General Pathology: Normal Immune Function Lorne Holland, M.D.

Normal Immune Function Immunity is a multilayered processImmunity is a multilayered process –Non-specific defenses impede invasion of the body by many organisms –Innate immunity allows for rapid defense against invading bacteria –Specific immunity allows for a robust, targeted defense against invading organisms

Non-specific Defenses Mechanical barriers such as skin and mucous membranesMechanical barriers such as skin and mucous membranes Environmental factors such as stomach pH, sebacous secretions by skin, commenselate organismsEnvironmental factors such as stomach pH, sebacous secretions by skin, commenselate organisms

Innate Immunity Molecules and receptors which recognize common patterns on typical bacterial pathogensMolecules and receptors which recognize common patterns on typical bacterial pathogens –Toll-like receptors –Phagocytosis –Complement

Macrophages Toll-like receptors to recognize common molecules on the surface of pathogensToll-like receptors to recognize common molecules on the surface of pathogens Scavenger receptors can do the same, but also recognize altered self molecules (oxidized LDL, glycated proteins, amyloid, apoptotic cells)Scavenger receptors can do the same, but also recognize altered self molecules (oxidized LDL, glycated proteins, amyloid, apoptotic cells)

Complement System

C3a & C5a- chemotactic for neutrophils and anaphylactoids C “membrane attack complex” C3b- opsonizaton

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Specific (Adaptive) Immunity The interaction between multiple cells to produce a response to a particular pathogenThe interaction between multiple cells to produce a response to a particular pathogen Most robust and adaptable type of immunityMost robust and adaptable type of immunity Has to “learn” from exposure to pathogens before it can respondHas to “learn” from exposure to pathogens before it can respond “Remembers” what it has seen before“Remembers” what it has seen before

Antigens Molecules which stimulate a specific immune responseMolecules which stimulate a specific immune response If large enough, it may have multiple regions (epitopes) which can elicit an immune responseIf large enough, it may have multiple regions (epitopes) which can elicit an immune response If small enough, it may not be able to stimulate an immune response alone, but may do so when attached to a larger molecule (hapten)If small enough, it may not be able to stimulate an immune response alone, but may do so when attached to a larger molecule (hapten)

Epitope

Hapten Albumin

White Blood Cell Maturation

Lymphocytes T-cells travel from bone marrow to thymus to be “educated”T-cells travel from bone marrow to thymus to be “educated” –Negative selection Cells which do not respond to usual immune stimulation undergo apoptosisCells which do not respond to usual immune stimulation undergo apoptosis Cells which respond too strongly to usual immune stimulation undergo apoptosisCells which respond too strongly to usual immune stimulation undergo apoptosis –Positive selection Cells which respond “just right’ to usual immune stimulation mature, enter circulation and often settle in lymphoid tissuesCells which respond “just right’ to usual immune stimulation mature, enter circulation and often settle in lymphoid tissues

T 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

Lymphocytes B-cells stay in marrow until mature then into circulation and often settle into lymphoid tissueB-cells stay in marrow until mature then into circulation and often settle into lymphoid tissue When B-cells are stimulated they can mature into plasma cellsWhen B-cells are stimulated they can mature into plasma cells Plasma cells secrete antibodiesPlasma cells secrete antibodies

Natural Killer Cells Do not respond to specific immune stimulusDo not respond to specific immune stimulus More generalized in response like macrophagesMore generalized in response like macrophages Directly kill cells which it senses are “not right” (virally infected, cancer, etc.)Directly kill cells which it senses are “not right” (virally infected, cancer, etc.) Inhibited by the presence of normal MHC I moleculesInhibited by the presence of normal MHC I molecules

Antigen Presenting Cells Multiple names depending on tissue where locatedMultiple names depending on tissue where located –Monocytes which have left the circulation and matured into macrophages (Kupffer cells, microglia, histiocytes) –Dendridic cells (Langerhans cells) from myeloid line and/or differentiation of local connective cells tissue cells (fibroblasts) and/or ????

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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 Presentation APCs phagocytose and digest suspicious substanceAPCs phagocytose and digest suspicious substance Fragments are attached to MHC II then presented on cell surfaceFragments are attached to MHC II then presented on cell surface Lymphocytes that have receptors which recognize the fragment bind and receive a costimulatory “handshake”Lymphocytes that have receptors which recognize the fragment bind and receive a costimulatory “handshake” Without costimulation, the lymphocyte will not respond and become anergicWithout costimulation, the lymphocyte will 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

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