Cell-Cell Interactions, T-Independent Antigens, CD5 B Cells, Cytokines

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Cell-Cell Interactions, T-Independent Antigens,
CD5 B Cells, Cytokines
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T Cell-B Cell Interactions(hapten-carrier effect)

• Th cells recognize carrier, B cells recognize
  hapten
• Th and B cells cooperate by interacting
• Interactions are class II self-MHC restricted

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Uniqueness of B Cells

• Express both immunoglobulin (Ig) and class II MHC
  on cell surface
• Capable of producing antibody of same specificity
  as that of its surface Ig
• AND
• Capable of functioning as an antigen presenting
  cell

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Mechanism of Hapten-Carrier

• Hapten recognized by Ig receptor on B cell
• Hapten-carrier endocytosed
• Carrier processed and presented on class II MHC
  to Th cell
• Activated Th cell produces cytokines
• Cytokines enable B cell to be activated to
  produce anti-hapten antibodies

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Antigen
CD40
T helper cell
TCR
B cell
B cell
MHC II
1. Antigen presentation to Th cell
CD28
B7
2. B7 expressed
Immunoglobulin receptor
3. Th cell is activated and expresses CD40
ligand, Cytokines secreted
Cytokine receptor
4. Cytokine binds to cytokine receptor, CD40
ligand binds to CD40
CD40 ligand
T helper cell
B cell
5. B cell activated
Cytokine
6. B cells proliferate, differentiate, secrete Ig
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B cell takes up and presents antigen
Th cells are primed by antigen-presenting cell
B-T cell cooperation B cells receive signals from
T cells
B cells divide
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B Cells In Secondary Responses

• Memory cells created during primary response
• Have high-affinity Ig receptors
• Can therefore take up antigens at much lower
  concentrations than other antigen presenting
  cells that lack Ig antigen receptors

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Thymus-Independent Antigens

• Activate B cells at high concentrations
• Large polymeric molecules with repeating
  determinants
• Poorly degraded
• Some activate both immature and mature B cells
  some only mature cells
• Responses dominated by CD5 B cells

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CD5 B (B-1) Cells

• First B cells appearing in development
• Express surface IgM, little or no IgD
• Produce mainly IgM from unmutated or minimally
  mutated germline genes
• Antibodies are of low avidity and bind multiple
  different antigens (polyreactive)
• Contribute most of the IgM in adult serum

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CD5 B Cells (continued)

• Do not develop into memory cells
• Are self-renewing
• Reside in peripheral tissues
• Predominant lymphocyte in peritoneal cavity

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CD5 B Cells and Conventional B Cells
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Tumors of B Cells
Tumor Equivalent normal cell
Location
Chronic lymphocytic leukemia
CD5 B-1 B cell
Blood
Lymphoid progenitor
Acute lymphoblastic leukemia
Bone marrow Blood
Pre-B cell leukemia
Pre-B cell
Periphery
Follicular center cell lymphoma Burkitts lymphoma
Mature B cell
B cell IgM secreting
Waldenstroms macroglobulinemia
Multiple myeloma
Plasma cell secreting various Ig isotypes
Bone marrow
Adapted from Immunobiology Janeway/Travers
Garland
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Cytokines

• Non-antibody proteins acting as mediators
  between cells, termed
• Monokines mononuclear phagocytes
• Lymphokines activated T cells, especially
  helper T cells
• Interleukins abbreviated IL with a number

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Properties of Cytokines

• Produced by cells involved in both natural and
  specific immunity
• Mediate and regulate immune responses
• Secretion brief and limited
  - not stored pre-formed
  - synthesis initiated by gene
  transcription - mRNA short-lived
  - cytokines produced as needed

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Properties of Cytokines(continued)

• Can be produced by many cell types and act on
  many cell types (pleiotropic)
• Can have similar actions (redundant)

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Properties of Cytokines (continued)

• 6. Can influence synthesis of other cytokines
• - produce cascades
  
• - enhance or suppress production of other
  
  cytokines
• - exert positive or negative regulatory
  mechanisms for immune responses
• Influence action of other cytokines - can be
  antagonistic, additive, synergistic

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Properties of Cytokines (continued)

• Bind to receptors with high affinity
• Cells responding to cytokine can be
• - same cell (autocrine)
• - nearby cell (paracrine)
• - distant cell by circulation (endocrine)
• Cellular responses to cytokines are slow, require
  new mRNA and protein synthesis

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Mediators and Regulators of Natural Immunity

• Tumor Necrosis Factor-alpha (TNF-a)
• Interleukin-1 (IL-1)
• Chemokines (Chemotactic cytokines)
• Type I Interferons (IFN-a and IFN-ß)
• Interleukin-12 (IL-12)
• Interleukin-10 (IL-10)

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Tumor Necrosis Factor (TNF-a)

• Produced by activated macrophages
• Most important mediator of acute inflammation in
  response to microbes, especially Gram-negative
  bacteria (LPS)
• Mediates recruitment of neutrophils and
  macrophages to site of inflammation
• Acts on hypothalamus to produce fever
• Promotes production of acute phase proteins

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Interleukin-1 (IL-1)

• Produced by activated macrophages
• Effects similar to those of TNF-a

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Chemokines

• Produced by many different leukocytes and tissue
  cells
• Large family of gt50 substances
• Recruit leukocytes to sites of infection
• Play a role in lymphocyte trafficking

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Type I Interferons (IFN-a and ß)

• IFN-a a family of many proteins produced by
  macrophages, IFN-ß a single protein produced by
  many cells
• Both IFNs inhibit viral replication
• Both increase expression of class I MHC
• Both activate NK cells

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Interleukin-12 (IL-12)

• Produced by activated macrophages and dendritic
  cells
• Stimulates production of IFN-?
• Induces differentiation of Th cells to become Th1
  cells
• Enhances cytolytic functions of cytotoxic T cells
  and NK cells
  

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Interleukin-10 (IL-10)

• Produced by activated macrophages, Th2 cells
• An inhibitory cytokine
• Inhibits cytokine production by activated
  macrophages
• Inhibits expression of class II MHC and
  costimulatory molecules on macrophages

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Mediators and Regulators of Specific Immunity

• Interleukin-2 (IL-2)
• Interleukin-4 (IL-4)
• Interleukin-5 (IL-5)
• Interleukin-10 (IL-10)
• Interferon-gamma (IFN-?)

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Interleukin-2 (IL-2)

• Produced by ThgtgtTc
• Main growth factor for T cells

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Autocrine Function of IL-2
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Interleukin-4 (IL-4)

• Produced by Th2 cells
• Stimulates Ig class switching to IgE isotype
• Stimulates development of Th2 cells from naïve Th
  cells
• Promotes growth of differentiated Th2 cells

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Interleukin-5 (IL-5)

• Produced by Th2 cells
• Promotes growth and differentiation of
  eosinophils
• Activates mature eosinophils
• IL-4 and IL-5 can work together Helminths
  opsonized with IgE can be killed by activated
  eosinophils

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Interleukin-10 (IL-10)

• Produced by activated macrophages, Th2 cells
• Inhibits production of IFN-? by Th1 cells needed
  to activate macrophages

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Interferon-gamma (IFN-?)

• Produced by Th cells gtgt Tc and NK cells
• Numerous functions in both natural and specific
  immunity

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Stimulators of Hematopoiesis
Colony-Stimulating Factors (CSF)

• Granulocyte-macrophage CSF (GM-CSF) promotes
  growth and differentiation of bone marrow
  progenitors
• Macrophage CSF (M-CSF) is involved in development
  and function of monocytes and macrophages
• Granulocyte CSF (G-CSF) stimulates production of
  polymorphonuclear leucocytes (PMN)

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Cytokines Regulate Ig Class Switching

• Fc region of antibodies determines effector
  function in different anatomical locations
• Class (isotype) switching produces class or
  subclass of antibody most effective in host
  defense
• Cytokines acting alone or in combination regulate
  class switching

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Cytokine Network

• Many cytokines have effects on many cells and
  organ systems in addition to functions in immune
  systems
• Referred to as the cytokine network

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Effects on Cells of Immune System
Activation of cells of immune system
Proliferation, Differentiation, Ig secretion and
selection
Proliferation, Differentiation, Cytokine productio
n
Cytokine production
IL1 IL2 IL4
IL1 IL2 IL4 IL5 IL6 IFN?
cytokines
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Cytokine Effects on Organ Systems
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Cytokine Effects on Various Cells