General Pathology:General Pathology:Normal Immune FunctionNormal Immune Function

Lorne Holland, M.D.Lorne Holland, M.D.Lorne.Holland@ucdenver.eduLorne.Holland@ucdenver.edu

Normal Immune FunctionNormal Immune Function

• Immunity is a multilayered processImmunity is a multilayered process– Non-specific defenses impede Non-specific defenses impede

invasion of the body by many invasion of the body by many organismsorganisms

– Innate immunity allows for rapid Innate immunity allows for rapid defense against invading bacteriadefense against invading bacteria

– Specific immunity allows for a Specific immunity allows for a robust, targeted defense against robust, targeted defense against invading organismsinvading organisms

Non-specific DefensesNon-specific Defenses

• Mechanical barriers such as skin and Mechanical barriers such as skin and mucous membranesmucous membranes

• Environmental factors such as Environmental factors such as stomach pH, sebacous secretions by stomach pH, sebacous secretions by skin, commenselate organismsskin, commenselate organisms

Innate ImmunityInnate Immunity

• Molecules and receptors which Molecules and receptors which recognize common patterns on typical recognize common patterns on typical bacterial pathogensbacterial pathogens– Toll-like receptorsToll-like receptors– PhagocytosisPhagocytosis– ComplementComplement

MacrophagesMacrophages

• Toll-like receptors to recognize Toll-like receptors to recognize common molecules on the surface of common molecules on the surface of pathogenspathogens

• Scavenger receptors can do the same, Scavenger receptors can do the same, but also recognize altered self but also recognize altered self molecules (oxidized LDL, glycated molecules (oxidized LDL, glycated proteins, amyloid, apoptotic cells)proteins, amyloid, apoptotic cells)

Complement System

Complement System

• C3a & C5a- chemotactic for neutrophils and anaphylactoids

• C56789- “membrane attack complex”

• C3b- opsonizaton

• http://www.youtube.com/watch?v=tJJAyPWQ3fk

Specific (Adaptive) Specific (Adaptive) ImmunityImmunity

• The interaction between multiple cells The interaction between multiple cells to produce a response to a particular to produce a response to a particular pathogenpathogen

• Most robust and adaptable type of Most robust and adaptable type of immunityimmunity

• Has to “learn” from exposure to Has to “learn” from exposure to pathogens before it can respondpathogens before it can respond

• ““Remembers” what it has seen beforeRemembers” what it has seen before

AntigensAntigens

• Molecules which stimulate a specific Molecules which stimulate a specific immune responseimmune response

• If large enough, it may have multiple If large enough, it may have multiple regions (epitopes) which can elicit an regions (epitopes) which can elicit an immune responseimmune response

• If small enough, it may not be able to If small enough, it may not be able to stimulate an immune response alone, stimulate an immune response alone, but may do so when attached to a but may do so when attached to a larger molecule (hapten)larger molecule (hapten)

Epitope

Epitope

Epitope

Epitope

Hapten

Hapten

Albumin

White Blood Cell Maturation

LymphocytesLymphocytes

• T-cells travel from bone marrow to T-cells travel from bone marrow to thymus to be “educated” thymus to be “educated” – Negative selectionNegative selection

•Cells which do not respond to usual immune Cells which do not respond to usual immune stimulation undergo apoptosisstimulation undergo apoptosis

•Cells which respond too strongly to usual Cells which respond too strongly to usual immune stimulation undergo apoptosisimmune stimulation undergo apoptosis

– Positive selectionPositive selection•Cells which respond “just right’ to usual Cells which respond “just right’ to usual

immune stimulation mature, enter circulation immune stimulation mature, enter circulation and often settle in lymphoid tissuesand often settle in lymphoid tissues

T LymphocytesT Lymphocytes

• “helper cells”– Once activated, activates complementary

B-cells (humoral immunity)– CD4 positive cells– Settle in lymphoid tissue with B-cells

• “cytotoxic cell”– Once activated, attacks cells bearing

recognized antigen (cell-mediated immunity)

– CD8 positive cells– In lymphoid tissues, but also in circulation

and other tissues

LymphocytesLymphocytes

• B-cells stay in marrow until mature B-cells stay in marrow until mature then into circulation and often settle then into circulation and often settle into lymphoid tissueinto lymphoid tissue

• When B-cells are stimulated they can When B-cells are stimulated they can mature into plasma cellsmature into plasma cells

• Plasma cells secrete antibodiesPlasma cells secrete antibodies

Natural Killer CellsNatural Killer Cells

• Do not respond to specific immune Do not respond to specific immune stimulusstimulus

• More generalized in response like More generalized in response like macrophagesmacrophages

• Directly kill cells which it senses are Directly kill cells which it senses are “not right” (virally infected, cancer, “not right” (virally infected, cancer, etc.)etc.)

• Inhibited by the presence of normal Inhibited by the presence of normal MHC I moleculesMHC I molecules

Antigen Presenting CellsAntigen Presenting Cells

• Multiple names depending on tissue Multiple names depending on tissue where locatedwhere located– Monocytes which have left the circulation Monocytes which have left the circulation

and matured into macrophages (Kupffer and matured into macrophages (Kupffer cells, microglia, histiocytes)cells, microglia, histiocytes)

– Dendridic cells (Langerhans cells) from Dendridic cells (Langerhans cells) from myeloid line and/or differentiation of local myeloid line and/or differentiation of local connective cells tissue cells (fibroblasts) connective cells tissue cells (fibroblasts) and/or ????and/or ????

• http://video.google.com/googleplayer.swf?docid=-1998725615426724660

Major Histocompatibility Complex• Molecules used to display peptide fragments

• Class I– Found on nearly all nucleated cells– Displays mostly (altered) self peptides– Binds with help of CD8– Three subclasses: A, B, C

• Class II– Found mostly on specialized antigen

presenting cells and other immune cells– Displays mostly exogenous, ingested

peptides– Binds with help of CD4– Three subclasses: DP, DQ, DR

Antigen PresentationAntigen Presentation

• APCs phagocytose and digest APCs phagocytose and digest suspicious substancesuspicious substance

• Fragments are attached to MHC II then Fragments are attached to MHC II then presented on cell surfacepresented on cell surface

• Lymphocytes that have receptors Lymphocytes that have receptors which recognize the fragment bind and which recognize the fragment bind and receive a costimulatory “handshake”receive a costimulatory “handshake”

• Without costimulation, the lymphocyte Without costimulation, the lymphocyte will not respond and become anergicwill not respond and become anergic

APC – T cell interaction

CD80 CD 86

CD28 CTLA-4

MHC II TCR CD4

APC T-cell

aka B7

Humoral Immunity

• B-cell receptors pick up antigen• Present peptides to T “helper” cell by MHC

II• Costimulation, as with APCs• B-cells become activated and produce more

membrane-bound antibody• Stimulation via bound antibody causes

differentiation into plasma cells and secretion of antibodies

• In some rare cases, T-cell independent antigens are recognized by B-cells

T cell – B cell interaction

BCR CD8

B-cell

Antibody Structure

Heavy Chains(G, A, M, E, or D)

Light Chains(Kappa or Lambda)

Antigen recognition sites

FC (fraction crystalizable) region

Antibodies/Immunoglobulins• IgM, the first type of antibody produced,

circulates as a pentamer• IgG, normally the most abundant antibody in

circulation, monomer• IgA, largest quantities found in secretions, some

also found in blood, usually a dimer• IgE, normally small amounts in blood, bind to

surface of mast cells and play a role in allergic responses

• IgD, normally not found in blood, expressed on the surface of some B-cells

Antibodies/Immunoglobulins

Isotype Switching

• IgM is the primary, initial antibody produced

• Further stimulation of CD40 on B-cell by CD40 ligand on activated T-cells can cause a shift in heavy chain production to G, A, or E

Cell-mediated Immunity

• Activated T “cytotoxic” cells recognize peptides expressed on cells by MHC I molecules

• Induce apoptosis of presenting cell• Also secrete a number of cytokines

which potentiate other parts of immune response

Cell-mediated immunity• Antibody dependent cytotoxicity

– NK cells, monocytes and neutrophils– Recognize Fc portion of antibody

attached to cell– Poorly understood mechanisms, but

likely involves release of perforins, granzyme, et al.

• Phagocytosis– Monocytes and neutrophils can also

bind Fc then engulf the cell

After Resolution

• Most responding cells undergo apoptosis when no longer needed

• A small number of “memory” cells are retained in lymphoid tissues

• These cells allow for rapid response to antigens when re-exposed and can secrete small amounts of antibody for years

• Vaccinations induce formation of “memory” cells

Questions?