Immunology Natural Defenses

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Immunology-- Natural Defenses

• Mhairi Sutherland

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Outline

• Components of whole blood
• Blood cells
• Differentiation
• Function
• Immune system
• Innate
• Adaptive

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Components of whole blood

• Serum vs. Plasma
• Serum cell-free liquid, minus the clotting
  factors
• Plasma cell-free liquid with clotting factors in
  solution (must use an anticoagulant)

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Blood cells

• Red blood cells
• Chickens are nucleated mammals are not
  nucleated.
• White blood cells
• Platelets

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Blood cell differentiation
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The distribution of lymphoid tissues in the
body Lymphocytes arise in the stem cells in the
bone marrow and then differentiate in the bone
marrow (B cells) or thymus (T cells). T and B
cells migrate via the peripheral blood to the
peripheral/secondary lymphoid organs lymph
nodes, spleen, addendix, Peyers patch
etc. Lymphocytes become activated by antigen in
these secondary lymphoid tissues (and lymphocytes
will recirculate between the blood and these
organs until they encounter antigen) The afferent
lymphatic vessels carry APC cells from infected
tissues to the lymph nodes where they activate T
cells Activated T cells (after they have
undergone proliferation and differentiation)
leave via the efferent lymphatic vessels
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White blood cells (leukocytes)

• Granulocytes
• Neutrophils
• Eosinophils
• Basophils
• Lymphocytes
• B cells
• T cells (many types)
• NK cells
• Monocytes/Macrophages
• Dendritic cells

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Divisions of leukocytes

• Granulocytes
• Neutrophils
• Band cells
• Eosinophils
• Basophils (segmented or not)

• Mononuclear cells
• Lymphocytes (many types)
• Monocytes
• Dendritic cells

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Immune system cells

• Innate immunity
• Granulocytes (i.e. neutrophils)
• Macrophages
• Dendritic cells
• Natural killer (NK) cells

• Adaptive immunity
• Lymphocyte
• B cells
• T cells
• Cytotoxic T cells (CTLs)
• Helper T cells (Th)
• Memory cells

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Neutrophils

• Granulocyte
• Phagocytes
• Short life span (hours)
• Very important at clearing bacterial infections
• Cytoplasmic granules

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Eosinophils

• A granulocyte
• A cell-killing cells
• Orange granules contain toxic compounds
• Important in parasitic infections

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Basophils

• A granulocyte
• A cell-killing cells
• Blue granules contain toxic and inflammatory
  compounds
• Important in allergic reactions

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Lymphocytes

• Many types important in both humoral and
  cell-mediated immunity
• B-cells produce antibodies
• T- cells
• Cytotoxic T cells
• Helper T cells
• Memory cells
• NK cells

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Monocytes/Macrophage

• Monocyte is a young macrophage
• There are tissue-specific macrophages
• MØ process antigen, are phagocytes and produce
  cytokines (esp., IL1 IL6)

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Dendritic cells

• Found mainly in lymphoid tissue
• Function as antigen presenting cells (APC)
• Most potent stimulator of T-cell response

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Cytokines

• Low molecular weight, soluble proteins that are
  produced in response to an antigen and function
  as chemical messengers for regulating the innate
  and adaptive immune system
• Innate immune system
• Macrophages and Dendritic cells
• Tumor necrosis factor-alpha (TNF-?)
• Interleukin-1 (IL-1)
• Interleukin-12 (IL-12)
• Adaptive immune system
• T-lymphocytes
• Interleukin-2 (IL-2)
• Interleukin-4 (IL-4)

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Innate vs. adaptive immunity

• Innate immunity
• First line of defense (present in all individuals
  at all times)
• Immediate (0 4 hours)
• Non-specific
• Does not generate lasting protective immunity
• Adaptive immune response (late gt 96 hours)
• Is initiated if innate immune response is not
  adequate (gt 4 days)
• Antigen-specific immunity
• Generates lasting protective immunity (e.g.
  Antibodies, memory T-cells)

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Immune system divisions

• Innate immunity
• First line of defense
• Adaptive (acquired) immunity
• Takes time to develop
• Humoral immunity (antibodymediated specific
  immunity)
• Cell-mediated immunity (The aspect of the
  adaptive immune response where antigen-specific T
  cell have a main role)

• Active immunity
• Passive or maternal immunity
• Injection of Immunoglobulin
• Absorption of maternal antibodies

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Innate immune system

• The first line of defense
• Penetration of the epithelial surface of the body
  by microorganism (e.g. bacteria)
• Engulfment of microorganism by macrophages,
  neutrophils, and dendritic cells
• Release of cytokines and chemokines
• Inflammation
• (Immunology animation Janeway)
• http//www.blink.biz/immunoanimations/

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Killing by granulocytes

• Macrophages and neutrophils recognize pathogen by
  means of cell-surface receptors
• Example mannose receptor, CD14 receptor,
  scavenger receptors, glucan receptor etc.
• Binding of MØ/neutrophils with pathogen leads to
  phagocytosis
• Bound pathogen is surrounded by phagocyte
  membrane
• Internalized (phagosome)
• Killing of pathogen (Phagolysosome)
• Oxidative burst (synthesis of hydrogen peroxide
  (H2O2)or free oxygen radicals)
• Acidification
• Antimicrobial peptides (e.g. defensins)
• Phagolysosome lysosome phagosome

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Phagocytosis
Mannose receptor
Lysosome
Phagosome
Scavenger receptor
LPS receptor (CD14)
Bacteria binding to macrophage receptors initiate
the release of cytokines and small lipid
mediators of inflammation
Phagolysosome
The macrophage expresses receptors for many
bacterial constituents
Macrophages engulf and digest bacteria to which
they bind
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Cell killing NK cells

• NK cells do not require prior immunization or
  activation
• They attach to target cells
• Cytotoxic granules are released onto surface of
  cell
• Effector proteins penetrate cell membrane and
  induce programmed cell death

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Inflammation
Inflammatory cells migrate into tissue, releasing
inflammatory mediators that cause pain
Bacteria trigger macrophages to release cytokines
and chemokines
Vasodilation and increased vascular premeability
cause redness, heat, and swelling
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Adaptive immune system

• Initiated by ingestion of pathogen by an immature
  dentritic cell
• Antigen-presenting cell (APC)
• Dendritic cells, macrophages, and B cells
• Migrate through lymph to the regional lymph nodes
• Interact with naive T lymphocytes (present
  antigen to activate T cells)
• Proliferation
• Differentiation
• (Show annimation Janeway (2001)
• IV (The immune response 8-2 Dentritic-cell
  migration

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Differentiation of APC
B cell
Dendritic cell
Macrophages
Antigen-presenting cells are distributed
differentially in the lymph node
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Lymphocytes (effector cells of the adaptive
immune system)

• Antigen receptors with single specificity (T and
  B cells)
• Gene re-arrangement
• T and B cells have 2 distinct recognition systems
  for detecting pathogens
• T cells - recognize intracellular pathogens (T
  cell receptors, TCR)
• B cells recognize extracellular pathogens
  (immunoglobins, BCR)
• Clonal selection
• Interaction of antigen and lymphocyte receptor
• Activation of lymphocyte
• Differentiation (progeny with identical
  specificity)

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Clonal selection
Removal of potentially self-reactive immature
lymphocytes by clonal deletion
Self antigen
Self antigen
Pool of naïve lymphocytes
Proliferation and differentiation of activated
specific lymphocytes to form a clone of effector
cells
Effector cells eliminate antigen
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Humoral immune response
V region At binding

• Cell-surface immunoglobulin receptors (BCR)
  detect extracellular pathogens
• Once activated, secrete immunoglobulins as
  soluble antibodies
• Antibodies
• Variable region (2 identical antigen-binding
  sites)
• Constant region (determines how antibody disposes
  of the pathogen once it is bound)

Fc region
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Production of antibodies
Pathogen is internalized and degraded
Plasma cells
B cell binds pathogen
TH1
B cells differentiate into antibody-secreting
plasma cells Produce antibodies against pathogen
Peptides from the pathogen are presented (MHC II)
to the T cell resulting in the activation of the
B cell
B cell proliferation
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Antibody classes

• IgM (pentimer)
• IgG
• IgA (Dimer)
• IgD
• IgE

Ab
Primary
Secondary
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Antibody interactions

• Antibodies can participate in host defenses in 3
  main ways
• Neutralization
• Ab bind and neutralize bacterial toxins, bacteria
  and virus particles preventing interaction with
  host cells
• Ingestion by macrophages
• Opsonization
• Allows recognition by phagocytes or NK cells
  (antibody-dependent cell mediated cytotoxicity,
  ADCC)
• Ingestion or killing
• Complement activation
• Activation of complement system
• Ingestion by phagocytes

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Antigen recognition by T-cells

• T cells detect presence of intracellular
  pathogens
• T cells receptors
• Peptide fragments
• Major histocompatibility complex (MHC)
• MHC I (cytotoxic T cells /CD8)
• MHC II (T helper (1 and 2)/ CD4)
• Cell death

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Antigen recognition by T-cells
TH2 cells recognize antigen presented by MHC II
and activates B cells
TH1 cells recognize antigen presented by MHC II
and activates macrophages
Cytotoxic T cells recognize antigen presented by
MHC I and kills the cell
Kills
Activates
MHC I
MHC II
Cytotoxic T cell
Virus-infected cell
TH1
Macrophage
Dead intracellular bacteria
Anti-toxin antibodies
Apoptotic cell
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Th1 and Th2 response
To
Th1
Th2
INF-?
IL-4 IL-10 IL-5 IL-6 IL-13
IL-2 TNF-?
NK
MØ
IL-8
B cell
Tc
PMN
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The end