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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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PowerPoint Slideshow about 'Value of the Immune System' - RoyLauris


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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

    • 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


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Value of the Immune System

  • Immune responses against infectious diseases

  • Bacterial pathogens, bacterial exotoxins and viral pathogens





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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)


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Innate Immunity

  • Cells and molecules present all the time

  • Cells are ready to respond immediately

  • Does not improve with use


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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


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Value of the Immune System

  • Components of the innate immune system

    • Cells

      • Phagocytes

      • PMNs & macrophages


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Value of the Immune System

  • Components of the innate immune system

    • Cells

      • Phagocytes

      • PMNs & macrophages

      • Macrophages & toll-like receptors (TLR)


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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


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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


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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


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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


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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


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START of December 15 discussion phagocytosis in which one of the following ways?


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Value of the Immune System phagocytosis in which one of the following ways?

  • 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)


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Value of the Immune System phagocytosis in which one of the following ways?

  • 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)


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Value of the Immune System phagocytosis in which one of the following ways?

  • 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


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Value of the Immune System phagocytosis in which one of the following ways?

  • 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


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Bonus phagocytosis in which one of the following ways? 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


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Value of the Immune System phagocytosis in which one of the following ways?

  • 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


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Value of the Immune System phagocytosis in which one of the following ways?

  • 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)


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Value of the Immune System phagocytosis in which one of the following ways?

  • 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


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Value of the Immune System phagocytosis in which one of the following ways?

  • Adaptive immunity

  • Antibodies

    Antibody isotypes and related properties

    Associated with the constant portion of the heavy chain


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Value of the Immune System phagocytosis in which one of the following ways?

  • 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


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Value of the Immune System phagocytosis in which one of the following ways?

Antibody isotypes and related properties

Associated with the constant portion of the heavy chain


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Value of the Immune System phagocytosis in which one of the following ways?

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


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Antibodies can phagocytosis in which one of the following ways?

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


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Antibodies can phagocytosis in which one of the following ways?

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


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TWO Clicker questions at the start of class phagocytosis in which one of the following ways?

  • 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


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The phagocytosis in which one of the following ways?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


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TWO of the five antibody isotypes are involved in providing phagocytosis in which one of the following ways?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


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Hold your iClicker in one hand and hold phagocytosis in which one of the following ways?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


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Antibodies can phagocytosis in which one of the following ways?

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


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Immunoglobulin isotypes phagocytosis in which one of the following ways?

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


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Antibodies can phagocytosis in which one of the following ways?

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


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Fetal/infant protection phagocytosis in which one of the following ways?

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


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Antibodies can phagocytosis in which one of the following ways?

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

blood vessel endothelial cell layer (IgG only)


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Antibodies can phagocytosis in which one of the following ways?

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


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Value of the Immune System phagocytosis in which one of the following ways?

Antibody isotypes and related properties

Associated with the constant portion of the heavy chain


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Value of the Immune System phagocytosis in which one of the following ways?

  • 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


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  • Lymphocytes phagocytosis in which one of the following ways?

  • 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)


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  • Lymphocytes phagocytosis in which one of the following ways?

  • 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


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Value of the Immune System phagocytosis in which one of the following ways?

  • 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)


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Destruction of cancer cells phagocytosis in which one of the following ways?

  • 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


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The phagocytosis in which one of the following ways?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?


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Value of the Immune System phagocytosis in which one of the following ways?

  • 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


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Value of the Immune System phagocytosis in which one of the following ways?

  • Clinical applications of immunology

    Diagnostic

    • Detection of colon cancer using radiolabeled monoclonal antibodies


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Value of the Immune System phagocytosis in which one of the following ways?

  • Clinical applications of immunology

    Therapeutic

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


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Value of the Immune System phagocytosis in which one of the following ways?

  • Clinical applications of immunology

    Therapeutic

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


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Remove tumor cells from bone marrow cell suspension phagocytosis in which one of the following ways?

  • 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


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Start of January 3, 2011 discussion phagocytosis in which one of the following ways?


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Systemic and Mucosal Immune Systems phagocytosis in which one of the following ways?

  • 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


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The Mucosal Immune System phagocytosis in which one of the following ways?

  • 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


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The Mucosal Immune System phagocytosis in which one of the following ways?

  • 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)


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The Mucosal Immune System phagocytosis in which one of the following ways?

  • and functioneffectively there in a variety of ways



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Cells of the Mucosal Immune System immunity

  • 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


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Cells of the Mucosal Immune System immunity

  • 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


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Lymphoid tissues of the Mucosal Immune System immunity

  • Peyer’s patches (example of GALT - gut associated lymphoid tissues)

  • Organization is ideal for sampling and responding to pathogens in the intestinal lumen


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Lymphoid tissues of the Mucosal Immune System immunity

  • 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


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Lymphoid tissues of the Mucosal Immune System immunity

  • 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)


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“Homing” of these effector lymphocytes immunity

  • 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


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Some immunityproblems 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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