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Topic 5 B cell

  • B cell here main contribute to humoral immunity

  • B cells are produced in lymph node
    • Naive B-lymphocyte go through recombination (like T cell), by receiving circulating free lgD antigen (by random chance) --> BCRs
    • --> activated B cell --> receptor-mediated endocytosis --> pull antigen in
    • --> In B cell, antigen produce an endosome, and B cell produce specific MHC2 that can bind to the antigen --> MHC2 expose to membrane, the B lymphocyte is activated
  • In T cell side:
    • macrophage will have MHC-2 (antigen specific) and MHC-1
    • How it interact with Naive T helper cell
      • Signal 1: T cell receptor (TCR) --> bind to antigen gotten by MHC2 & CD4 protein --> bind to MHC2
      • Signal 2: macrophage have long protein B7 that can bind the CD28 in T helper cell
      • Signal 3: Macrophage secrete IL-1, IL-1 bind to T helper
        • Signal 1 + Signal 2 + Signal 3 --> costimulation
          • T cell activated --> T helper secrete IL-2 --> can bind and activate T cell too -->==IL-4==, ==IL-5== secretion --> make the T cell to Th2 cell
  • Why T cell side matters to B cell? --> cause clonal expansion
    • IL-4 released by T helper cell --> activate B lymphocyte --> proliferation of B cell (with special BCRs)
    • IL-5 function after the clonal expansion --> B cell start to differentiation
      • --> memory B cells with BCR
      • --> plasma cells /effector B cells
    • IL-5 and IL-6 activate plasma cells--> secrete ==antibodies== (specific to antigen)
  • Then antibodies can beat antigens
    • Neutralization: anitbody bind to the antigens on the surface of bacteria or virus
    • Precipitation: bind to circulating free antigens, and cause them to have precipitation
    • Lysis: produce protein that can cause the bacteria to lysis
    • Attract macrophages: antibody could produce proteins that attract the macrophage to kill the antibody

B cell Tolerance

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  • B cell will have VDJ recombination process to produce BCR, which is random --> will produce B cells that recognize self-antigens

    • ==Solution==: quality control system called tolerance

  • Central Tolerance: Bone marrow; before B cells enter the blood, it must prove it is not dangerous

    • Stage: Immature B cells, expressing lgM on surface
    • Self-antigen Test:
      • protein, DNA, cell surface markers
      • Possible outcomes:
        • if B cell doesn't bind to any self-antigen
          • --> to the spleen to complete maturation
        • else if B cell binds tightly to a self-antigen
          • --> stop B cell moving from marrow; this triggers Receptor editing, RAG reactivation
            • the cell keeps the RAG1 and RAG2 genes activated
            • it deletes the existing light chain and rearranges a new one
            • In other word, it creates a new BCR with a new specificity
            • if pass: Survival and export to periphery
            • else (still have auto-reactive): cell tries again or dies
          • Die: Clonal deletion (apoptosis)
            • the cell activates the intrinsic apoptotic pathway
        • else if weak reaction
          • The B cell binds weakly or to a soluble self-antigen
          • Cell becomes permanent non-responsiveness and die due to competition in the periphery
  • Peripheral tolerance (as backup system)
    • Location in spleen, lymph nodes, and circulation
    • Stage: Transitional and mature B cells
    • Mechanisms of removal:
        1. Follicular exclusion: auto-reactive B cells are chemically excluded form the Follicles, which will let them die
        1. Resource Competition
        2. B cells compete for a critical survival cytokine called ==BAFF== (B cell activating factor)
        3. Normal B cells are better at capturing BAFF
        1. Lack of T cell help
        2. For a B cell to fully activate and cause damage, it usually needs confirmation signal from a helper T cell
        3. If a B cell presents a self-antigen to a T cell, but the T cell (which has its own tolerance checks) does not recognize it, the B cell receives no help (no CD40L signal).
          • Key Mechanism of B cell: Linked Recognition
            • B cells do not just show exactly what they bound to on the outside
            • But they will cut the peptide and then present the parts, to T cells TCR
Feature Central Tolerance Peripheral Tolerance
Location Bone Marrow 26 Spleen / Lymph Nodes 27
B Cell Stage Immature B Cell (IgM+) 28 Transitional / Mature B Cell 29
Primary Trigger Binding to self-antigen in marrow 30 Binding to self-antigen in periphery
Key Mechanism 1 Receptor Editing: RAG reactivation to change receptor 31313131 Anergy: Functional unresponsiveness 32
Key Mechanism 2 Clonal Deletion: Apoptosis via Bim 33 Follicular Exclusion: Denied entry to survival niches 34
Key Mechanism 3 Anergy: If antigen is soluble/weak Starvation: Competition for BAFF 35