B Cell Development/Activation/Fx Flashcards
Types of epitopes
Mitogen
Chemical that induces cells to undergo mitosis - certain mitogens can trigger lymphocyte DNA replication and division in an antigen-independent manner
Hapten
Small, organic molecule that is foreign but too small to induce and adaptive immune response unless it is bound to a larger (typically protein) antigen
What portion of the Ab determines its class?
There are five different heavy chain constant regions, which dtermine the five different Ab classes
Complementarity determining regions (CDRs)
Abs
aka Hypervariable regions
Each heavy and light chain contains 3 sub-regions that strongly impact Ab/Ag binding affinities (but not ID of Ag)
Ig domains
Repetitive looped domains created by intra-chain disulfide bonds
IgD
Marker for naive, mature B cells - necessary for naive B cell activation
IgA
Monmer in serum and dimer in secretions
Dimer - two IgA molecules joined by a J chain
Mucosal immunity
B cell development before antigen contact
RAG deficiency
Cause of SCID - characterized by lack of T/B cell function
Inability to successfully recombine the TCR/BCR genes causing developing lymphocytes to undergo apoptosis
Pt’s present w/ failure to thrive, absent thymic shadow on CXR, and repeated severe bacterial/viral/ any other infections early in life
Bone marrow stromal cells in B cell development
Provide cell adhesion molecules (CAMs) and cytokines (i.e. IL-7) to nurture B cell development
Stromal cells also present Ag during negative selection
What process simultaneously produces IgM and IgD in a mature, naive B cell
Alternative splicing
Which BCR gene is rearranged first?
The heavy chain gene
What initiates immunoglobulin light chain gene rearrangement?
A functional μ (IgM) heavy chain protein
What type of selection do immature B cell clones undergo in the bone marrow?
Negative selection - if they react w/ self-Ags = apoptosis
When do immature B cells exit the bone marrow
After surviving negative selection - enter circulation and then secondary lymphoid tissue primary lymphoid follicles
What causes B cells to develop into mature B cells?
Interacting with DCs in a primary lymphoid follicle - DCs secrete cytokines that drive B cells to maturity
Alternative splicing of the H chain mRNA in mature, naive B cells
Does not change Ag-binding affinity or Ag specificity - it just allows the cell to express IgD and IgM versions of the BCR at the same time
X-linked Bruton’s Agammagolbulinemia
Primary immunodeficiency that results from defects in the B cell-specific, Bruton’s tyrosine kinase (BTk) that is express early in B cell development
B cells fail to mature beyond the pre-B stage
Infants are usually well for first six months of life - subsequently develop recurrent infections - particularly w/ encapsulated bacterial and mucosal pathogens**
Circulating B cells and all Ig classes are absent
T cell development is unaffected
Summarize B cell development
- Stem cell in bone marrow
- Successful rearrangement of μ heavy chain gene
- Successful rearrangement of κ or λ light chain gene & production of surface IgM BCR
- Negative selection in bone marrow
- Continuing development in primary lymphoid follicle
- Alternative splicing to make IgM and IgD
- Mature B cell
Where does B cell activation occur?
In secondary lymphoid tissues (typically the follicle)
T-cell dependent B cell activation signals
- BCR crosslinking by specific Ag plus BCR co-receptor complex (CD19, 21, and 81) activation - stimulates endocytosis of the BCR-bound antigen, B cell Ag presentation, and B cell migration to the T cell zone in secondary lymhpoid tissue
- CD4+ Th2 cells provide help through cytokines and direct physical interactions to drive B cell proliferation and differentiation
After antigen-mediated activation of a mature B cell - alternative splicing to produce IgD is turned off
Plasmablasts
Secrete low affinity IgM - do not undergo affinity maturation
Opsonization
Coating surface of extracellular path w/ IgG/C3b
Require Fcγ receptors on phagocyte surface (IgG)
or CR1 receptors (C3b)
Ab-Dependent Cell-Mediated Cytotoxicity (ADCC)
NK cells and neutrophils bind to and kill target coated w/ IgG
NK cell use FcγR/CD16 receptors for this (binds to the Fc fragment)
FcεRI
FcεRI - expressed by mast cells, basophils, and IL-5 activated eosinophils - coated w/ IgE
Parasite Ag crosslinking of FcεRI-bound IgE results in cellular degranulation and release of inflammatory mediators (i.e. histamine) and enzymes
Either kill or evoke tissue response that expels parasite
Neutralization
IgG/A/M bind and inhibit pathogen infection or pathogen/toxin/venom damage to tissues
Tissue distribution of IgM
Pentameric IgM does not enter tissues efficiently - mostly found in circulation
Tissue distribution of IgA
Actively transported into colustrum and onto mucosal surfaces (trans-cytosis)
Brambell receptor (FcRB)
Trans-cytoses IgG across vascular endothelium into either extracellular tissue space or across the placenta into fetal circulation
Poly-Ig receptor (PIgR)
Trans-cytoses IgA dimers from the basolateral surface of mammary alveolar epithelial or mucosal epithelial cells to the apical surface of those cells (using an endocytic vesicale)
Natural Passive Immunity
IgG and IgA from mother to child
IgG - crosses placenta (protects for ~ 6mo.)
IgA - secreted into breast milk and colostrum (confers protection in the oropharynx and the gut)
Compared to IgG, is IgM lower/higher binding affinity for a given Ag?
IgM has a lower relative affinity than the other class types of Ig
Effector functions of IgM
Neutralization and classical complement activation
Effector functions of IgG
- Neutralization
- Classical complement activation
- ADCC (NK and neutrophil FcγR/CD16 dependent)
- Opsonization (neutrophil and macrophage FcγR dependent)
What comformation of IgA is found in circulation and what is its effector function?
Monomeric IgA is found in circulation and promotes neutralization and opsonization
A. Plasmablasts that secrete IgM
B. Activated B cell clones that have undergone class switching to IgA
C. Plasma cells that secrete IgG
D. Memory B cells that have Ige BCRs
Plasmablasts that secrete IgM
Which processes has an IgG-secreting plasma cell MOST LIKELY undergone in the germinal center? (choose the SINGLE BEST answer)
Somatic recombination to switch from producing IgM to IgG
alternate mRNA splicing to switch from making the BCR to making secreted antibody
Production of WHICH CYTOKINE induces B cell clones in a germinal center to class switch to produce IgA?
IL-5
Nucleotides are added or subtracted at the DJ and VJ junctions in the BCR heavy and light chain genes but not in the TCR 𝛂 and 𝝱 chain genes
Alternate splicing
- Used to simulataneously express surface IgM and IgD in immature B cell
- Also allows to make a secreted form of the BCR and membrane receptor BCR
Which immunoglobulin would have the least sequence variability between B cell clones
IgM
Lower variability because it is less somatically mutated compared to other antibody classes such as IgG or IgA. Additionally, IgM antibodies are often produced before the process of affinity maturation, which increases the variability of antibodies.
What type of Ag can TCR bind?
Linear epitope Ags
IL-4
Could have also listed IL-13
Both tell B cells to class switch to IgE
IL-4 also pushes the T cell response toward the Th2 response
