Immunology: Humoral Immune Responses
What 2 types of cells can fully activated B cells become?
B cells become either: -antibody-secreting cells = *plasma cells* -*memory cells*
How do B cells and T cells interact?
B cells bind a protein antigen, which causes receptor-mediated endocytosis of the antigen. The antigen is processed and presented on MHC II and is recognized by T cells. The CD40 ligand on the T cell can bind to CD40 on the B cell, which activates the B cell. Additionally, CD28 on the T cell binds to a B7 molecule on the B cell, which causes full activation of the T cells.
In general, how do primary and secondary humoral immune responses differ?
Both quantitatively and qualitatively (both the amount and type of Ig made). *A primary response produces smaller amounts of antibodies compared to repeated exposures.
What is the function of IgM?
Complement activation
What influences the type of heavy chain produced by B cells?
Cytokine release
What is isotype switching?
During differentiation, some B cells switch to produce antibodies of a different heavy chain class. (B cells generally make IgM, and they can switch to make IgG, IgE, or IgA)
When is the IgM response the greatest?
During the *early phase* of the humoral response. IgM is also the greatest if the antigen is NOT a protein and: -is multivalent -cross-links many receptors, or -activates complement strongly
What cytokine causes IgG production by B cells?
IFN-γ
What cytokine causes IgE production by B cells?
IL-4
What is required for Ig receptors to fully activate a B cell?
Ig receptors bind antigen and cluster, which triggers biochemical signals from receptor-associated signaling molecules. Also requires *cross-linking* of 2 or more Ig receptors: -2 or more antigens in an aggregate, OR -repeating epitopes of 1 antigen
What are immunoreceptor tyrosine-based activation motifs (ITAMs)
Molecules contained within the cytoplasmic portions of Igα and Igβ (parts of the B cell receptor complex). ITAMs are phosphorylated by kinases and initiate biochemical signaling for B cell proliferation and differentiation.
What is the size of the peak response in a primary response compared to a secondary response?
Primary has a smaller peak response, secondary is larger
What is the lag after immunization in primary and secondary humoral immune responses?
Primary: 5-10 days Secondary: 1-3 days
What are the differences in antibody isotypes in primary vs. secondary humoral responses?
Primary: IgM > IgG Secondary: IgG > IgM (could also make IgA or IgE depending on the type of organism)
What is the antibody affinity in primary humoral responses compared to secondary responses?
Primary: lower average affinity, more variable Secondary: higher average affinity due to affinity maturation
What types of molecules can B cells recognize?
Proteins, polysaccharides, lipids, and small chemicals
What is affinity maturation?
The process by which repeated exposure to an antigen results in production of antibodies with increasing affinity for that antigen
What mediates humoral immunity?
antibodies
What interaction is needed to cause isotype switching?
*CD40* on the B cell must bind to the CD40 ligand on the T cell, which gives the signal for isotype switching. In the absence of CD40 or CD40L, only *IgM* is produced by B cells.
Describe the response that happens with a protein antigen.
-Naive CD4 cells recognize the protein antigen and are activated -B cells specific for the protein antigen are also activated -CD4 cells and B cells come together in the lymphoid organ -CD4 cells stimulate the proliferation and differentiation of B cells, with antibody responses occurring within 3-7 days
With a protein antigen, what 3 changes occur in B cells to enhance interaction with CD4 T cells?
1. Increased expression of B7 costimulators - provide second signals for T cell activation 2. Expression of receptors for cytokines from helper T cells 3. Reduction of expression of receptors for chemokines produced in the lymphoid follicle that are designed to keep B cells in the follicle (allows the B cells to leave the follicle so that they can activate T cells in the T cell area of the lymph node)
How can B cells be activated by complement?
2 ways: -B cells have a receptor for a complement protein, when complement binds it provides signals to activate the B cell -Microbes can activate complement in an innate response (via alternative or lectin pathways). The microbes become coated with breakdown products of C3, and C3d binds to B cells via a complement receptor (CR2 or CD21). Complement, especially when bound to CR2, provides the 2nd signal (antigen is signal 1) to initiate B cell proliferation and differentiation.
What is a secondary humoral immune response?
Any response that occurs after the first exposure to a particular antigen
How does IgG cause antibody feedback?
IgG binds the antigen. This complex binds to the B cell: the Fc tail of the antibody binds to the Fc receptor on the B cell. This interaction causes the release of negative signal to turn off B cell responses.
How are naive B cells activated?
IgM or IgD bind the antigen (first signal) and then coreceptors bind (second signal). This causes proliferation/clonal expansion of antigen-specific B cells, which then differentiate into effector cells (plasma cells), which secrete antibodies.
What is the function of IgE?
Immunity against helminths (worm-based infections), eosinophil responses, mast cell degranulation in hypersensitivity reactions
What is the function of IgA?
Mucosal immunity (IgA is transported through epithelia)
What cytokine causes IgM production by B cells?
None - IgM is the default antibody secreted by B cells
When are helper T cells involved in B cell activation?
Only if the antigen is a protein. When TH2 cells are involved, they will cause isotype switching.
When and where does affinity maturation occur?
Only occurs when CD4 TH2 cells are involved - occurs in the germinal centers of lymphoid follicles
What is the function of IgG?
Opsonization, phagocytosis, complement activation, neonatal immunity via placental transfer
Compared to the B cell that produced it, does an antibody have more or less specificity for the antigen?
Secreted antibodies have the *same specificity* for the recognized antigen that the B cell had
What cytokine causes IgA production by B cells?
TGF-β
Why do helper T cells stimulate isotype switching?
This allows the humoral immune response to adapt to optimally combat the organism. IgM is non-specific, so there is no guarantee that there will be a good connection between the antibody and the organism. When isotype switching occurs, IgA, IgE, and IgG all have higher specificity and more efficient binding of the antigen.
When and where are humoral immune responses initiated?
When *antigen-specific B cells* in the *lymphoid follicles* of the spleen, lymph nodes, and mucosal lymphoid tissues recognize antigens that have been transported and concentrated in the B cell-rich follicles of lymphoid organs. (T cells are more in the cortex of lymph nodes)
When can T helper cell-dependent antibody response occur?
When the antigen is a *protein* Proteins are processed in APCs and recognized by CD4 cells. CD4 cells are powerful inducers of isotype switching and affinity maturation
When does T helper cell-independent antibody response occur?
When the antigen is a polysaccharide, lipid, or small chemical, the B cells are directly activated. This type of stimulation causes minimal isotype switching and affinity maturation, which means that the humoral response is weaker than when the antigen is a protein.
How are memory cells created?
a B cell which expresses high-affinity Ig can become a memory B cell
What microbes/substances does humoral immunity act against?
extracellular microbes, microbial toxins, and microbes that have a capsule *also it is important to note that the humoral immune system has the potential to act against any microbe because every intracellular microbe has an extracellular state
What immunoglobulins do naive B cells express?
membrane-bound IgM and IgD