Immunology VI: B cell development & activation Flashcards
B-cell function:
gives rise to plasma cells that secrete antibodies capable of binding to an organism, microbe or molecule
The secreted antibodies have antigen-binding sites identical to those of the receptor molecules on the B-cell surface:
-Antibodies belong to the class of proteins known as immunoglobulins (many proteins in this superfamily)
-Once secreted they can protect the host against a wide variety of pathogens
B-cell development:
B-cells develop first from hematopoietic stem cells, and then into common lymphoid progenitors under the influence of:
IL-7
The B-cells are released into circulation as immature, naive B cells
B-cell development: Bone Marrow:
B-cells develop from common lymphoid precursors into pre-pro B cells.
B cells then become irreversibly committed to the B-cell lineage once they reach the pro-B cell stage.
-It is during this stage that immunoglobulin gene recombination begins.
As B-cells mature, their expression of surface B-cell _________ change.
Markers;
These markers allow for communication with stromal cells int he bone marrow.
The B-cell receptor (BCR):
Membrane bound antibody that associates with a disulfide-linked heterodimer (Ig-alpha & Ig-Beta)
Ig-alpha: has a long cytoplasmic tail that associated with intracellular signaling molecules.
As the pro-B cells matures to a pre-B cell it begins to express an immature _________________
BCR (B cell receptor)
Productive BCR:
B cell passes the pre-B cell checkpoint and becomes a pre-B cell
Unproductive BCR:
B cells will undergo apoptosis
Prior to maturation into an immature B cell, the pre-B cell goes through a second checkpoint:
BCR is checked for self-reactivity
-If (+): Pre-B cell tries to rearrange light chain genes of the BCR and will be checked again for self-reactivity
If still (+) pre b cell will undergo apoptosis.
-If (-): becomes immature (aka transitional) B cell and leaves the bone marrow
From the bone marrow immature B cell (aka transitional) travel to the __________
spleen
Once in the spleen the immature B cell begins expressing:
-CD21-The complement co-receptor
-IgD in addition to IgM as the isomer of the portion of the BCR
From there the B-cell is considered mature but naive and enters general circulation.
From general circulation, the B cell will migrate to a lymphoid follicle with a _______
Lymph node: bean shape structure encapsulated with a reticular network and packed full of lymphocytes, macrophages, and dendritic cells.
3 main regions:
-Cortex
-Paracortex
-Medulla
Lymph node cortex:
contains lymphocytes (predominantly B-cells), macrophages and follicular dendritic cells arranged into primary follicles.
After antigen exposure primary follicles will enlarge into secondary follicles with germinal centers.
Lymph node paracortex:
Contains mostly T-lymphocytes and dendritic cells:
-The dendritic cells express high levels of HLA-2 molecules & present them to T-helper cells for T-helper activation and polarization
Lymph node medulla:
More sparsely populated with lymphoid-linage cells.
-Often plasma cells actively secreted antibody molecules.
Within a lymph node, a naive B-cell encounters an antigen in one of two ways:
1) The antigen flows into the lymph node through afferent lymphatics and binds to the BCR
2) Macrophages or dendritic cells encounter an antigen in the periphery and bring it to a lymph node.
-Here they will present the antigen to a B-cell and the antigen binds to the BCR
The antigen binds to the BCR with the help of:
B-cell co-receptor:
-CD21: co-receptor that binds an antigen bound to the complement component C3d
-CD19: signal transduction protein
Initiates downstream signaling cascade promoting B cell survival & proliferation.
Now the B-cell and Tfh cell are locked in an immunologic synapse:
-Co-stimulatory interaction iCOSL and iCOS will stimulate production of cytokines by the Tfh cells
-Under the influence, the B cell will proliferate and begin to produce antibodies.
After it’s interaction with Tfh cell:
Some B-cells will differentiate into plasma for antibody secretion:
-Early primary response
-Initially the antibodies will be medium-affinity
Some B-cells will move into the germinal centers of lymphoid follicles:
-Late primary response
-The influence of particular cytokines secreted by Th1 or Th2 cells will induce antibody class switching.
-Somatic hypermutation will result in production of high-affinity antibodies.
During antibody class switching, the original antibody (IgM) may be switched to a different class:
ex) IgA, IgE, IgG etc…
During class-switching, the specific portion of IgM will be cut off and then re-attached with a different antibody.
Different cytokines secreted by the T-helper cells will induce class switching:
Th1 cells secrete INF-y which stimulates class switching to IgG subtypes
TGF-beta: stimulates class switching to IgA
Th2 cells secrete IL-4 & IL-5, which stimulates class switching to IgE.
-Also induces secretion of large amounts of IgM.
Th1 cells secrete INF-y which stimulates class switching to:
IgG subtypes
TGF-beta stimulates class switching to:
IgA
Th2 cells secrete IL-4 & IL-5, which stimulates class switching to:
IgE
-Also induces secretion of large amounts of IgM.
During the late primary response some B-cells move into the germinal center of lymph nodes to undergo somatic hypermutation.
During somatic hyper mutation:
the variable region of an antibody will mutate at a very high rate.
Then it will be tested for antigen binding:
-If it binds with higher affinity it is kept
-If it binds with lower affinity or self the B-cell will undergo apoptosis.
Somatic hypermutation step 1:
The B-cell starts in the dark zone of the germinal center where it loses it’s HLA expression and mutate it’s BCR genes.
Somatic hypermutation step 2:
The BCR moves into light zone of the germinal center and samples follicular dendritic cells for the antigen:
-Self-reactivity or binding with low affinity to the antigen results in apoptosis
Somatic hypermutation step 2 part 2:
If the B-cell binds with high-affinity to the antigen, it will re-present it on an HLA-2 and be re-stimulated by a Tfh.
Somatic hypermutation step 3:
Once re-stimulated by a T-fh cell, the B-cell will either differentiate into:
a plasma cell or memory B-cell
Plasma cells:
No longer have BCR and secrete a large number of antibody molecules.
Memory B-cells:
Circulate in the periphery:
-Once they re-encounter their specific antigen, they will proliferate and differentiate into plasma cells
Continue to express the BCR
Much longer-lived that naive B-cells
Differentiation into memory B cells is unclear
Antibodies are protein molecules:
-TWO HEAVY CHAINS: can be divided into a “constant” region (Fc) and “variable” (Fab) region.
It is the variable regions that undergoes genetic shuffling.
_The specificity of an antibody is determined by the Fab region and the antibody portion of the light chain.
-TWO LIGHT CHAINS
There are 6 categories of antibody functions:
1) neutralization:
antibody binds to pathogen or toxin, inactivating in and preventing binding to cells.
There are 6 categories of antibody functions:
2) Agglutination:
Prevents the pathogen from binding to cells and promotes clearance of pathogen.
There are 6 categories of antibody functions:
3) Opsonization
Antibody binds to Fc receptor and promotes phagocytosis.
There are 6 categories of antibody functions:
4) Complement activation:
a) initiates classical pathway of complement pathway.
b) promotes phagocytosis
There are 6 categories of antibody functions:
5) Anti-body dependent cell mediated cytotoxicity:
Antibody activates Fc receptor on natural killer cells & inducing apoptosis of infected cell.
There are 6 categories of antibody functions:
6) Degranulation:
Antibody activates Fc granulocytes triggering degranulation.
There are 5 main classes of antibodies, what are they?
IgM, IgG, IgD, IgE, IgA
IgM:
Monomer found as part of the BCR.
First class of antibody secreted during the primary immune response:
-Secreted as a pentamer
-Tends to have a lower -affinity for it’s antigen
Function:
-Very good at activating complement
-Good at agglutinating pathogens: immobilizes the pathogens allowing for phagocytosis
IgG:
Most common antibody found in serum.
-Variety of different classes: IgG1, IgG2, IgG3, IgG4
Secreted as a monomer
Produced later in the humoral response.
Functions:
-Opsonization: bind the Fc receptor on phagocytes & enhances phagocytosis
-IgG1 & IgG3 are good at activating complement
-IgG2alpha is good at triggering antibody-mediated cytotoxicity by natural killer cells.
IgA:
Predominantly found as a dimer secreted into tears, saliva, breast milk, and mucus.
Functions:
-Neutralizing pathogens
-Agglutinating pathogens
Can also be found in blood as a monomer, with similar functions to IgG.
-Also good at inducing degranulation of granulocytes
IgE:
Secreted as a monomer in small quantities.
Functions:
-Binds to cells with and Fc receptor for IgE triggering degranulation of granulocytes. (eosinophils, basophils, mast cells)
IgD:
Secreted as a monomer in very small quantities.
Most prevalent in secretions of the upper respiratory tract:
-binds to basophils and mast cells
