• Immune system
• relies on a multilevel network of physical
  barriers, immunologically active cells, and a
  variety of chemicals
• Three main lines of defense
• First
• Physical barrier
• Second
• Defend the host from infection by other organisms
  
• Third
• Stronger immune response as well as immunological
  memory

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Defense Mechanisms of the Host

• first line of defense
• any barrier that blocks invasion at the portal of
  entry
• nonspecific
• second line of defense
• protective cells and fluids
• inflammation and phagocytosis
• nonspecific
• third line of defense
• acquired with exposure to foreign substance
• produces protective antibodies and creates memory
  cells
• specific

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Physical or Anatomical Barriers First Line of
Defense

• Skin and mucous membranes of respiratory,
  urogenital, eyes and digestive tracts
• outermost layer of skin is composed of epithelial
  cells compacted, cemented together and
  impregnated with keratin
• few pathogens can penetrate if intact
• flushing effect of sweat glands
• damaged cells are rapidly replaced
• mucous coat impedes attachment and entry of
  bacteria
• blinking and tear production
• stomach acid
• nasal hair traps larger particles

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Nonspecific Chemical Defenses

• Sebaceous secretions
• Lysozyme
• enzyme that hydrolyzes the cell wall of bacteria
• High lactic acid and electrolyte concentration in
  sweat
• Skins acidic pH
• Hydrochloric acid in stomach
• Digestive juices and bile of intestines
• Semen contains antimicrobial chemical
• Vagina has acidic pH

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Structure and Function of the Organs of Defense
and Immunity

• Immunology
• study of the bodys second and third lines of
  defense
• Functions of a healthy functioning immune system
• Constant surveillance of the body
• Recognition of foreign material
• Destruction of entities deemed to be foreign

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Immune System

• Large, complex, and diffuse network of cells and
  fluids that penetrate into every organ and tissue
• Four major subdivisions of immune system are
• Reticuloendothelial system (RES)
• Extracellular fluid (ECF)
• Bloodstream
• Lymphatic system

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1. Reticuloendothelial System (RES)

• Network of connective tissue fibers
• interconnects other cells
• meshes with the connective tissue network of
  surrounding organs
• Inhabited by phagocytic cells
• mononuclear phagocyte system
• macrophages ready to attack and ingest microbes
  that passed the first line of defense

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2. Extracellular Fluid

• Fluid not contained in cells
• Found in
• blood
• between cells
• lymph fluid

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3. Blood

• Whole blood consists
• Plasma
• 92 water, metabolic proteins, globulins,
  clotting factors, hormones
• Platelets
• Blood cells
• red blood cells
• white blood cells
• Serum
• liquid portion of the blood after a clot has
  formed
• minus clotting factors

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White Blood Cells

• Leukocytes
• Housekeeping and defense
• Scavenge dead or worn-out cells
• Disease organisms
• Squeeze out of blood vessels and enter tissues
• Develop from stem cells in bone marrow
• Granulocytes
• Neutrophils
• Eosinophils
• Basophils
• Agranulocytes
• Monocytes
• Macrophages
• Lymphocytes
• B-cells
• T-cells

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White Blood Cells

• Neutrophils
• 55-90
• lobed nuclei with lavender granules
• phagocytes
• Eosinophils
• 1-3
• orange granules and bilobed nucleus
• destroy eucaryotic pathogens
• Basophils, mast cells
• 0.5
• constricted nuclei, dark blue granules
• release potent chemical mediators
• Lymphocytes
• 20-35
• large nucleus
• involved in the specific immune response
• B (humoral immunity)
• T cells (cell-mediated immunity)
• Monocytes, macrophages

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4. Lymphatic System

• Provides a route for return of extracellular
  fluid to the circulatory system
• Acts as a drain-off system for the inflammatory
  response
• Renders surveillance, recognition, and protection
  against foreign material

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Lymphatic System

• Lymphatic fluid
• Lymphatic vessels
• Lymphoid Organs and Tissues
• Thymus
• Lymph nodes
• Spleen

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Innate Immunity

• Second line of defense

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Second Line of Defense

• Humoral
• cells and mechanisms that defend the host from
  infection by other organisms
• does not confer long-lasting or protective
  immunity to the host
• provide immediate defense against infection

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Actions of the Second Line of Defense

• Recognition
• Inflammation
• Phagocytosis
• Interferon
• Complement

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1. Recognition

• Toll-like receptors (TLRs)
• protein receptors within cell membrane of
  macrophages
• recognize structurally conserved molecules
  derived from microbes
• Detect foreign molecules and signal the
  macrophage to produce chemicals which
• stimulate an inflammatory response (nonspecific)
• promote the activity of B and T cells (specific)

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2. Inflammatory Response

• Classic signs and symptoms characterized by
• Redness
• increased circulation and vasodilation in injured
  tissue
• Warmth
• heat given off by the increased blood flow
• Swelling
• increased fluid escaping into the tissue as blood
  vessels dilate
• edema
• WBCs, microbes, debris and fluid collect to form
  pus
• helping prevent spread of infection
• Pain
• stimulation of nerve endings
• Possible loss of function

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Insert figure 14.13 Events in inflammation
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Unique Characteristics of Leukocytes

• Diapedesis
• migration of cells out of blood vessels into the
  tissues
• Chemotaxis
• migration in response to specific chemicals at
  the site of injury or infection

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Fever

• Initiated by circulating pyrogens
• reset the hypothalamus to increase body
  temperature
• signals muscles to increase heat production and
  vasoconstriction
• exogenous pyrogens
• endogenous pyrogens
• Benefits of fever
• inhibits multiplication of temperature-sensitive
  microorganisms
• impedes nutrition of bacteria
• increases metabolism and stimulates immune
  reactions

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3. Phagocytes and Phagocytosis

• 3 main types of phagocytes
• Neutrophils
• general-purpose
• react early to bacteria and other foreign
  materials, and to damaged tissue
• Eosinophils
• attracted to sites of parasitic infections and
  antigen-antibody reactions
• Macrophages
• derived from monocytes
• scavenge and process foreign substances to
  prepare them for reactions with B and T
  lymphocytes

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Activities of Phagocytosis

• To survey tissue compartments and discover
  microbes, particulate matter and dead or injured
  cells
• To ingest and eliminate these materials
• To extract immunogenic information from foreign
  matter

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4. Interferon

• Small protein produced by certain white blood
  cells and tissue cells
• alpha interferon
• lymphocytes and macrophages
• beta interferon
• fibroblasts and epithelial cells
• gamma interferon
• T cells

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Interferon

• Produced in response to viruses, RNA, immune
  products, and various antigens
• Bind to cell surfaces and induce expression of
  antiviral proteins
• Inhibit expression of cancer genes

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5. Complement (C)

• Consists of 26 blood proteins
• work in concert to destroy bacteria and viruses
• Complement proteins are activated by cleavage
• Classical pathway
• activated by the presence of antibody bound to
  microorganism
• Alternative pathway
• begins when complement proteins bind to normal
  cell wall and surface components of microorganisms

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Adaptive Immunity

• Third line of defense

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Adaptive Line of Defense

• acquired immunity
• stronger immune response as well as immunological
  memory
• Production of specific antibodies
• dual system of B and T lymphocytes
• in response to an encounter with a foreign
  molecule
• antigen
• allows for the generation of responses that are
  tailored to specific pathogens or
  pathogen-infected cells

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Specific Immunity Adaptive Line of Defense

• Two features that characterize specific immunity
• specificity
• antibodies produced
• function only against the antigen that they were
  produced in response to
• memory
• lymphocytes are programmed to recall their
  first encounter with an antigen
• respond rapidly to subsequent encounters

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Classifying Immunities

• Active immunity
• person is challenged with antigen that stimulates
  production of antibodies
• creates memory, takes time and is lasting
• Passive immunity
• preformed antibodies are donated to an individual
• does not create memory, acts immediately, and is
  short term
• Natural immunity
• acquired as part of normal life experiences
• Artificial immunity
• acquired through a medical procedure such as a
  vaccine

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Combinations of acquired immunity

• Natural active immunity
• acquired upon infection and recovery
• Natural passive immunity
• acquired by a child through placenta and breast
  milk
• Artificial active immunity
• acquired through inoculation with a selected Ag
• Artificial passive immunity
• administration of immune serum or globulin

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Development of the Immune Response System

• Cell receptors or markers confer specificity and
  identity of a cell
• Major functions of receptors are
• perceive and attach to nonself or foreign
  molecules
• promote the recognition of self molecules
• receive and transmit chemical messages among
  other cells of the system
• aid in cellular development

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Introduction to Antigens / Immunogens

• Antigen (Ag)
• Any substance that stimulates an immune response
• Requirements for antigenicity
• foreignness (recognition of nonself)
• large size
• complexity

most antigenic
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Characteristics of Antigens

• Perceived as foreign
• not normal constituent of the body
• Epitope
• antigenic determinant
• small molecular group that is recognized by
• Antibodies
• B cells
• T cells

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Special Categories of Antigens

• Alloantigens
• cell surface markers of one individual that are
  antigens to another of that same species
• Superantigens
• potent T cell stimulators
• provoke an overwhelming response
• Allergen
• antigen that provokes allergy
• Autoantigens
• molecules on self tissues for which tolerance is
  inadequate

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Cooperation in Immune Reactions to Antigen

• antigen-presenting cells (APCs)
• large phagocytes that process T-cell-dependent
  antigens
• alters the antigen and attaches it to its MHC
  receptor for presentation to lymphocytes

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Major Histocompatibility Complex (MHC)

• Receptors found on all cells except RBCs
• Also known as human leukocyte antigen (HLA)
• Plays a role in
• recognition of self by the immune system
• rejection of foreign tissue
• Two classes
• Class I
• Class II

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Lymphocyte Receptors

• Lymphocytes role in surveillance and recognition
  is a function of their receptors
• B-cell receptors
• bind free antigens
• T-cell receptors
• bind processed antigens

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Lymphocytes

• In the bone marrow, lymphocytic stem cells
  differentiate into either T or B cells
• B cells stay in the bone marrow
• T cells migrate to the thymus
• Both T and B cells migrate to secondary lymphoid
  tissue

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Antibody Structure and Functions

• Immunoglobulins
• Large Y-shaped protein
• Contains 2 identical fragments (Fab) with ends
  that bind to specific antigen
• Fc binds to various cells and molecules of the
  immune system

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Classes of Antibodies

• IgD
• important in B cell activation
• IgM
• released by plasma cells during the primary
  immune response
• IgG
• crosses the placenta and confers passive immunity
• IgA
• helps prevent attachment of pathogens to
  epithelial cell surfaces
• IgE
• causing histamine release when activated

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B-cell Activation and Antibody Production

• Antibodies in Serum (Antiserum)
• The 1st introduction of an Ag to the immune
  system
• produces a primary response
• gradual increase in Ab titer
• The 2nd contact with the same Ag
• produces a secondary, or anamnestic, response
• due to memory cells produced during the initial
  response

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T Cells Cell Mediated Immunity

• Cell mediated immunity requires the direct
  involvement of T lymphocytes
• T cells act directly against Ag and foreign cells
  when presented in association with an MHC carrier
• T cells secrete cytokines that act on other cells
• Sensitized T cells proliferate into long-lasting
  memory T cells

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Types of T cells

• T helper cells (CD4 or TH)
• regulate immune reaction to antigens
• involved in activating macrophages and improving
  opsonization
• differentiate into T helper 1 (TH1) cells or T
  helper 2 (TH2) cells
• Cytotoxic T cells (CD8 or TC)
• destroy foreign or abnormal cells by secreting
  perforins
• lyse cells
• Natural killer cells
• lack specificity
• circulate through the spleen, blood, and lungs

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Antibody-Antigen Interactions

• Opsonization
• process of coating microorganisms or other
  particles with specific antibodies
• more readily recognized by phagocytes
• Agglutination
• Ab aggregation
• cross-linking cells or particles into large
  clumps
• Neutralization
• Abs fill the surface receptors on a virus or the
  active site on a microbial enzyme
• prevent it from attaching
• Antitoxins
• special type of Ab that neutralize a bacterial
  exotoxin

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Primary and Secondary Responses to Antigens

• Primary response
• after first exposure to an Ag
• immune system produces IgM and a gradual increase
  in Ab titer (concentration of antibodies) with
  the production of IgG
• Secondary response
• after second contact with the same Ag
• immune system produces a more rapid, stronger
  response due to memory cells
• anamnestic response

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Immunization

• Passive immunization
• patient is given preformed antibodies
• form of immunotherapy
• Active immunization
• patient is vaccinated with a microbe or its
  antigens
• providing a form of advance protection

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Immunotherapy Preformed Ab

• Immune serum globulin
• gamma globulin
• contains immunoglobulin extracted from the pooled
  blood of at least 1,000 human donors
• Treatment of choice for preventing measles,
  hepatitis A and replacing Ab in the immune
  deficient
• Treatment is injected intramuscularly and lasts
  2-3 months

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Immunotherapy Preformed Ab

• Specific immune globulin (SIG)
• prepared from convalescent patients in a
  hyperimmune state
• Contains high titer of specific Ab
• sera produced in horses are available for
  diphtheria, botulism, spider and snake bites

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Vaccines

• Type of active immunity
• Provide an antigenic stimulus that does not cause
  disease
• Most vaccine preparations are based on one of the
  following antigen preparations
• Killed whole cells or inactivated viruses
• Live, attenuated cells or viruses
• Antigenic molecules derived from bacterial cells
  or viruses
• Genetically engineered microbes or microbial
  antigens

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Disorders in Immunity
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Immunopathology

• Allergy, hypersensitivity
• misdirected expression of immune responses to an
  allergen (antigen)
• Involves the same types of immune reactions as
  those at work in protective immunities
• Autoimmunity
• abnormal responses to self Ag
• Immunodeficiency
• deficiency or loss of immunity
• Four types..

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Type I Hypersensitivity

• Two levels of severity
• Atopy
• any chronic local allergy such as hay fever or
  asthma
• Anaphylaxis
• a systemic, often explosive reaction that
  involves airway obstruction and circulatory
  collapse

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Contact With Allergens

• Generalized predisposition to allergies is
  familial
• not to a specific allergy
• Allergy can be affected by age, infection, and
  geographic area
• Atopic allergies may be lifelong or may be
  outgrown
• may also develop later in life

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Mechanism of Type I Allergy

• Develop in stages
• Sensitizing dose
• on first contact with allergen
• specific B cells form IgE which attach to mast
  cells and basophils
• generally no signs or symptoms
• Provocative dose
• subsequent exposure with the same allergen binds
  to the IgE-mast cell complex

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Chemical Mediators and Allergic Symptoms

• Act alone or in combination
• General targets include
• skin, upper respiratory tract, GI tract, and
  conjunctiva
• Responses
• rashes, itching, redness, rhinitis, sneezing,
  diarrhea, shedding tears
• Systemic targets
• smooth muscles, mucous glands, and nervous tissue
• Responses
• vascular dilation and constriction resulting in
  change in blood pressure and respiration

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Specific Diseases

• Atopic disease
• hay fever, rhinitis seasonal, inhaled plant
  pollen or mold
• asthma
• Eczema
• Food allergy
• intestinal portal can affect skin and respiratory
  tract
• vomiting, diarrhea, abdominal pain
• possibly severe
• eczema, hives, rhinitis, asthma, occasionally
  anaphylaxis
• Drug allergy
• common side effect of treatment
• reaction from mild atopy to fatal anaphylaxis

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Anaphylaxis

• Sudden respiratory and circulatory disruption
  that can be fatal in a few minutes
• Allergen and route are variable
• Bee stings, antibiotics or serum injection

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Diagnosis of Allergy

• Important to determine if a person is
  experiencing allergy or infection
• Skin testing

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Treatment and Prevention

• General methods include
• Avoiding allergen
• Use drugs that block the action of the
  lymphocytes, mast cells, chemical mediators
• antihistamines
• Desensitization therapy
• injected allergens
• may stimulate the formation of high-levels of
  allergen-specific IgG that act to block IgE

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Type II Hypersensitivity

• Reactions that lyse foreign cells
• Involve antibodies and complement
• leading to lysis of foreign cells
• Transfusion reactions
• ABO blood groups
• Rh factor
• hemolytic disease of the newborn

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Human ABO Antigens and Blood Types

• Genetically determined RBC glycoproteins
• inherited as 2 alleles of A, B, or O
• 4 blood types A, B, AB, or O
• type O persons lack both A and B antigens
• Tissues other than RBCs also carry A and B
  antigens

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Antibodies Against A and B Antigens

• Serum contains pre-formed antibodies that react
  with blood of another antigenic
  type-agglutination
• Type A
• contains Abs that react against B antigens
• Type B
• contains Abs that react against A antigens
• Type O
• contains Abs that react against A and B antigens
• Type AB
• contains no Abs that react against A or B
  antigens

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Rh Factor

• Rhesus factor
• RBC antigen
• type results from combination of 2 alleles
• Either there or not
• Rh-
• Rh
• Inheriting one dominant gene results in the
  production of the Rh antigen
• no pre-formed antibodies exist
• must have exposure

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Rh Factor and Hemolytic Disease of the Newborn

• Hemolytic Disease of the Newborn (HDN)
• Rh- mother forms antibodies to her Rh fetus
• requires subsequent exposure to the antigen to be
  hemolytic
• Prevention
• use of passive immunization with antibodies
  against the Rh antigen
• prevents sensitization of mother

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Type III Hypersensitivity

• Large quantity of foreign Ag stimulates Ab
• produce small, soluble Ag-Ab complexes
• Immune complexes become trapped in tissues and
  incite a damaging inflammatory response
• arthus reaction
• local reaction to series of injected Ag to same
  body site
• serum sickness
• systemic disease resulting from repeated
  injections of foreign proteins

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Type IV Hypersensitivity

• T cell-mediated
• Delayed response to Ag involving activation of
  and damage by T cells
• Delayed allergic response
• skin response to allergens
• tuberculin skin test, contact dermititis from
  plants, metals, cosmetics
• Graft rejection
• reaction of cytotoxic T cells directed against
  foreign cells of a grafted tissue
• MHC markers of donor tissue (graft) are different
• host may reject graft graft may reject host

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Immunodeficiency Diseases

• Components of the immune response system are
  absent
• B and T cells, phagocytes, and complement
• 2 general categories
• primary immunodeficiency
• Congenital
• usually genetic errors
• T-cell or B-cell defect
• severe combined immunodeficiency (SCID)
• secondary diseases
• acquired after birth
• caused by natural or artificial agents
• Chemotherapy
• AIDS

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Diagnosing Infections
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Survey of Microbial Disease

• Methods of identifying unknown microbes fall into
  three categories
• Phenotypic
• observable microscopic and macroscopic
  characteristics
• Genotypic
• genetic make-up
• Immunological
• Serology
• antibody-antigen reactions

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1. Phenotypic Methods

• Microscopic morphology
• fresh or stained microorganisms from specimen
• shape, size, stain reaction, cell structures
• Macroscopic morphology
• colony appearance
• texture, size, shape, pigment, growth
  requirements
• Physiological / biochemical characteristics
• detection of presence or absence of particular
  enzymes or metabolic pathways
• Chemical analysis
• analyze specific chemical composition
• cell wall peptides, cell membrane lipids

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2. Genotypic Methods

• Assess genetic make-up
• Culture is not necessary
• Precise, automated methods, quick results
• DNA analysis
• Assess the proportion of G C nucleotides
  relative to A T content
• Determine DNA or ribosomal RNA sequences
• using probes and polymerase chain reactions

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3. Immunological Methods

• Specific antibodies used to detect antigens
• Serology
• attempts to detect signs of infection in a
  patient by identifying specific antibodies in
  vitro
• Visible reactions include
• Precipitates
• color changes
• release of radioactivity
• Tests can be used to identify and to determine
  the amount of antibody in serum
• titer

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Specimen Collection and Laboratory Methods

• Sampling body sites or fluids for suspected
  infectious agent
• Results depend on specimen collection, handling,
  transport and storage
• Aseptic procedures should be used

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Agglutination and Precipitation Reactions

• Agglutination testing
• antibody cross links whole-cell antigens
• forms complexes that settle out and form visible
  clumps
• blood typing, some bacterial and viral diseases
• Precipitation tests
• soluble antigen is made insoluble by an antibody
• syphilis
• Western blot
• Immunoelectrophoresis
• separates antigens into bands
• HIV

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Immunoassays

• Extremely sensitive to detect trace antigens and
  antibodies
• Radioimmunoassay (RIA)
• antigens and antibodies labeled with radioactive
  isotopes
• Enzyme-linked immunosorbent assay (ELISA)
• enzyme-antibody complex produces a colored
  product when an enzyme-substrate reaction occurs

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In vivo Testing

• Antigens introduced directly into the body
• determine the presence or absence of antibodies
• tuberculin skin test
• allergy testing

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Cancer and the Immune system
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The Immune System and Cancer

• Overgrowth of abnormal tissue arises
• due to malfunction of immune surveillance
• Tumors
• benign (nonspreading)
• self-contained
• malignant
• spreads from tissue of origin to other sites
• Appear to have genetic alteration that transforms
  a normal cell
• Possible causes include
• errors in mitosis, genetic damage, activation of
  oncogenes, or retroviruses

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Tracheal Tumor
Scleral Tumor
Breast Cancer
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Interrelationship Between Genes and Cancer

• Cancer cell often have damaged chromosomes
• A specific alteration in a gene can lead to
  cancer
• Predisposition for some cancers is inherited
• Rates of cancer are highest in individuals who
  cannot repair damaged DNA
• Mutagenic agents cause cancer
• Cells contain genes that can be transformed to
  cancer-causing oncogenes
• Tumor-supressor genes exist in the normal genome

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Role of Viruses in Cancer

• Some viruses carry oncogenes
• whose products cause transformation of host cells
  into cancer cells
• Viral genome may be inserted into regulatory
  sites
• Human papillomavirus cervical cancer
• Epstein-Barr virus Burkitts lymphoma

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Burkitts Lymphoma
Abnormal Cervical Cells
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Function of Immune System in Cancer

• Cells with cancer-causing potential arise
  constantly in the body
• but the immune system normally discovers and
  destroys them
• Cell-mediated immunity, TC, NK macrophages,
  antibodies
• Immune system fails in cancer
• may not be immunogenic enough
• may retain self-markers and not be targeted
• Maybe a slight or transient failure allows cancer
  to develop