Immunology for Surgeons:The Basics 101

Principles of SurgeryJeff Warren, MD, FRCSC

October 19, 2010

Objectives 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

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

Lymphocytes

T-cells Thymus CD3+ CD4+ -- Helper and DTH CD8+ -- cytotoxic and

suppressor

NK Cells Non B-cell, non T-cell

lymphocytes +IL-2 --> LAK cells

B-cells 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, ??

Immunoglobulin

Immunoglobulin -- Fab and Fc

Antigen Recognition Immunogen: can stimulate immune response Antigen: recognized by immune system

Immunogenicity: Complexity: proteins > CHO > nucleic acids > lipids Size: usually > 5000 Da Foreigness: xenogeneic > allogeneic > syngeneic >

autologous

MHC 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 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)

Class III: Complement

MHC Class I and Class II

Antigen Presenting Cells (APC) Capable of activating CD4+ T-cells Recognition usually occurs in 2o lymphoid

organs: spleen, lymph nodes, GALT, Peyer’s patches…

Monocyte and macrophage lineage: Dendritic cells (skin) Kupfer cells (liver) Glial cells (CNS)

B-cell subset

Anynucleatedcell

APC

Ag Recognition

…but not enough…need Co-StimulatorySignal 2

T-cell receptor

Phagocytosis Mononuclear (monocytes) vs

polymorphonuclear (neutrophils) Engulfed foreign particle --> phagosome +

lysosome --> phagolysosome Oxygen-dependent mechanisms:

Myeloperoxidase, superoxide anion, H2O2, singlet O2, OH- radicals

Oxygen-independent mechanisms: Cationic proteins, lysozymes, proteinases

Phases of Phagocytosis

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 --> 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:

proteins, glycoproteins, peptides Grossly include interleukins, lymphokines,

and chemokines; redundancy and pleitropism make this classification obsolete today.

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 --> 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

IL-2

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 --> 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

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

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!

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)

Who were these guys?…

Dr. Albert Sabin Dr. Jonas Salk

Hypersensitivity Reactions Type I: immediate hypersensitivity

IgE mediated --> 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

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

Alternative: ANTIBODY vs CELLULAR rejection

THE END

Thank you and Good Luck!