Immunology for Surgeons: The Basics 101 - PowerPoint PPT Presentation


Title: Immunology for Surgeons: The Basics 101


1
Immunology for SurgeonsThe Basics 101
  • Principles of Surgery
  • Jeff Warren, MD, FRCSC
  • October 19, 2010

2
Objectives
  • The Players -- T-cells and B-cells
  • Immunoglobulins
  • Antigen Recognition
  • Phagocytosis
  • Mediators and Complement
  • Immunization
  • Hypersensitivity Reactions
  • Transplant Immunology Basics

3
Immunology
  • Conceptually challenging
  • Complex series of reactions triggered by
    immunogens
  • Compartmentalize to simplify, but actual events
    at molecular and cellular level are
    boundary-less and only partially understood
  • More we learn the less we know

4
Introduction
  • Innate vs Adaptive immunity
  • Self vs non-self vs altered self
  • Three phases of immune response
  • Cognitive phase
  • Activation phase
  • Effector phase
  • Primary and Secondary responses
  • Lymphoid organs primary/secondary
  • Humoral and Cell-mediated responses

5
(No Transcript)
6
Lymphocytes
  • T-cells
  • Thymus
  • CD3
  • CD4 -- Helper and DTH
  • CD8 -- cytotoxic and suppressor
  • NK Cells
  • Non B-cell, non T-cell lymphocytes
  • IL-2 --gt LAK cells
  • B-cells
  • Bursa fasicularis (birds)
  • Fetal liver and bone marrow
  • CD19/CD20
  • --gt plasma cells --gt Ab production
  • APCs

7
B-cell--gtPlasma cell--gt Ig production
  • IgA secretory, dimer
  • IgG most abundant, 2o response, opsonin, C
    binding
  • IgM 1o repsonse, Cbinding, pentamer
  • IgE mast cells and basophils, Type I
    hypersensitivity
  • IgD small quantities, ??

8
Immunoglobulin
9
Immunoglobulin -- Fab and Fc
10
Antigen Recognition
  • Immunogen can stimulate immune response
  • Antigen recognized by immune system
  • Immunogenicity
  • Complexity proteins gt CHO gt nucleic acids gt
    lipids
  • Size usually gt 5000 Da
  • Foreigness xenogeneic gt allogeneic gt syngeneic gt
    autologous

11
(No Transcript)
12
MHC
  • HLA in humans on chromosome 6
  • With Ag --gt Self vs non-self vs altered self
  • Class I A and B regions, on all nucleated cells
    and platelets, recognized CD8 T-cells --gt lysis
  • Class II D region, on APCs, recognized CD4
    helper T-cells --gt activation and proliferation
    of helper T-cells (--gt cytokines), cytotoxic
    T-cells (--gt lysis), and B-cells (--gt plasma
    cells --gt Ab)
  • Class III Complement

13
MHC Class I and Class II
14
Antigen Presenting Cells (APC)
  • Capable of activating CD4 T-cells
  • Recognition usually occurs in 2o lymphoid organs
    spleen, lymph nodes, GALT, Peyers patches
  • Monocyte and macrophage lineage
  • Dendritic cells (skin)
  • Kupfer cells (liver)
  • Glial cells (CNS)
  • B-cell subset

15
Any nucleated cell
APC
16
Ag Recognition
but not enough need Co-Stimulatory Signal 2
17
(No Transcript)
18
T-cell receptor
19
Phagocytosis
  • Mononuclear (monocytes) vs polymorphonuclear
    (neutrophils)
  • Engulfed foreign particle --gt phagosome
    lysosome --gt phagolysosome
  • Oxygen-dependent mechanisms
  • Myeloperoxidase, superoxide anion, H2O2, singlet
    O2, OH- radicals
  • Oxygen-independent mechanisms
  • Cationic proteins, lysozymes, proteinases

20
Phases of Phagocytosis
21
Complement
  • Component proteins mediators of inflammation and
    cell lysis
  • Numbered according to chronological discovery,
    not necessarily order of activity in cascade
    reactions
  • Traditionally divided into Classic, Alternative,
    and Lectin pathways
  • Small stimulus --gt amplified effect
  • Initiated by Ag-Ab immune complexes and microbial
    products
  • C3a and C5a are chemotactic
  • Some components are anaphylatoxins --gt mast cell
    degranulation, smooth muscle contraction,
    increased vascular permeability
  • End-product is C5b-8 MAC

22
Complicated!
23
simplified.
24
Cytokines
  • Greek -cyto, cell and -kinos, movement
  • Large group of cell-signaling molecules
  • proteins, glycoproteins, peptides
  • Grossly include interleukins, lymphokines, and
    chemokines redundancy and pleitropism make this
    classification obsolete today.

25
Interleukins
  • IL-1 pro-inflammatory and wound healing
    macrophages, neutrophils, fibroblasts, NK cells,
    endothelial cells, vascular smooth muscle fever,
    vasodilation, hypotension, collagen deposition,
    T-and B-cell proliferation, IL-2 and IL-2R
    up-regulation
  • IL-2 T-cell growth factor in response to IL-1
    NK cells and activated T-cells (auto- and
    para-crine) up regulates many other cytokines,
    namely TNF and CSF deficiency --gt SCID
  • IL-3 hematopoetic growth factor
  • IL-4 inhibits macrophages
  • IL-6 inhibits TNF
  • IL-8 neutrophil chemokine
  • IL-10 inhibits monocytes/macrophages and
    anti-inflammatory

IL-4, 6, and 10 are inhibitory cytokines
26
IL-2
27
Tumor necrosis factor (TNF)
  • Hemmorhagic necrosis in methycholanthrine
    -induced sarcomas in mice
  • TNF-alpha 1o monocytes/macrophages, but NK cells
    and neutrophils also
  • Stimulates neutrophils
  • Endothelial cells --gt IL-1
  • Procoagulant, increased vascular permeability
  • Catabolism and cachexia in malignant disease
  • Apoptotic mediator
  • Gram negative shock --gt endotoxin --gt TNF-alpha
    --gt hypotension DIC
  • TNF-ß T- and B-cells
  • Wound healing, PG and collagen deposition
  • Cytolytic and cytostatic for many tumor cell lines

28
(No Transcript)
29
Interferons
  • Glycoproteins
  • Inhibit viral proliferation via signaling
    pathways and translation machinery inhibition
  • INF-alpha -- macrophages
  • INF-beta -- epithelial cells, fibroblasts,
    macrophages
  • INF-gamma -- T-cells and NK cells
  • Antiproliferative
  • Can induce differentiation
  • Stimulate or inhibit a variety of cells to
    release other cytokines

30
Chemokines
  • Low molecular weight cytokines that serve as
    chemoattractants
  • 4 cysteine molecules linke by disulfide bonds
  • C-C or C-X-C and their receptors
  • IL-8 is actually a chemokine that binds CXCR1 or
    CXCR2 on neutrophils
  • 100s of chemokines identified and the catalogue
    continues to grow!

31
(No Transcript)
32
(No Transcript)
33
Immunization
  • Active injection of intact attenuated organism
    or component. Recipient mounts an immune response
    with the goal being memory
  • DPT, MMR, pneumovax, HepB, vaccine, polio
    vaccines
  • Passive exogenous active component is given to
    recipient immediate but temporary immunity
  • Antitoxins C.tetani antitoxin
  • Immunoglobulin IgG to immundeficient recipient
  • Specific immune globulin RhoGAM (prevent
    sensitization to Rh Abs crossing placenta from
    Rh infant at delivery)

34
Who were these guys?
Dr. Albert Sabin
Dr. Jonas Salk
35
Hypersensitivity Reactions
  • Type I immediate hypersensitivity
  • IgE mediated --gt mast cells and basophils
  • Anaphylaxis, hay fever, food allergy
  • Type II cytotoxic reactions
  • IgG and/or IgM mediated preformed Abs
  • ABO and Rh incompatibility, myasthenia gravis,
    Graves disease, ITP
  • Type III immune complex mediated
  • Deposition of Ab-Ag complexes
  • PSGN, serum sickness, SLE, rheumatoid arthritis
  • Type IV DTH
  • Previously sensitized CD4 T-helper cells
  • Tuberculin skin test, contact dermatitis

36
Transplant Rejection
  • Hyperacute
  • Preformed Ab immediate in the OR
  • ABO incompatible or high titre donor specific HLA
    Class I Ab
  • Acute
  • T-cell mediated days to weeks
  • Treatment and prevention via T-cell depletion
    ATG or IL-2R blocker
  • Chronic (CAN)
  • Kidneys IF/TA
  • Immune and non-immune mechanisms
  • Difficult to predict, prevent, or belay

37
Alternative ANTIBODY vs CELLULAR rejection
38
THE END
  • Thank you and Good Luck!
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Immunology for Surgeons: The Basics 101

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Transcript and Presenter's Notes

Title: Immunology for Surgeons: The Basics 101


1
Immunology for SurgeonsThe Basics 101
  • Principles of Surgery
  • Jeff Warren, MD, FRCSC
  • October 19, 2010

2
Objectives
  • The Players -- T-cells and B-cells
  • Immunoglobulins
  • Antigen Recognition
  • Phagocytosis
  • Mediators and Complement
  • Immunization
  • Hypersensitivity Reactions
  • Transplant Immunology Basics

3
Immunology
  • Conceptually challenging
  • Complex series of reactions triggered by
    immunogens
  • Compartmentalize to simplify, but actual events
    at molecular and cellular level are
    boundary-less and only partially understood
  • More we learn the less we know

4
Introduction
  • Innate vs Adaptive immunity
  • Self vs non-self vs altered self
  • Three phases of immune response
  • Cognitive phase
  • Activation phase
  • Effector phase
  • Primary and Secondary responses
  • Lymphoid organs primary/secondary
  • Humoral and Cell-mediated responses

5
(No Transcript)
6
Lymphocytes
  • T-cells
  • Thymus
  • CD3
  • CD4 -- Helper and DTH
  • CD8 -- cytotoxic and suppressor
  • NK Cells
  • Non B-cell, non T-cell lymphocytes
  • IL-2 --gt LAK cells
  • B-cells
  • Bursa fasicularis (birds)
  • Fetal liver and bone marrow
  • CD19/CD20
  • --gt plasma cells --gt Ab production
  • APCs

7
B-cell--gtPlasma cell--gt Ig production
  • IgA secretory, dimer
  • IgG most abundant, 2o response, opsonin, C
    binding
  • IgM 1o repsonse, Cbinding, pentamer
  • IgE mast cells and basophils, Type I
    hypersensitivity
  • IgD small quantities, ??

8
Immunoglobulin
9
Immunoglobulin -- Fab and Fc
10
Antigen Recognition
  • Immunogen can stimulate immune response
  • Antigen recognized by immune system
  • Immunogenicity
  • Complexity proteins gt CHO gt nucleic acids gt
    lipids
  • Size usually gt 5000 Da
  • Foreigness xenogeneic gt allogeneic gt syngeneic gt
    autologous

11
(No Transcript)
12
MHC
  • HLA in humans on chromosome 6
  • With Ag --gt Self vs non-self vs altered self
  • Class I A and B regions, on all nucleated cells
    and platelets, recognized CD8 T-cells --gt lysis
  • Class II D region, on APCs, recognized CD4
    helper T-cells --gt activation and proliferation
    of helper T-cells (--gt cytokines), cytotoxic
    T-cells (--gt lysis), and B-cells (--gt plasma
    cells --gt Ab)
  • Class III Complement

13
MHC Class I and Class II
14
Antigen Presenting Cells (APC)
  • Capable of activating CD4 T-cells
  • Recognition usually occurs in 2o lymphoid organs
    spleen, lymph nodes, GALT, Peyers patches
  • Monocyte and macrophage lineage
  • Dendritic cells (skin)
  • Kupfer cells (liver)
  • Glial cells (CNS)
  • B-cell subset

15
Any nucleated cell
APC
16
Ag Recognition
but not enough need Co-Stimulatory Signal 2
17
(No Transcript)
18
T-cell receptor
19
Phagocytosis
  • Mononuclear (monocytes) vs polymorphonuclear
    (neutrophils)
  • Engulfed foreign particle --gt phagosome
    lysosome --gt phagolysosome
  • Oxygen-dependent mechanisms
  • Myeloperoxidase, superoxide anion, H2O2, singlet
    O2, OH- radicals
  • Oxygen-independent mechanisms
  • Cationic proteins, lysozymes, proteinases

20
Phases of Phagocytosis
21
Complement
  • Component proteins mediators of inflammation and
    cell lysis
  • Numbered according to chronological discovery,
    not necessarily order of activity in cascade
    reactions
  • Traditionally divided into Classic, Alternative,
    and Lectin pathways
  • Small stimulus --gt amplified effect
  • Initiated by Ag-Ab immune complexes and microbial
    products
  • C3a and C5a are chemotactic
  • Some components are anaphylatoxins --gt mast cell
    degranulation, smooth muscle contraction,
    increased vascular permeability
  • End-product is C5b-8 MAC

22
Complicated!
23
simplified.
24
Cytokines
  • Greek -cyto, cell and -kinos, movement
  • Large group of cell-signaling molecules
  • proteins, glycoproteins, peptides
  • Grossly include interleukins, lymphokines, and
    chemokines redundancy and pleitropism make this
    classification obsolete today.

25
Interleukins
  • IL-1 pro-inflammatory and wound healing
    macrophages, neutrophils, fibroblasts, NK cells,
    endothelial cells, vascular smooth muscle fever,
    vasodilation, hypotension, collagen deposition,
    T-and B-cell proliferation, IL-2 and IL-2R
    up-regulation
  • IL-2 T-cell growth factor in response to IL-1
    NK cells and activated T-cells (auto- and
    para-crine) up regulates many other cytokines,
    namely TNF and CSF deficiency --gt SCID
  • IL-3 hematopoetic growth factor
  • IL-4 inhibits macrophages
  • IL-6 inhibits TNF
  • IL-8 neutrophil chemokine
  • IL-10 inhibits monocytes/macrophages and
    anti-inflammatory

IL-4, 6, and 10 are inhibitory cytokines
26
IL-2
27
Tumor necrosis factor (TNF)
  • Hemmorhagic necrosis in methycholanthrine
    -induced sarcomas in mice
  • TNF-alpha 1o monocytes/macrophages, but NK cells
    and neutrophils also
  • Stimulates neutrophils
  • Endothelial cells --gt IL-1
  • Procoagulant, increased vascular permeability
  • Catabolism and cachexia in malignant disease
  • Apoptotic mediator
  • Gram negative shock --gt endotoxin --gt TNF-alpha
    --gt hypotension DIC
  • TNF-ß T- and B-cells
  • Wound healing, PG and collagen deposition
  • Cytolytic and cytostatic for many tumor cell lines

28
(No Transcript)
29
Interferons
  • Glycoproteins
  • Inhibit viral proliferation via signaling
    pathways and translation machinery inhibition
  • INF-alpha -- macrophages
  • INF-beta -- epithelial cells, fibroblasts,
    macrophages
  • INF-gamma -- T-cells and NK cells
  • Antiproliferative
  • Can induce differentiation
  • Stimulate or inhibit a variety of cells to
    release other cytokines

30
Chemokines
  • Low molecular weight cytokines that serve as
    chemoattractants
  • 4 cysteine molecules linke by disulfide bonds
  • C-C or C-X-C and their receptors
  • IL-8 is actually a chemokine that binds CXCR1 or
    CXCR2 on neutrophils
  • 100s of chemokines identified and the catalogue
    continues to grow!

31
(No Transcript)
32
(No Transcript)
33
Immunization
  • Active injection of intact attenuated organism
    or component. Recipient mounts an immune response
    with the goal being memory
  • DPT, MMR, pneumovax, HepB, vaccine, polio
    vaccines
  • Passive exogenous active component is given to
    recipient immediate but temporary immunity
  • Antitoxins C.tetani antitoxin
  • Immunoglobulin IgG to immundeficient recipient
  • Specific immune globulin RhoGAM (prevent
    sensitization to Rh Abs crossing placenta from
    Rh infant at delivery)

34
Who were these guys?
Dr. Albert Sabin
Dr. Jonas Salk
35
Hypersensitivity Reactions
  • Type I immediate hypersensitivity
  • IgE mediated --gt mast cells and basophils
  • Anaphylaxis, hay fever, food allergy
  • Type II cytotoxic reactions
  • IgG and/or IgM mediated preformed Abs
  • ABO and Rh incompatibility, myasthenia gravis,
    Graves disease, ITP
  • Type III immune complex mediated
  • Deposition of Ab-Ag complexes
  • PSGN, serum sickness, SLE, rheumatoid arthritis
  • Type IV DTH
  • Previously sensitized CD4 T-helper cells
  • Tuberculin skin test, contact dermatitis

36
Transplant Rejection
  • Hyperacute
  • Preformed Ab immediate in the OR
  • ABO incompatible or high titre donor specific HLA
    Class I Ab
  • Acute
  • T-cell mediated days to weeks
  • Treatment and prevention via T-cell depletion
    ATG or IL-2R blocker
  • Chronic (CAN)
  • Kidneys IF/TA
  • Immune and non-immune mechanisms
  • Difficult to predict, prevent, or belay

37
Alternative ANTIBODY vs CELLULAR rejection
38
THE END
  • Thank you and Good Luck!
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