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Flashcards in B Cell Immunity Deck (18)

B cell development in fetus

-the location of hematopoiesis is in developing liver
-the liver remains the major site of fetal hematopoiesis until shortly before birth when stem cells travel by blood to the spleen and bone marrow (hence why cord blood has stem cells)
-population of the bone marrow may be facilitated by chemotactic and growth factors released from bone matrix and connective tissue cells
-the bone marrow remains the primary site of hematopoiesis in adults until death, although some hematopoietic stem cells in connective tissue of the abdominal mesenteries can be induced to form hematopoietic colonies by cytokines released during inflammation


Phases of B cell

Phase 1- generation of B cells in bone marrow
Phase 2- elimination of self-reactive B cells in bone marrow
Phase 3- activation of B cells by foreign antigen in secondary lymphoid tissues
Phase 4- differentiation to antibody-secreting plasma cells and memory B cells in secondary lymphoid tissues


B cells in the bone marrow

-B cells produced by bone marrow every day throughout life
-2.5 billion cells/day start path towards becoming a B cell
-55 billion cells/day die because they fail to productively rearrange immunoglobulin or are autoreactive
-30 billion cells/day leave the bone marrow
-when B cells exit bone marrow, they are called "mature naive" B cells


Stages of B cell development

Stem cell- H chain are germline, L chain are germline, no IG
Early pro-B cell- DJ arrangement in heavy chain
Late pro B cell- V-DJ arrangment in heavy chain
Large preB cell- VDJ rearranged in heavy chain, Ig status- u heavy chain is made
Small preB cell- VDJ rearranged in heavy chain, V-J arranging in light chain, Ig status- u chain in ER
Immature B cell- VDJ rearranged, VJ rearranged, u heavy chain, lambda or K light chain, IgM on surface


B cells in secondary lympohid organs and circulation

-Immature B cell (IgM+, IgD-)- leaves bone marrow and enters peripheral circulation
-Immature B cell (IgMhigh, IgDlow)- alternative splicing to give both D and M chains, gain access to primary lymphoid follicle and matures
-Mature naive B cell (IgMlow, IgDhigh)-enters circulation and binds specific antigen in lymphoid tissue drain infection
-antigen actibated B lymphoblast- alternative splicing to secrete Ig Isotype switching, somatic hypermutation
-antibody-secreting plasma cell- fighting the current infection
-memory cell- IgG preparing for future infection


Surrogate light chain

-the B cells must produce a functional heavy chain chain to survive
-it uses the surrogate light chain to test the function of the heavy chain
-the Pre B cell has a rearranged heavy chain but a surrogate light chain
-this signals:
-the end of heavy chain rearrangment
-cell survival
-cell proliferation
-then the light chain rearrangement commences


Proteins involved in B cell stages

-RAG1 and RAG2- lymphoid-specific recombinase, increase during Early and Late pro-B cell (heavy chain rearrangement) as well as during Small pre-B cell (light chain rearrangment)
-TdT, surrogate light chain components- N nucleotide addition, shows during Early pro-B cell and starts dropping off after small preB cell


Immature B cells in bone marrow- leave or stay?

-no reaction with a self antigen-> immature B cell moves to the blood and expresses IgD and IgM
-reaction with self antigen-> immature B cell is retained in bone marrow


Self reactive B cell in marrow

-immature B cell continues to rearrange light chain genes
-immature B cell makes a new light chain and thus and IgM with a different specificity
-if the new receptor is not self reactive then the B cell leaves the bone marrow
-if the new receptor is self reactive light chain genes continue rearranging
-successive new receptors are self-reactive, no further rearrangments are possible and the cell apoptoses


Activation of B cells in an immune response

-Bone marrow- unrestricted repertoire of immature B cells. Tolerance inducion
-blood and secondary lymphoid tissues- self-tolerant mature B cells and anergized B cells. Additional tolerance induction
-B cells fail to enter lymphoid follicles- short-lived B cells with half-life of about 3 days
-B cells successfully enter lymphoid follicles- long-lived, mature, recirculating, naive B cells (half life 3-8 weeks)
-B cells stimulation by antigen- long-lived, mature, recirculating, memory B cells. Expression of high affinity IgG, IgA, or IgE


Stimulate adaptive immunity

-pathogens adhere to epithelium
-skin wounds allow pathogens to penetrate epithelium
-local infection, innate immunity
-dendritic cells take infection to lymph node and stimulate adaptive immunity
-effector cells and molecules of adaptive immunity travel to the infected tissue
-dendritic cell takes up pathogen for degeneration
-pathogen is taken apart in the dendritic cell
-pathogen proteins are unfolded and cut into small pieces
-peptides bind to MHC molecules and the complexes go to the cell surface
-T cell receptors bind to peptide: MHC complexes on the dendritic cell surface


T-independent antigens

-antibody response and activates T cells when there is TD antigen
-TI-1 antigen and TI-2 (repeated polysaccharides on bacterium) antigen are not long lived or memory (like LPS)


Activation of B cells

-B cell become activated when their receptors are cross-linked by antigens
-antigens that can stimulate B cells through toll receptors can bypass the need for T cell help. This may be a fundamental mechanism to response to important bacterial pathogens


Most antigens are T dependent

-Naive CD4 T cells are activated by antigens presented by dendritic cells in lymph node
-Naive B cells activated by antigen are trapped in the T cell zone of the lymph node
-antigen-activated B cells present antigen to helper T cells, forming cognate pairs
-the primary focus for expansion of antigen activated B cells is in the medullary cords
-the secondary focus for expansion of antigen-activated B cells is the germinal center
-antigen binding to B cell receptor delivers the first signal to the B cell
-T helper cell delivers the second signal via CD40 ligand and cytokines


T cell and B cell interaction

-Helper T cell adheres to the B cell and beings to synthesis cytokines and CD40 ligand
-the helper T cell reorients its cytoskeleton and secretory apparatus toward the B cell
-cytokines are released into the narrow space between the B cell and the T cell


Germinal center

-most of the development of B cell responses take place in the lymph node. Initially this is within the medullary cords but much of this expansion is within the germinal center
-follicular dendritic cells (not dendritic cells just have dendrites) hold antigenon their surface for the B cells
-T cell surround the germinal center
-patient with hyper-IgM syndrome has no germinal centers


Activated B cell

--somatic hypermutation of immunoglobulin V regions (AID) in rapidly proliferating germinal center centroblasts
-germinal center centrocyte with low affinity surface immunologlobulin - B cell receptor is not cross-linked and centrocyte cannot present antigen to T cell cell-> apoptosis
-germinal center centrocyte with high affinity surface immunoglobulin- B cell receptor is cross-linked and antigen is presented to helper T cell-> centrocyte receives help, survives and divides


Antigen selected centrocyte possible paths

-antigen-selected centrocytes mature under the influence of an IL-10 secreting helper T cell
-centrocyte differentiate into plasma cells
-make antibodies that fight and terminate the current infection

-antigen-selection centrocytes mature under the influence of an IL-4 secreting helper T cell
-Centrocytes differentiate into memory B cells
-the investment that prevents future infections from causing disease