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Value of the Immune System. Protection from infectious diseases ( Immune responses against infectious diseases ) The “threats” - Bacterial pathogens, toxins and viral pathogens Innate immunity – phagocytes, NK cells and complement When innate immunity is not good enough

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value of the immune system
Value of the Immune System
  • Protection from infectious diseases (Immune responses against infectious diseases)
    • The “threats” - Bacterial pathogens, toxins and viral pathogens
    • Innate immunity – phagocytes, NK cells and complement
      • When innate immunity is not good enough
    • Adaptive immunity – lymphocytes & antibodies
    • Systemic and mucosal immune “systems”
  • Destruction of cancer cells (Cancer immunology )
    • Normal (self) -> cancer (non-self markers)
  • Clinical applications (Clinical applications of immunology)
    • Diagnostic
    • Therapeutic
  • Some problems caused by the immune system
    • Allergic reactions (allergens are non-self; IgE antibodies and mast cells)
    • Autoimmunity (loss of self/non-self discrimination)
    • Transplant rejection (another person is not self to me)
      • Survival of fetus
      • Bone marrow transplants
        • Graft-vs-host disease
value of the immune system2
Value of the Immune System
  • Immune responses against infectious diseases
  • Bacterial pathogens, bacterial exotoxins and viral pathogens
value of the immune system6
Value of the Immune System
  • Immune responses against infectious diseases
  • Bacterial pathogens, toxins and viral pathogens
  • Innate immunity – what does that mean?
    • Cells (phagocytes and NK cells) and molecules present all the time
    • Cells are ready to respond immediately
    • Response does not improve with use
    • Not uniquely specific (cells can bind to a wide variety of pathogens)
    • Generally effective against bacterial pathogens (and not viruses or exotoxins)
innate immunity
Innate Immunity
  • Cells and molecules present all the time
  • Cells are ready to respond immediately
  • Does not improve with use
innate immunity8
Innate Immunity
  • Not uniquely specific (cells can bind to a wide variety of pathogens)
  • Generally effective against bacterial pathogens (and not viruses or exotoxins)

A

B

A

value of the immune system9
Value of the Immune System
  • Components of the innate immune system
    • Cells
      • Phagocytes
      • PMNs & macrophages
value of the immune system10
Value of the Immune System
  • Components of the innate immune system
    • Cells
      • Phagocytes
      • PMNs & macrophages
      • Macrophages & toll-like receptors (TLR)
value of the immune system11
Value of the Immune System

Macrophages & toll-like receptors (TLRs)

10-12 different TLRs can (collectively) bind a wide range of pathogens

Each macrophage has all of the set of TLRs

innate immune responses
Innate Immune Responses
  • Phagocytosis animation (select “Normal phagocytosis by a macrophage”)
    • Initiated by attachment of phagocyte surface receptor to molecule(s) on pathogen
    • e.g., TLRs bind to PAMPS (pathogen-associated molecular patterns)
    • Shared by many different bacteria
    • Large number of TLRs that can bind large number of PAMPS
    • Bacterial cell is ingested
    • Phagosome forms around the intact bacterial cell
    • Phagosome fuses with lysosome -> phagolysosomeanimation
    • Lysosome contains variety of degradative enzymes and toxic forms of oxygen
  • Bacterial cell is degraded in the phagolysosome
  • Degraded contents are expelled from phagocyte (not shown)
  • Phagocyte can continue to phagocytize indefinitely
  • No improvement in the rate or success of phagocytosis
two clicker questions at the start of class
TWO Clicker questions at the start of class
  • 1. Toll-like receptors (TLRs) participate in which one of the following important steps in an innate immune response?
  • A bacterial capsule interferes with macrophage-mediated phagocytosis in which one of the following ways?
  • HANDOUT of two recently changed ppt slides on ends of classroom tables
slide14
Toll-like receptors (TLRs) participate in which one of the following important steps in an innate immune response?
  • A. degradation of a bacterial cell in a phagolysosome
  • B. activation of complement
  • C. attachment by macrophages to molecules (e.g., PAMPs) on the surfaces of bacterial cells
  • D. development of a lymphoid cell into a fully functional blood monocyte
slide15
A bacterial capsule interferes with macrophage-mediated phagocytosis in which one of the following ways?
  • A. kills the macrophage
  • B. prevents the attachment of receptors on the macrophage surface (e.g.,, TLRs) with molecules on the bacterial cell surface (e.g., PAMPs)
  • animation
  • C. downregulates the production of all of the toxic forms of oxygen that can kill bacterial cells in a phagolysosome
  • D. interferes with somatic recombination; renders the macrophage not specific for any bacterial PAMP
value of the immune system17
Value of the Immune System
  • Components of the innate immune system
    • Molecules
      • Complement (often abbreviated with a capital C)
      • A set of >30 different proteins (most are enzymes)
      • Acting in a collaborative fashion with several outcomes
        • Attract phagocytes to an area of bacterial infection
        • Increase phagocytic activity of phagocytes
        • Assist phagocytes to attach to bacteria
        • Directly kill bacteria (destroy bacterial cell membrane)
value of the immune system18
Value of the Immune System
  • Complement must first be activated to function
  • Three different ways complement can be activated
  • Outcome is the same in all three (diagram is of alternative pathway)
value of the immune system19
Value of the Immune System
  • Immune responses against infectious diseases
  • When the innate immune system is not good enough
    • Phagocytes can not attach to pathogens
      • bacterial pathogens
        • no bacterial surface molecules to which phagocyte can bind
        • e.g., no PAMPS to which TLRs can bind
        • bacterial surface molecules covered by a capsule – animation
      • viruses
        • Usually nothing on virus to which phagocyte can attach
value of the immune system20
Value of the Immune System
  • When the innate immune system is not good enough
    • Phagocytosis is not completely successful (several animations below)
      • bacterium escaping from the phagosome prior to the lysosome fusing with the phagosome
      • bacterium preventing the phagosome from fusing with the lysosome
      • bacterium preventing the lysosome from moving to the phagosome
      • bacterium preventing acidification of the phagosome following ingestion (tuberculosis)
      • bacterium killing a phagocyte
slide21

Bonus Clicker question – If a phagocygte (e.g., macrophage) is able to attach to a bacterial cell and ingest it, but is not able to carry out the remaining steps of phagocytosis to destroy the ingested cell, what might be a way for this phagocyte to get some assistance (“help”)?

  • A. activated complement
  • B. natural killer (NK) cell activity
  • C. T-cytotoxic cell
  • D. TH1-helper cell
value of the immune system22
Value of the Immune System
  • When the innate immune system is not good enough
    • Phagocytosis is not completely successful (several animations below)
      • bacterium escaping from the phagosome prior to the lysosome fusing with the phagosome
      • bacterium preventing the phagosome from fusing with the lysosome
      • bacterium preventing the lysosome from moving to the phagosome
      • bacterium preventing acidification of the phagosome following ingestion (tuberculosis)
      • bacterium killing a phagocyte
    • Complement is not activated or not successful
      • Bacteria block complement activation
      • Capsule prevents complement activation
      • Bacteria alter the membrane – prevents the final stage of C-mediated killing

Elongation of O-Polysaccharide Preventing the Insertion of MAC* into the Cell Wall of Gram-Negative Bacteria

*MAC = complement membrane attack complex

value of the immune system23
Value of the Immune System
  • Immune responses against infectious diseases
  • Adaptive immunity – what does that mean? (essentially a review)
    • Cells (lymphocytes) are present, but few in number and not ready to respond immediately (must “wait” until it binds to the antigen for which it is specific)
    • Each lymphocyte is uniquely specific (each one can bind to only one antigen)
    • Response doesimprove with use (the lymphocyte population expands as an “adaption” to the first exposure to the antigen -> “memory” cells)
    • Generally effective against bacterial pathogens, extracellularviruses, virus-infected cells and exotoxins
    • Antibodies are the molecular component of the adaptive immune system
    • Adaptive response can also assist the innate immune system
      • Can help macrophages (TH1-helper lymphocytes)
      • Can activate complement (antibody when it binds to antigen)
value of the immune system24
Value of the Immune System
  • Adaptive immunity
  • Antibodies
  • Antigen-specific proteins secreted by plasma cells and (almost) identical to the original antigen-specific receptor on the surface of the originalB-lymphocyte
value of the immune system25
Value of the Immune System
  • Adaptive immunity
  • Antibodies

Antibody isotypes and related properties

Associated with the constant portion of the heavy chain

value of the immune system26
Value of the Immune System
  • Adaptive immunity
  • Antibodies

Antibody isotypes and related properties

Associated with the constant portion of the heavy chain

Five different isotypes, depending on which one of the constant portion genes is chosen when making a complete heavy chain after variable portion has been created

Called Immunoglobulins (Ig) when referring to isotype

IgM isotype – has selected the mu gene

IgD isotype – has selected the delta gene

IgG isotype – has selected one of the four gamma genes

IgA isotype – has selected one of the two alpha genes

IgE isotype – has selected the epsilon gene

Selection of constant portion of heavy chain appears to be under the influence of the TH2-helper cell

value of the immune system27
Value of the Immune System

Antibody isotypes and related properties

Associated with the constant portion of the heavy chain

value of the immune system28
Value of the Immune System

Antibodies can

1. Prevent attachment of exotoxins, bacteria, viruses (IgG and IgA are best)

antibody only needs to bind to the antigen to prevent attachment – neutralization

Animation for toxin neutralization http://student.ccbcmd.edu/courses/bio141/lecguide/unit5/humoral/abydefense/neutexo/toxin_neut.html

slide29

Antibodies can

2. Assist macrophages to attach to pathogens (IgG only) – opsonization

(Animation - http://student.ccbcmd.edu/courses/bio141/lecguide/unit5/humoral/abydefense/opsonization/opson_IgG.html)

Macrophages have a receptor that binds to portion of the IgG isotype

slide30

Antibodies can

3. Assist NK cells to attach to virus-infected cells and tumor cells (IgG only)

NK cell “sensitization for killing”

also called antibody-dependent cellular cytotoxicity (ADCC)

Animation - http://student.ccbcmd.edu/courses/bio141/lecguide/unit5/intro/nk/adcc.html

NK cells also have a receptor for the IgG isotype antibody

Receptors for Ig molecules are called Fc receptors

NK cell

two clicker questions at the start of class32
TWO Clicker questions at the start of class
  • 1. The isotype of an antibody molecule is determined by which one of the following?
  • 2. TWO of the five antibody isotypes are involved in providing protection to a fetus or nursing infant. These two isotypes are indicated by which one of the following set? (select oneletter as your answer)
  • Handout with an added ppt slide and a modified ppt slide are on the ends of the classroom tables
the isotype of an antibody molecule is determined by which one of the following
The isotype of an antibody molecule is determined by which one of the following?
  • A. randomly selected V,D,J and V,J gene fragments
  • B. the constant portion of the light chain (either kappa or lambda)
  • C. the amino acids that actually bind to the antigen
  • D. the constant portion of the heavy chain
slide34

TWO of the five antibody isotypes are involved in providing protection to a fetus or nursing infant. These two isotypes are indicated by which one of the following set? (select oneletter as your answer)

  • A. IgM and IgE
  • B. IgG and IgE
  • C. IgG and IgA
  • D. IgM and IgD
slide35

Hold your iClicker in one hand and hold both hands up as high as you can reach. When the time starts, keep both hands raised up high and then simply select one of the answers below.

  • A. I am in class and am using only my own iClicker
  • B. I am not in class and someone is using my iClicker for me so I can get credit even if I don’t come to class
antibodies can
Antibodies can

4. Activate complement (IgM and IgG)

Antibody must first bind to antigen before C is activated

Animation of classical (antibody-initiated) pathway

http://student.ccbcmd.edu/courses/bio141/lecguide/unit4/innate/c1act_flash.html

immunoglobulin isotypes
Immunoglobulin isotypes

Secreted version of IgM (pentamer with “J” chain)

antibodies can38
Antibodies can

5. Cross the intestinal cell lining (epithelium) and continue to function in the gi tract

only dimeric form of IgA has this property

has a secretory component (not shown in dimeric IgA diagram)

Dimeric IgA is also called “secretory” IgA (sIgA)

sIgA

Monomeric IgA in blood

fetal infant protection
Fetal/infant protection

Antibodies can

6. Cross the human placenta from mother to fetus (IgG only)

7. Dimeric IgA also found in breast milk -> gi tract of a nursing infant

slide40

Antibodies can

8. Move from the blood stream into surrounding tissue areas -“diffuse” across

blood vessel endothelial cell layer (IgG only)

slide41

Antibodies can

9. “Sensitize” mast cell -> allergic reaction (IgE only)

Mast cell has a receptor for the IgE isotype

Animation - http://highered.mcgraw-hill.com/olcweb/cgi/pluginpop.cgi?it=swf::535::535::/sites/dl/free/0072437316/120110/micro38.swf::IgE%20Mediated%20Hypersensitivity

value of the immune system42
Value of the Immune System

Antibody isotypes and related properties

Associated with the constant portion of the heavy chain

value of the immune system43
Value of the Immune System
  • Lymphocytes
  • Roles of T-helper (CD4) cells
    • Phagocytosis is not completely successful (several animations below)
      • bacterium escaping from the phagosome prior to the lysosome fusing with the phagosome
      • bacterium preventing the phagosome from fusing with the lysosome
      • bacterium preventing the lysosome from moving to the phagosome
      • bacterium preventing acidification of the phagosome following ingestion (tuberculosis)
      • bacterium killing a phagocyte
    • TH1helpmacrophages
    • Animation - http://student.ccbcmd.edu/courses/bio141/lecguide/unit5/cellular/cmidefense/macronk/th1macro.html
slide44

Lymphocytes

  • Roles of T-helper (CD4) cells
    • TH2help B-lymphocytes
    • Influence/control
      • Cellreplication
      • Differentiation into plasma cells
      • (Some daughter cells retained as memory cells)
      • Antibody secretion
      • Isotype of secreted antibody (IgM, IgD, IgG, IgA, IgE)
slide45

Lymphocytes

  • Role of T-cytotoxic (CD8) cells
    • Destruction of virus-infected cells and tumor cells
    • Animation - http://student.ccbcmd.edu/courses/bio141/lecguide/unit5/intro/apc/apoctl.html
      • Perforins & granzymes (the “granules” in the image to the left)
      • Fas-Fas ligand (FasL)

T-cytotoxic cell expresses Fas ligand

“target” cell expresses Fas

value of the immune system46
Value of the Immune System
  • Destruction of cancer cells

Normal (self) -> cancer (non-self markers)

T-cytotoxic cells respond to non-self (tumor) peptides presented by MHC Class I

Mechanisms are the same as for virus-infected cell (see previous ppt slide)

slide47

Destruction of cancer cells

  • Natural Killer (NK) cells by themselves
  • Animation - http://student.ccbcmd.edu/courses/bio141/lecguide/unit4/innate/nkapop.html
  • ADCC (antibody-dependent cellular cytotoxicity)
  • Animation - http://student.ccbcmd.edu/courses/bio141/lecguide/unit5/humoral/abydefense/adcc/adccanim.html

Same mechanism for tumor cell

the challenges of cancer immunology
The challenges of cancer immunology
  • Why do tumor cells still survive if immune responses exist and are active?
  • What can we do to assist the immune system to more effectively kill tumor cells?
value of the immune system49
Value of the Immune System
  • Clinical applications of immunology
  • Using Monoclonal antibodies – pure preparation of one specificity of antibody using cell culture
  • (Hybridoma Techniques 1001-315, offered in Spring quarters)
  • Animation – http://highered.mcgraw-hill.com/olcweb/cgi/pluginpop.cgi?it=swf::535::535::/sites/dl/free/0072437316/120110/micro43.swf::Monoclonal%20Antibody%20Production
value of the immune system50
Value of the Immune System
  • Clinical applications of immunology

Diagnostic

    • Detection of colon cancer using radiolabeled monoclonal antibodies
value of the immune system51
Value of the Immune System
  • Clinical applications of immunology

Therapeutic

treatment of cancers using monoclonal antibodies (…..mab)

value of the immune system52
Value of the Immune System
  • Clinical applications of immunology

Therapeutic

    • ADCC-mediated NK cell killing of B-lymphocytes that are secreting antibodies that cause symptoms of rheumatoid arthritis
slide53

Antibodies specific for a selected cell surface molecule

    • e.g., bone marrow stem cells (express CD34)
    • FITC-labeled anti-CD34 antibodies
    • Isolate BM stem cells using fluorescence-activated cell sorter (FACS)
remove tumor cells from bone marrow cell suspension
Remove tumor cells from bone marrow cell suspension
  • Attach a magnetic bead to Fc portion of monoclonal antibody specific for non-self antigen on surface of tumor cells
  • Mix cell suspension with these “magnetic” antibodies
  • Antibodies will bind to only tumor cells (antibody specific for only non-self antigens on the tumor cell)
  • Pass entire cell suspension past a magnet
  • Tumor cells are drawn to magnet
  • Non-tumor cells keep flowing past

Tumor cell

systemic and mucosal immune systems
Systemic and Mucosal Immune Systems
  • Systemic Immune System – responding to threats inside the body
    • Phagocytes (macrophages, PMNs, dendritic cells), NK cells, complement
    • Lymph nodes, lymphatic system, spleen, blood circulation
    • Responding to pathogens that have entered the body (broken skin, insect bites, viruses that have successfully crossed intact barriers, e.g, membranes)
    • Tumors, transplants, self tissues (autoimmunity)
  • Mucosal Immune System – responding to pathogens at membrane mucosal surfaces
the mucosal immune system
The Mucosal Immune System
  • The vast majority of human pathogens enter the body at mucosal surfaces
  • Surface area is HUGE – small intestine alone has over 2000 ft2 of surface area
  • Constant interaction with literally billions of pathogens, potential pathogens and resident “commensal” pathogens (normal flora)
  • Immune system has evolved to create a special version designed to provide protection from infections at these mucosal surfaces and within the spaces encompassed by the mucosal layers (e.g., lumen of the gi tract)
  • Even the entrance into the gi tract (i.e., the mouth) has a complex set of mucosal immune system tissues
the mucosal immune system58
The Mucosal Immune System
  • Even the isotype of antibody (sIgA) is uniquely designed to move into these mucosal areas and resistdestruction by the rather harsh proteolytic environment of mucosal areas (e.g., digestive enzymes in the gi tract)
the mucosal immune system59
The Mucosal Immune System
  • and functioneffectively there in a variety of ways
cells of the mucosal immune system
Cells of the Mucosal Immune System
  • Designed to constantly “sample” contents of the intestinal lumen
  • Dendritic cells can literally stretch through epithelial cell junctions and reach into the lumen to bind to pathogens there
cells of the mucosal immune system62
Cells of the Mucosal Immune System
  • All of the cell types needed for almost any type of immune response (innate and adaptive) are found just below the surface of the gut epithelium
lymphoid tissues of the mucosal immune system
Lymphoid tissues of the Mucosal Immune System
  • Peyer’s patches (example of GALT - gut associated lymphoid tissues)
  • Organization is ideal for sampling and responding to pathogens in the intestinal lumen
lymphoid tissues of the mucosal immune system64
Lymphoid tissues of the Mucosal Immune System
  • In addition to DCs reaching across the epithelial layer
  • M (microfold) cells endocytose and phagocytize antigens in the gi lumen
  • Dump the antigen fragments into the Peyer’s patch
  • DCs take in the degraded antigens, process & present them to T-cells
  • T-helper cells “help” B-cells
lymphoid tissues of the mucosal immune system65
Lymphoid tissues of the Mucosal Immune System
  • Stimulated (effector) T-cells and B-cells leave the Peyer’s patch
  • Cells move through a lymphatic system associated with the gi tract
    • Mesenteric lymph nodes
      • Connected by a network of lymphatic vessels
      • Found only in the mesentery
  • Move into the “inside-the-body” lymphatic system
  • Cells eventually enter the blood circulation
  • (via the left subclavian blood vessel)
homing of these effector lymphocytes
“Homing” of these effector lymphocytes
  • Effector lymphocytes generated in the mucosal immune system almost always return to that system
  • Unique set of adhesion molecules designed to “stop” these lymphocytes near the gut
  • Lymphocytes then populate the tissue spaces just below the epithelial cell layer
  • Response remains associated with those membranes (does not usually become involved in responding to “internal” pathogens (that is the function of the systemic immune system)
  • Almost an entirely “separate” mucosal immune system
some problems caused by the immune system
Some problems caused by the immune system
  • Allergic reactions
    • allergens are non-self
    • IgE antibodies and mast cells
    • Skin-testing
    • Desensitization (allergy “shots”)
  • Autoimmunity
    • Loss of self/non-self discrimination
    • Some examples of autoimmune diseases
    • HLAs and predisposition to autoimmunity
  • Transplant rejection
    • HLAs
    • HLA tissue matching
    • Survival of fetus (more details coming)
    • Bone marrow transplants (more details coming)
      • Graft-vs-host disease (and use of BM stem cells)
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