Development of the Lymphatic System

John R. Palisano, Ph.D.

  1. Introduction
    1. Function of the lymphatic system
      1. Defense against foreign invaders
      2. Rejection of donor tissues/organs
      3. Prevention of fluid build-up in tissues associated with capillaries
    2. Structure of the lymphatic system
      1. Lymph Vessels
      2. Lymph Nodes
        1. Lymph follicles
          A lymph node
        2. Afferent lymphatic vessels
        3. Efferent lymphatic vessels
    3. Additional lymphatic tissues
    4. Evolution of the lymphatic system
      1. Primitive lymphatic systems
      2. Advanced lymphatic systems
    5. Development of the lymphatic system
      1. Definitions of humoral and cell-mediated immunity
      2. Development of immunity in chicken
        1. Embryonic origin of lymphoidal organs
        2. Origin of lymphoid stem
        3. Cell migration of lymphoid cells
        4. Bursectomy experiments
      3. Development of immunity in mammals (mouse model)
        1. Embryonic origin of lymphoidal organs
      4. Origin of lymphoid stem
      5. Cell migration of lymphoid cells
      6. Thymectomy experiments
  2. Single-cell level induction
    1. Introduction
      1. Cell application rather than tissue
      2. Inducing and responding cells
      3. Determines cell differentiation
    2. Immune system
      1. Example of cell-level induction
      2. B-cell reception of antigen
      3. Response to helper T cell
        1. Paracrine factors
        2. Juxtacrine factors
      4. Reciprocal dialogue between B and T cells
        1. Results in differentiation and proliferation
  3. Humoral immunity
    1. Clonal selection theory
      1. Five major postulates
      2. Naive lymphocyte expands to plasma cell or memory cell
        Diagram explaining clonal selection (click to enlarge, or click here)
    2. Experimental evidence for clonal selection theory
    3. Cooperation between B and T cells
    4. Classes of antibodies
    5. Immunoglobulin diversity - driven by single-cell level induction
      1. Immunoglobulin gene structure
        1. 3 unlinked gene families code for Ig peptide chains
        2. Each have gene segments coding for variable regions of molecule
        3. Small gene segments: J (joining) and D (diversity)
      2. Lambda light chains
        1. VL and CL regions separate genes
        2. In humans, VL codes from N-terminus end to position 95; CL from position 110 to C-terminal end
        3. Intervening 15 amino acids. by JL
        4. Number of segments of light chain: VL, JL, and CL
      3. Kappa light chain
        1. In mice kappa light chain, 90 to 300 VK gene segments, five JK, and one CK segment
        2. In humans, 75-80 VK segments, five JK, and one CK segment
      4. Ig heavy chain
        1. In humans, 100-300 VH segments, nine JH
        2. In mice, 1000 to 1500 VH and JH known as D segments
        3. Short DNA segments between VH and JH known as D segments
          • contribute significantly to the hypervariability in heavy chain variable region
          • Mice - 12 D gene segments
          • Humans - 5 D gene segments
        4. Five heavy constant gene segments
          An antibody molecule
  4. Generation of V-region diversity
    1. Gene rearrangement of light chains
      1. CL linked to VL region by V & J segments
      2. Introns removed
      3. V and J gene segments spliced together
      4. The V-J gene segments linked to C gene segments by transcription
    2. Heavy chain
      1. Presence of D gene segment between VH and JH segments
      2. V region of Ig heavy chain - random splicing of VH, DH, and JH segments
      3. While diversity is achieved by splicing, not all combinations of gene segments provide usable peptide
    3. N-region addition
      1. Another way to generate Ab diversity
      2. One to 10 nucleotides inserted between V and D and between D and J
    4. Somatic mutation
      1. Gene segment rearrangement and N-region addition do not explain the known variability in VL and VHregions
      2. Amino acid substitutions result from single base changes within the VH region
      3. Mutations result in Ab with greater affinity for Ag
        1. Exhibit enhanced stimulus to divide
        2. Occurs after B cells undergone heavy-chain class switch
      4. Frequency of somatic mutations - 10-3 to 10-4 base pairs/cell/generation
  5. Summary of Ig diversity
    1. Variable region
      1. Three hypervariable regions in each variable region
      2. Hypervariable regions interact with immunogen
      3. Designated as CDR1, CDR2, and CDR3
        1. CDR1 and CDR2 coded by V gene
        2. CDR3 by conjunction of V and J gene segments
        3. CDR1 and CDR2 variability generated by somatic mutations
        4. CDR3 by V-J splicing around position 96-97
      4. CDR3 diversity generated 3 different ways
        1. Random coupling of VK and JK segments
        2. Imprecise joining of DNA
        3. Functional site diversity increased by N-region addition
    2. Constant region diversity generation
      1. Constant region Ig heavy chains vary according to Ig isotypes
      2. Each Ig isotype coded by four or five different CH exons
      3. During an Ab response, Ig isotypes synthesized in a sequence
    3. Ig type switching
      1. Selection of the required VDJ segments
        1. Early event in development of B cells
        2. VDJ arrangement cannot change once selection occurs
      2. Selection for specific Ig isotype late event
      3. Isotype selection of C-regions genes deleted by looping out of the unwanted segments and deletion.
  6. Cellular immunity
    1. Second system that protects vertebrates
    2. T lymphocytes
      1. Like B lymphocytes, T lymphocytes have antigen receptors in membrane
      2. Antigens stimulate production and differentiation of differnt T cell populations
        1. Cytotoxic T lymphocyte
        2. T helper lymphocyte
        3. Natural killer cell
      3. Clonal selection hypothesis accounts for large scale production of T cells as it does B cells

Selected Bibliography

Carlson, B.M. 1996. Patten's Foundations of Embryology. 6th ed. New York: McGraw-Hill, Inc.

Gilbert, Scott F. 2000. Developmental Biology. 6th ed. Sunderland, MA: Sinauer Associates, Inc., Publishers.Larsen, W.J. 1998.

Essentials of Human Embryology. New York: Churchill Livingstone Publishers.Oppenheimer, S.B. and G. Lefevre, Jr. 1989.

Introduction to Embryonic Development. 3rd ed. Boston: Allyn and Bacon.Pough, F.H., J.B. Heiser and W.N. McFarland. 1996.

Vertebrate Life. 4th ed. Upper Saddle River, NJ: Prentice Hall.Tizard, I.R. 1995.

Immunology: An Introduction. 4th ed. Philadelphia: Saunders College Publishing.Walker, Warren F. 1987.

Functional Anatomy of the Vertebrates: An Evolutionary Perspective. Philadelphia: Saunders College Publishing.

 

Study Questions

1. Briefly describe the architecture of a typical lymph node and discuss how it facilitates to the function of the lymph node.

2. What are the five postulates of the clonal selection theory?

3. How does the variable region of an antibody molecule differ from the constant region of the molecule?

4. What is meant by the phrase "single-cell level induction"?

5. What are the three major ways in which the diversity of the variable region of the antibody molecule is increased in differentiating B lymphocytes?

 

Hot Links

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http://www.tulane.edu/~dmsander/Big_Virology/BVHomePage.html

 

 

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