Study of the Immune System

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Study of the Immune System
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Now that we know all about microbes..

• What provokes us to fight against microbes?
• How do we know that they are foreign?
• What initiates the response?

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Introduction to Antigens

• 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

• Epitope
• antigenic determinant
• small molecular group that is recognized by
• Antibodies
• B cells
• T cells

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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
• 3 main lines of defense
• 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
• Stronger immune response
• produces protective antibodies and creates memory
  cells
• specific

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Physical or Anatomical Barriers First Line of
Defense

• Skin and mucous membranes
• outermost layer of skin
• few pathogens can penetrate if intact
• flushing effect of sweat glands
• mucous coat impedes attachment and entry of
  bacteria
• blinking and tear production
• stomach acid
• nasal hair traps larger particles
• Vaginal secretions

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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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Blood

• Plasma
• Serum - fluid portion
• complement proteins and antibodies
• Three types of formed elements
• Erythrocytes
• Platelets
• Leukocytes
• Divided into granulocytes and agranulocytes

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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 eukaryotic pathogens
• Basophils, mast cells
• 0.5
• constricted nuclei, dark blue granules
• release potent chemical mediators
• Lymphocytes
• 20-35
• large nucleus
• involved in specific immune responses
• B (humoral immunity)
• T cells (cell-mediated immunity)
• Monocytes, macrophages

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Innate Immunity

• Second line of defense

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Second Line of Defense

• cells and mechanisms that defend the host from
  infection by other organisms
• genetically-encoded to recognize
• common pathogenic features
• foreign substances
• 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
• cytokines
• stimulate an inflammatory response (nonspecific)
• promote the activity of B and T cells (specific)

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2. Functions of inflammation

• Mobilize and attract immune cells to site
• Set mechanisms to repair tissue damage
• Destroy microbes and block further invasion

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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
• helps prevent spread of infection
• Pain
• stimulation of nerve endings
• Possible loss of function

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Fever

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

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3. Phagocytosis

• nonspecific defense mechanism
• clear microbes from infected tissues
• capture and digestion of foreign particles

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Phagocytes

• 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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4. Interferon

• Type of cytokine
• 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
• proteins are activated
• work in concert to destroy bacteria and viruses

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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
• 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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Acquired Immunity Generates Two Responses to Most
Pathogens

• B lymphocytes
• (B cells)
• involved in producing antibodies against epitopes
• Humoral immune response
• T lymphocytes
• (T cells)
• provide resistance through lysis of infected or
  abnormal cells
• Cell-mediated immune response

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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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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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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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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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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)
• Autoimmunity
• abnormal responses to self Ag
• Immunodeficiency
• deficiency or loss of immunity
• Four types..

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Type Systems involved Examples
I Immediate Hypersensitivity IgE Mast cells Hay fever Asthma
II Antibody Mediated IgG Ab IgM Ab Blood group incompatability
III Immune Complex Mediated IgG Ab-mediated inflammation Arthritis Serum sickness
IV T-cell Mediated Delayed hypersensitivity Cytotoxic rxns Injection rxns Contact dermatitis Graft rxns
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1. Type I Hypersensitivity

• Two levels of severity
• Atopy
• any chronic local allergy
• Ex 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

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

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Treatment and Prevention

• General methods include
• Avoiding allergen
• Use drugs
• block the action of the lymphocytes, mast cells
• antihistamines
• Desensitization therapy
• injected allergens

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2. Type II Hypersensitivity

• 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

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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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3. 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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4. 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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Evasion of the Immune System by Pathogenic
Microorganisms
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Why develop a strategy for evasion?

• Pathogen evolution
• Microorganism capable of causing disease
• Must subvert host immune system
• Successful pathogens effective evasion

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Defenses against human host responses

• Antiphagocytic factors
• Glycocalyx / Capsules (Encapsulation)
• Host cell invasion
• Grow intracellularly
• Neighbor cell transfer
• Syncytium
• Latency
• Genetic changes
• Antigenic shift
• Antigenic drift

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Antiphagocytic Factors
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The Bacterial Surface Coating? Glycocalyx

• Coating of molecules external to the cell wall
• Functions
• attachment
• inhibits killing by WBCs

Talaro, 2008
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Capsules

• Formation correlates with pathogenicity
• Encapsulated cells protect against WBCs
• Chemicals similar to those in human body
• Negative charges on capsule and phagocyte surface
• Slippery
• Pseudopodia cannot grip them

Bauman, 2011
Some Killers Have Pretty Nice Capsules S.
pneumoniae K. pneumoniae H. influenzae P.
aeruginosa N. meningitidis C. neoformans
http//medicineworld.org/stories/lead/2-2009/how-a
-deadly-fungus-evades-the-human-immune-system.html
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Streptococcus pyogenes

• GAS
• Most serious streptococcal pathogen
• Many surface antigens that enable virulence and
  evasion

Talaro, 2008
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S. pyogenes. Theres an app for
that
Capsule made of hyaluronic acid (HA) Chemically masked from HA in human tissues
M-protein Makes surface projections that resist phagocytosis
C-carbohydrates Protect bacterium from being dissolved by lysozyme
C5a protease Catalyzes cleavage of C5a protein (hinders C-associated aspects neutrophil response)
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Host Cell Invasion
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Survive inside phagocytes after ingestion

• Ingested by alveolar phagocytes
• Prevent fusion with lysosomes
• Multiply intracellularly
• After cell death, attract more phagocytes and
  continue cycle
• Mycobacterium

Bauman, 2011
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Neighboring cell transfer

• Can escape out of phagosomes
• Transfer to neighbor cells w/o leaving host cell
• Not exposed to Ab
• Listeria monocytogenes

Pommerville, 2007
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Syncytium

• Induces cells to fuse
• Multinucleate giant cell
• Allows pathogen to move from cell to cell
• HIV
• RSV
• Paramyxoviruses

Talaro, 2008
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Latency

• Pathogen remains inactive for period of time
• Reactivate at later date
• Herpes

Bauman, 2011
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Genetic Changes
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Viruses

• Glycoprotein spikes
• Adherence
• Recognized by host immune system
• Influenza A B
• Contains two types of spikes
• Hemagglutin (HA)
• Neuraminidase (NA)

Pommerville, 2007
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Genetic changes of viruses

• Antigenic drift
• Mutation in spikes
• Change their aa composition
• Small changes
• Single strain
• Antigenic shift
• Shift of gene strand with one from another host
• Human, pig, birds, etc.
• Abrupt, major change
• Reorganization of strains
• H1N1

Bauman, 2011