Antibody Synthesis week 2 Flashcards Preview

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Flashcards in Antibody Synthesis week 2 Deck (13):
1

When triggered by antigen, B-cells differentiate into what cell type? What is the difference btwn B-cells and this cell type?

B-cells are also antigen presenting cells. What cells to they present antigens to? What molecule do they use to present antigens to these cells?

B-lymphocytes are cells that specialize in the ability to produce Immunoglobulin (Ig) molecules with specific antigen binding capacity. B-cells, when triggered by antigen, will differentiate into plasma cells capable of producing antibodies (Ab). B-cells do not secrete Ab; only plasma cells produce soluble Ig (i.e., Ab).

B-cells are also antigen-presenting cells (the receptor for antigens are the surface Ig) and are capable of internalizing (antigen bound to Ig) and processing peptide antigen to be presented in the context of MHC class II molecules to CD4+ helper T-cells.

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2

What B-cell functions/processes are T-cells required for?

B-cells have the potential to form a clone of immunoglobulin with greater affinity for antigen (affinity maturation) and a different constant region heavy chain (isotype switching). These two events require CD4+T-
helper cells. T-helper cells are also required for generation of memory B-cells (see lecture notes on Immune memory).

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3

How do B-cells get into lymph nodes?

Where in lymph nodes does maturation of B-cells occur?

Where in the lymph node do B-cells differentiate into plasma cells?

What cells within lymph nodes bind antigens and present them to B-cells? What kind of receptors do these cells contain to recognize antigens?

What do B-cells do with antigens they are presented? Where in the LN do B-cells go after being presented antigens?

 

  • The B-cell moves into the LN through the HEV via chemokines.
  • The maturation of B-cells occurs within (primary and secondary) follicles and germinal centers in the cortex of the lymph node. These B-cell rich areas are critical sites where B-cells reside in order to differentiate to plasma cells, switch isotypes, undergo affinity maturation and generate memory cells.
  • B-cells differentiate into plasma cells in the medullary cords. Afterwards, the plasma cell then travel into the lymphatic vessels
  • Antigens enter the afferent lymphatic vessel from the site of infection and are dumped into the cortex of the LN where it encounters follicular dendritic cells (FDC). FDC contain complement receptors that recognize complement side chains/fragments attached to antigens on pathogens.
  • Once inside the paracortex, they travel to the cortex where they encounter antigen bound to the FDC. If the B-cell contains Ig specific for the antigen they will endocytose the antigen attached to the FDC and process it for presentation by MHC II molecules. At this point the B-cell will migrate to the paracortex cortext border where they will interact with T-helper cells.

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4

What is the key to B-cell activation? What may act as an activation in place of this?

The key to B-cell activation is cross-linking of Ig on the B-cell surface. Complement receptor CR2 may act as an activation co-receptor in place of antibody crosslinking.

see top of pg 50 of course notes

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5

Explain the role of CR2 receptor in activation of B-cells.

CR1 on B-cells binds to C3b on the surface of pathogens. C3b is cleaved into iC3b and C3d by Factor I. CR2 binds to C3d and is activated. CD19 interacts with CR2 to trigger cell signaling after activation of the CR2 receptor. The CR2 receptor can also be activated by C3d on soluble antigens. please see slide 13 of PP!

6

What receptor do follicular dendritic cells recognize antigens by in order to present them to B-cells?

Complement receptor (CR2) on follicular dendritic cells also acts to trap and display antigen to Ig on B-cells.

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7

What type of T-cells do B-cells present antigens in to in the context of MHC class II molecules? Where are these T-cells located within the LN?

What two things does activation of TCRs on these T-cells trigger the expression of? What does this do to the B-cell?

Affinity maturation and memory B-cell formation occurs in the germinal centers of lymphoid tissues in the presence of TFH cells: Interaction between peptide in association with MHC class II molecules on B-cells and a group of T-helper cells called T-follicular helper (TFH) occurs. The TFH subset is the only one of the several CD4+ T-cells found in germinal centers. The triggering TCR on TFH leads to expression of CD40 ligand and secretion of cytokines essential for isotype switching, affinity maturation and generation of memory B-cells (see lecture notes on “Immune Memory” later in this block for further details)

please see figures on pg 51 of course notes

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8

What is affinity maturation? What causes it?

What is required for affinity maturation? Explain this process and the cells involved.

Affinity maturation of antigen binding site of antibodies results from somatic hypermutation of the antigen-binding site.  Somatic hypermutations occur within the variable region genes of Ig to generate a clone of antibody with greater affinity for antigen. Affinity maturation does not occur unless CD40 on B-cells is triggered. B-cells in the germinal center with highest affinity for antigen receive survival signals and begin to proliferate after receiving signal from TFH. B-cells containing Ig with lower affinity for antigen will not receive the survival signal and will die. This will assure that the B-cell containing the Ig that underwent somatic hypermutation in the Ig binding region will have the highest affinity to antigen. Only those B-cells having the highest affinity for antigen will survive and go into the periphery and end up in mucosal and/or inflamed tissues (sites of infection).

Wikipedia:

Clonal selection: B cells that have undergone SHM (somatic hypermutation) must compete for limiting growth resources, including the availability of antigen and paracrine signals from Tfh cells. The follicular dendritic cells (FDCs) of the germinal centers present antigen to the B cells, and the B cell progeny with the highest affinities for antigen, having gained a competitive advantage, are favored for positive selection leading to their survival. Positive selection is based on steady cross-talk between Tfh cells and their cognate antigen presenting GC B cell. Because a limited number of Tfh cells reside the germinal center, only highly competitive B cells stably conjugate with Tfh cells and thus receive T cell-dependent survival signals. B cell progeny that have undergone SHM, but bind antigen with lower affinity will be out-competed, and be deleted. Over several rounds of selection, the resultant secreted antibodies produced will have effectively increased affinities for antigen.

attached is pg 52 of course notes

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9

What is necessary to induce isotype switching? What cells induce isotype switching? Where are these cells located?

What induces a B-cell to switch to one isotype of Ig over another?

Engagement of CD40 and exposure to cytokines induce isotype switching-IgM to IgG, IgA, or IgE. The CD40 receptor on B-cells binds to CD40L on TFH, TH1, and TH2 cells which triggers cytokine release from these T-cells. The type of cytokine that engages its receptor on B-cells will determine the isotype of the Ig. Specific T-helper cells produce specific cytokines.

It should be made clear that TH1 and TH2 interact with B-cells at the border between the cortex and medullary regions of the LN for the purpose of class switching. But only TFH cells are found in germinal centers where affinity maturation and memory B-cells occurs.

see pg 53 of course notes

10

State what cytokines are released by Th1, Th2, and Tfh cells to induce isotype switching.

What are the functions of each of these T-cells?

Th1: release IFN-gamma, GM-CSF, TNF-alpha, LT, and IL-2. Th1 cells release these cytokines to help macrophages suppress intracellular infections.

Th2: release IL-4, IL-5, IL-10, IL-13, and TGF-beta to help basophils, mast cells, eosinophils, and B-cells respond to parasite infections

TfH: release IL-4, IL-21, IFN-gamma to help activate B-cells, stimulate isotype switching, affinity maturation, and formation of memory B-cells.

attached is slide 25 of PP

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11

Explain the interaction between the development of Th1 vs Th2 cells with exposure to a pathogen. What stimulates the development of one over the other?

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12

What defines a T-independent antigen response? What is the result (as it pertains to B-cells) of these types of responses?

T-cells recognize ONLY peptides presented by MHC molecules. If Ag is not a protein (If it is a polysaccharide, lipid or nucleic acid), the Ag can still elicit an immune response, but without T-cell help. All T-independent antibody responses are IgM, There is no affinity maturation, no class switching and no memory B-cells are formed.

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13

What is Hyper IgM syndrome? What is it due to? What chromosome is implicated? What is the result of this disorder?

Patients lack CD40 ligand on CD4+ T cells. Gene for CD40 ligands is on X-chromosome

• Ig genes within B-cells cannot switch to other isotypes

• Poor antibody response since no affinity maturation is possible

• Secondary lymphoid tissues have no germinal center

Pt presentation: severe pyogenic (pus producing) infections early in life

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