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HSCI 359-62 Translational Health Science Internship in Argentina

HSCI 359-62 Translational Health Science Internship in Argentina. Introduction to Immunology II. Several Levels of Protection Against Infections. 1) Nonspecific Barriers (Mechanical, Chemical, and Biological) Innate Branch of our Immune System Acquired or Adaptive Branch

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HSCI 359-62 Translational Health Science Internship in Argentina

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  1. HSCI 359-62 Translational Health Science Internship in Argentina

  2. Introduction to Immunology II

  3. Several Levels of Protection Against Infections • 1)Nonspecific Barriers • (Mechanical, Chemical, and Biological) • Innate Branch of our Immune System • Acquired or Adaptive Branch of our Immune System

  4. The cells of the Immune system ?

  5. Cells of the Adaptive Immune Response http://versatilehealth.com

  6. Variable Region Constant Region Transmembrane Region B Lymphocytes (yellow) (green) B cell

  7. B Lymphocytes • Any chemical structure that is recognized by a BCR is called an antigen (antibody-generating molecule) • More specifically BCRs recognize/bind to a portion of the antigen called “epitope”. epitope antigen (yellow) The BCR is also called sIg (surface immunoglobulin) (green) B cell

  8. Figure 2-10

  9. Antibody-Antigen Interaction Antigen binding sites Multiple weak interactions hold the antigen associated with the variable region of the antibody molecule Electrostatic interactions Hydrophobic interactions Hydrogen bonds Van der Waals forces

  10. B Lymphocytes • As a group, B cells have the potential to recognize almost any microbial antigen  organic molecules like proteins, DNA, sugars, etc. B cell #3 B cell #1 B cell #2

  11. One little B cell so many pathogens... •  The body produces millions of B lymphocytes every day, each able to recognize a different antigen • Once B cells are made (and checked for a few things we do not have time to talk about!) they exit the bone marrow and travel to lymphatic tissue (e.g. lymph nodes) • Once in the LN, if a B lymphocyte 1 recognizes an antigenvia its BCR (e.g. a viral protein, a bacterial sugar) and 2 receivessecondary, “co-stimulatory” signals(more on this later)  that B cell that experiences 1+2 proliferates (i.e. divides), generating a clone of cells containing the same unique type of BCR on their surfaces (i.e. recognizing the same target molecule).

  12. B Lymphocytes inside Lymph Nodes A Pacman infection, leads to “Clonal expansion” of B cell bearing Pacman-specific receptors Recognition of Antigen + Secondary Signal B cell #3 B cell #3 B cell #3 B cell #3 B cell #3 B cell #3 B cell #3 B cell #3 B cell #3 B cell #3 B cell #3 B cell #3 B cell #3 B cell #1 B cell #3 B cell #3 B cell #2 B cell #5 B cell #4

  13. 1) Later, some cells of the clone differentiate into plasma cells that secrete Pacman-specific receptors  antibodies that bind Pacman! 1 B cell #3 B cell #3 B cell #3 B cell #3 2 2) Other cells of the clone differentiate into “memory” B cells that will stay in our bodies until Pacman infects us again B cell #3 B cell #3 B cell #3 B cell #3 B cell #3 B cell #3 B cell #3 B cell #3 B cell #3 B cell #3

  14. Figure 1-19 part 1 of 2 Memory B Cell Encounter Antigen Activation Proliferation Differentiation Plasma Cell

  15. B Lymphocytes • The body produces millions of B lymphocytes every day, and each B cell has a unique BCR, which has the capacity to bind a unique chemical structure . B cell #3 B cell #1 B cell #2

  16. Problem... • The human genome is not big enough • to code for a different gene for each BCR • on the surface of each B cell • (we make millions of B cells daily!)… The human genome has ~20,000-25,000 protein-coding genes

  17. Antibody Diversity The problem is taken care of during B cell development by joining together gene modules in various combinations. Immature B Cell genomic DNA Gene coding for the BCR heavy chain V1 V2 V3 D1 D2 D3 D4 J1 J2 CM CD CG ~ 50 ~ 20 ~ 6 ~ 10 Selection of Gene Segments and DNA Recombination Mature B Cell genomic DNA Gene coding for the BCR heavy chain V3 D2 J1 CG The newly formed “VDJ” DNA segment codes for the Variable Region of the immunoglobulin The “C” DNA segment codes for the Constant Region of the immunoglobulin

  18. Figure 4-2

  19. Antibody Diversity • During the process of cutting and pasting gene segments, more diversity is created by adding or removing bases from the segment’s ends. • This process creates millions of unique B cells with unique BCRs, each waiting for the right antigen to come along. • Remember that once a B cell gets activated, it transforms into a factory that produces and secretes antibodies. • The antibody-mediated branch of our immune defenses is often regarded asHumoral Immunity.

  20. How do antibodies work? •  Neutralization of microbes.

  21. Figure 2-20 • However, the cell can decide which type of gene segment to use to make the constant portion of the antibody molecule • This creates different types of immunoglobulins with different properties but Identical specificity Protein Immunoglobulin Isotypes Constant Region of H chain Once the gene is rearranged, the cell uses always the same newly formed VDJ segment to make the Variable region of the heavy chain of the antibody molecule DNA

  22. Immunoglobulin Isotypes • By choosing from a menu of different “C” gene segments, B cells that are activated by antigen can make different “flavors” of antibodies with identical variable regions (i.e. specific for the chosen antigen) but having different “tails”. • Depending on the type of “tail” that antibody molecules have, they are classify within Five different classes: • IgM • IgG (there are 4 subclasses of this) • IgE • IgD • IgA (there are 2 subclasses of this),

  23. Variable Region Constant Region What can a tail do? •  Antibodies are bifunctional molecules: one end (variable region) binds to the antigen, and the other end (tail of constant region) links the antigen-antibody complex to effectors cells. (yellow) Fc Domain (green)

  24. Figure 9-32 How do antibodies work? • Opsonization of microbes Antibody binding to the surface of microbes targets them for destruction by macrophages and other cells. Phagocytic cells (macrophages and neutrophils)have receptors for the Fc domain of the tail of IgG molecules (also for IgA) Binding to antibody-opsonized pathogens triggers phagocytosis

  25. Figure 9-34 How do antibodies work? ADCC Antibody Dependent Cellular Cytotoxicity NK cellshave receptors for antibodies of the IgG and IgA isotypes Engagement of receptor with the Ag-Ab complex activates cell-killing mechanisms that eliminate the target cell.   

  26. What can a tail do? IgG • Most abundant in serum and in the fluids in tissues ~75% of the total Igs (10-15 mg/ml in a normal adult) • Only class of Ig that is transported across the placenta -->passive immunization • Stable proteins IgG has a half life of about 20 days, therefore you get protection from mother's Ig after birth.

  27. Two subclasses of IgA • IgA1 - major subclass • in serum (monomeric) • IgA2 - major subclass in extracellular fluids (dimeric)

  28. Secretion of IgA through epithelial cells • IgA is the main Immunoglobulin found in secretions • (saliva, colostrum, tears, fluids of the mucus membranes, etc.) • Milk--passive immunity in intestinal tract of newborns

  29. A pentamer of IgM has the potential for 10 binding sites!! (also known as a “valency of 10”)

  30. IgM • The class of Immunoglobulin produced in the early stages of a primary response to antigen. • Efficiently binds to and activates complement proteins, initiating the complement cascade

  31. Figure 2-29

  32. Antibody production during infections (or vaccinations) • Primary response to antigen: the first time B cells encounters an antigen • outside the bone marrow they secrete one type of antibody: always IgM . • Later, they switch to IgG production and secretion. IgG • In a secondary response (i.e. second exposure to antigen), IgG production begins immediately and goes to a high level. There is a complete switch to IgG

  33. Different subsets of cytokines favor switching to different classes • In certain occasions, and depending on the type of pathogen the body is fighting, B cells may switch antibody production to IgA or IgE after making IgM.

  34. Activation of B cells inside lymphatic tissue

  35. Signal 1 Signal 2 T cell-dependent activation of B cells • For most antigens, signaling from the the BCR is not enough to activate a naïve B cell • A second signal called a “co-stimulatory signal” is also required. • Help from activated T helper (Th) cells is the second signal required for clonal expansion and differentiation of B cells leading to antibody production. • Such antigens are thus said to be T-cell dependent.

  36. T cell-dependent activation of B cells • The help comes in two forms: contact help and cytokine help. • Activated Th cells have CD40L on their surfaces, which binds to CD40 on the surface of B cells. When these two proteins interact, a “co-stimulatory signal” is sent to the B cell. • In humans, genetic defects in either CD40 or CD40L results in the absence of T cell-dependent antibody responses!

  37. T cell-dependent activation of B cells • TheT helper cell also releases cytokines(IL-2, IL-4, and IL-5) that signal the B cell to divide • These cytokines are also needed for the B cell to start synthesizing antibodies for secretion. • The receptors for these cytokines are expressed on B cells only after the initial activation triggered by antigen binding to the BCR • (Thus, only activated B cells are capable of responding to stimulation from Th cells) CD40 CD40L

  38. Once activated, B cells make a career choice: plasma cells or memory B cells • How a B cell makes that decision is still not very clear • Plasma cells • Larger • Specialized for secretion (a lot of ER and Golgi) • No BCR • Do not proliferate, they circulate for a few days then die • Memory cell • Formation takes place after class switching (memory cells never express IgM) • The CD40-CD40L interaction is needed to make memory cells • Retain the ability to proliferate and are very long-lived (decades?) • They can re-enter lymphoid organs and undergo affinity maturation

  39. Naïve and memory B cells have different activation requirements • The requirements for activation of naïve B cells are more stringent than those of memory B cells • Memory B cells have already been selected based on their ability to recognize a foreign antigen in a specific manner. Thus, when they encounter an antigen in a subsequent exposure, theycan by-pass most of the Th cell help. • Memory cells express cytokine receptors, so if they encounter their cognate antigen during an attack, cytokines (i.e. IFN-g) released by other cells of the immune system are sufficient to provide co-stimulation.

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