Transcript Immunology for Surgeons: The Basics 101

Immunology for Surgeons:
The Basics 101
Principles of Surgery
Jeff Warren, MD, FRCSC
October 19, 2010
Objectives
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The Players -- T-cells and B-cells
Immunoglobulins
Antigen Recognition
Phagocytosis
Mediators and Complement
Immunization
Hypersensitivity Reactions
Transplant Immunology Basics
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
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Introduction
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Innate vs Adaptive immunity
Self vs non-self vs altered self
Three phases of immune response:
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Cognitive phase
Activation phase
Effector phase
Primary and Secondary responses
Lymphoid organs: primary/secondary
Humoral and Cell-mediated responses
Lymphocytes
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T-cells
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Thymus
CD3+
CD4+ -- Helper and DTH
CD8+ -- cytotoxic and
suppressor
NK Cells
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Non B-cell, non T-cell
lymphocytes
+IL-2 --> LAK cells
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B-cells
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Bursa fasicularis (birds)
Fetal liver and bone
marrow
CD19+/CD20+
--> plasma cells --> Ab
production
APCs
B-cell-->Plasma cell--> Ig production
IgA: secretory, dimer
 IgG: most abundant, 2o response, opsonin, C’ binding
 IgM: 1o repsonse, C’binding, pentamer
 IgE: mast cells and basophils, Type I hypersensitivity
 IgD: small quantities, ??
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Immunoglobulin
Immunoglobulin -- Fab and Fc
Antigen Recognition
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Immunogen: can stimulate immune response
Antigen: recognized by immune system
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Immunogenicity:
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Complexity: proteins > CHO > nucleic acids > lipids
Size: usually > 5000 Da
Foreigness: xenogeneic > allogeneic > syngeneic >
autologous
MHC
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HLA in humans on chromosome 6
With Ag --> Self vs non-self vs altered self
Class I: A and B regions, on all nucleated cells and
platelets, recognized CD8+ T-cells --> lysis
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Class II: D region, on APCs, recognized CD4+ helper
T-cells --> activation and proliferation of helper T-cells (-> cytokines), cytotoxic T-cells (--> lysis), and B-cells (-> plasma cells --> Ab)
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Class III: Complement
MHC Class I and Class II
Antigen Presenting Cells (APC)
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Capable of activating CD4+ T-cells
Recognition usually occurs in 2o lymphoid
organs: spleen, lymph nodes, GALT, Peyer’s
patches…
Monocyte and macrophage lineage:
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Dendritic cells (skin)
Kupfer cells (liver)
Glial cells (CNS)
B-cell subset
Any
nucleated
cell
APC
Ag Recognition
…but not enough…
need Co-Stimulatory
Signal 2
T-cell receptor
Phagocytosis
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Mononuclear (monocytes) vs
polymorphonuclear (neutrophils)
Engulfed foreign particle --> phagosome +
lysosome --> phagolysosome
Oxygen-dependent mechanisms:
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Myeloperoxidase, superoxide anion, H2O2, singlet
O2, OH- radicals
Oxygen-independent mechanisms:
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Cationic proteins, lysozymes, proteinases
Phases of Phagocytosis
Complement
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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 --> amplified effect
Initiated by Ag-Ab immune complexes and microbial products
C3a and C5a are chemotactic
Some components are anaphylatoxins --> mast cell
degranulation, smooth muscle contraction, increased
vascular permeability
End-product is C5b-8 MAC
Complicated!…
…simplified.
Cytokines
Greek -cyto, cell; and -kinos, movement
 Large group of cell-signaling molecules:
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proteins, glycoproteins, peptides
Grossly include interleukins, lymphokines,
and chemokines; redundancy and
pleitropism make this classification
obsolete today.
Interleukins
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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 upregulation
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 --> SCID
IL-3: hematopoetic growth factor
IL-4: inhibits macrophages
IL-6: inhibits TNF
IL-8: neutrophil chemokine
IL-10: inhibits monocytes/macrophages and antiinflammatory
IL-4, 6, and 10 are “inhibitory” cytokines
IL-2
Tumor necrosis factor (TNF)
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Hemmorhagic necrosis in methycholanthrine -induced
sarcomas in mice
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TNF-alpha: 1o monocytes/macrophages, but NK cells and
neutrophils also
 Stimulates neutrophils
 Endothelial cells --> IL-1
 Procoagulant, increased vascular permeability
 Catabolism and cachexia in malignant disease
 Apoptotic mediator
 Gram negative shock --> endotoxin --> TNF-alpha -->
hypotension + DIC
TNF-ß: T- and B-cells
 Wound healing, PG and collagen deposition
 Cytolytic and cytostatic for many tumor cell lines
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Interferons
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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
Chemokines
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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!
Immunization
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Active: injection of intact attenuated organism or
component. Recipient mounts an immune response
with the goal being memory
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DPT, MMR, pneumovax, HepB, vaccine, polio vaccines
Passive: exogenous active component is given to
recipient; immediate but temporary immunity
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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)
Who were these guys?…
Dr. Albert Sabin
Dr. Jonas Salk
Hypersensitivity Reactions
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Type I: immediate hypersensitivity
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Type II: cytotoxic reactions
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IgG and/or IgM mediated; preformed Abs
ABO and Rh incompatibility, myasthenia gravis, Graves
disease, ITP
Type III: immune complex mediated
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IgE mediated --> mast cells and basophils
Anaphylaxis, hay fever, food allergy
Deposition of Ab-Ag complexes
PSGN, serum sickness, SLE, rheumatoid arthritis
Type IV: DTH
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Previously sensitized CD4+ T-helper cells
Tuberculin skin test, contact dermatitis
Transplant Rejection
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Hyperacute
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Acute
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Preformed Ab; immediate: “in the OR”
ABO incompatible or high titre donor specific HLA
Class I Ab
T-cell mediated; days to weeks
Treatment and prevention via T-cell depletion: ATG
or IL-2R blocker
Chronic (CAN)
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Kidneys IF/TA
Immune and non-immune mechanisms
Difficult to predict, prevent, or belay
Alternative: ANTIBODY vs CELLULAR rejection
THE END
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Thank you and Good Luck!