B Cells And Humoral Immunity Flashcards
Progenitor B cell characteristics (Pro-B cells)
- expresses CD19 but has not yet recombined to for BCRs and membrane bound antibodies
no membrane bound antibody expressed
DJ rearrangements on both chromosomes in the H-chain occurs (Early pro)
V-DJ rearrangement on first chromosome for the H-Chain occurs (late pro)
Precursor B cell
Pre-B cell
Express CD19 and has undergone some recombination to express heavy chains and surrogate light chains
- light chains are primarily rearranged in this stage. If the chains do not recombinant, under goes apoptosis
Express no BCRs or membrane bound antibodies
Immature B cells
B cells that have fully undergone recombination of chains and express membrane bound IgM only (no IgD)
Expresses both heavy and light chain recombinant and
Mature expresses IgD and IgM
- no more recombination at this stage*
Bruton X-linked recessive agammagloulinemia
Dysfunctional/ absence of Gamma chain production which results in no antibody production
There is also a mutation in Burton’s tyrosine kinase which is essential for BCR signaling
Clinical symptoms:
- no visible tonsils
- recurrent and unusual infections typically in early childhood
- very low or absent antibody levels
Treated via weekly IV purified immunoglobulin
Membrane bound vs secreted antibodies
Differ in processing of the RNA that produces an anchor for the membrane bound and no anchor for the free antibodies
Recombinantion of BCR and antibody chains
recombination of VDJs is mediated by a complex that includes RAG (recombination activating gene)
light chains = VJ segments only
Heavy chains = VJD segments
heavy chains determine the isotope of the antibody/receptor
What is unique to B cells as it pertains to rearrangement
Can be “rescued” and not immediately destroyed like T cell receptors.
- occurs in strongly reactive B cells as well and instead of undergoing apoptosis immediately, its receptors are edited
- requires RAG expression to do so and rearranges ONLY the light chains*
Self reactive B cells
Results in clonal deletion via negative selection
Occurs in bone marrow for B cells and thymus for T cells
Either apoptosis, receptor editing or anergy occurs
Anergy
B cells that present with a weaker reaction to self antigens become anergy (unresponsive)
- this usually means the B-cell recognizes soluble, free floating self-antigens, but not membrane bound antigens.
- caused by reduced expression of IgM compared to mature B cells which results in unable to respond to subsequent antigen encounters
- unknown as to why they stick around and dont die*
Clonal ignorance
B-cells that are self-reactive but do not respond during development become clonal ignorant
- often caused by not presenting with non-self antigens during development. Results in activation only in high concentrations of pathogenic antigens
- neither anergy, receptor edited or apoptosis*
Immature -> mature B cells
B cells start in center of bone marrow and express only IgM.
- if they do not react with self antigens, they migrate to the periphery and express both IgD and IgM
Require CD19 and CD20 as well as NO CD 21 gene express
Positive selection of B cells
B cells that dont enter the follicles of the spleen will die (usually within 3 days)
Survival signal is express of CD21
Memory and mature B cells are selectively favored to enter the follicles of the spleen in order to activate/ proliferate
Marginal zone B cells
Enter the follicles of the spleen and reside in the germinal centers
- once in the spleen, they do not leave
Role is to respond to conserved antigens on most bacteria to initiate an immune response quickly
Actions of mature B cells
Antibody secretion
Isotope switching based on cytokines in the area
Affinity maturation
Turn into a memory B cells
B cell activation
Secreted antibodies with IgM being the first (standard) type secreted.
- cytokines present nearby can change the type of antibody secreted
Come from WBCs/ T cells and inflammation cells
Signals required for B cell activation
First signal: antigen to BCRs (at least 2)
Second signal: helper T cell CD40:CD40L signaling
Signal 1 (cross-linking)
Cross linking of the BCRs by signaling molecules Ig(alpha) and Ig(beta)
- essentially binding antigen to the BCR
Induces signal transduction into the B cell to let it know to start proliferating and differentiating
- up-regulates MHC 2, CCR7 and B7
- internalizes antibody:antigen complexes
- Activates adhesion molecules for 2nd signal
- migrate to edge of follicle and interacts with T helper cells to get the 2nd signal
Signal 2 (T-dependent antigen)
CD40: CD40L and MHC2 : TCR CD4 binding results in proliferation and production of antibodies as well as isotope switching if needed
- increases IL-4 which further stimulates proliferation and production of antibodies
- note the antibodies are produced in response to only the epitope of the antigen seen by the BCR, not the TCR*
- does produce memory*
Signal 2 (T-independent antigen)
Possible alternative pathway for B cell activation if T helper cells are not able to present
Produced when B cells interact with non-protein antigens free floating in the system
- mainly done via B-1 cells in the marginal zone
- does produce antibodies but are short lived, low affinity IgM only antibodies.
does not generate memory
B-1 cells
Develop in fetal liver
Self renewing and found in body cavities
Responses to conserved carb antigens on bacteria
Secrete IgM
- possess High IgM/ low IgD membrane bound receptors
Thymus-independent response and antigens
Limited V-region
B-2 cells
Develop in bone marrow
Circulate throughout the body and are activated in peripheral lymphoid organs
Primarily responds to protein antigens
Secreted IgM first, then secretes other isotopes based on environment
- possess high IgM and IgD membrane bound receptors
Diverse V-region repertoire
Thymus-dependent response (require T-cell help)
Most common and convention B cells
Marginal zone B cells
Develop in the bone marrow
stay in the spleen
Respond to conserved carb antigens on bacteria
Secreted IgM only
- membrane bound high IgM/ low IgD
Limited V-region repertoire
thymus -independent response
Transient hypogammagloulinemia of infancy
Infant is unprotected by maternal antibodies. Presents with recurrent infections as infants have low overall antibodies
- presents at 6 months when material antibodies are usually gone
Idiopathic, however the following causes are hypothesized:
- maternal antibodies suppress fetal antibody production
- abnormal T cells do not produce signals for B cells
- B cells are immature and/or abnormal.
Germinal centers
Sites of lymph nodes where rapid B cell proliferation occurs
- also site of affinity maturation to a specific antigen
Isotype switching occurs here as well when needed
4 postulates of clonal selection
Each B and T cell expresses a single type of receptor with a unique level of specificity
B and T cells are activated when it encounters a pathogen expressing the specific antigen that cell is unique for.
Activated B and T cells proliferate and differentiate but will always keep the same level of specificity as the parent cell
Self-reactive B and T cells are eliminated through clonal deletion
Affinity maturation
Generates antibodies with varying affinities for the same antigen
- almost uniquely localized in germinal centers
Unique only to B cells
Somatic hypermutations occur to the variable regions of the antibodies making bounds stronger (increased affinity)
essentially natural selection of B-cells
Isotope class switching
Always starts as IgM and then based on the environment, genetic manipulation will occur causing switching of the heavy chains.
- light chains dont switch
Cytokines regards for each type of class switching
IFN-y, TGF-B and IL-4 = IgG
IL-4 only = IgE
TGF-B, BAFF and mucosal cytokines = IgA
B cell memory
Produced via plasma cells that have under gone affinity maturation.
-DOES NOT CHANGE SPECIFICITY TO TARGET
- if it does not undergo through affinity maturation, plasma cell will die rather quickly
Because of the necessity of undergoing affinity maturation, Secondary/memory responses have a higher affinity and less IgM overall.
Selective IgA deficiency
most common primary immunodeficiency
Produces normal amount of other types of antibodies other than IgA
Unless exposed to an infection that they are less protected against, usually asymptomatic
Patients have issues with bacterial infections In mucosal surfaces (respiratory,GI) and with blood transfusions (most blood transfers have IgA in them, and defied the patients can develop auto immune responses towards these antibodies)
X-linked hyper IgM syndrome
Very high levels of IgM but cant class switch well. - decreased levels across the board of other types
Recurrent respiratory infections are common
X-linked recessive disorder and have low life expectancy barring a bone marrow transplant (<30 years)
- children present with very high recurrence rates of pneumocystis Jirovecii infections*
- fungal infections found most commonly in lungs
Common variable immunodeficiency
Low levels of IgG, IgA and IgM
- normal IgE levels however
Reduces proliferation fo T cells also and is often diagnosed in patients that receive an infection from vaccines
- chronic lung disease patients are highly susceptible at acquiring this disease*
Tolerance vs autoimmunity
Tolerance: state of unresponsiveness by lymphocytes to an antigen after interaction via that antigen
Autoimmunity: inappropriate response to self-antigens involving activation of auto-reactive lymphocytes
- “anti-tolerance” of self antigens via B and T cells
Two main types of tolerance
Central: deletion via maturation in thymus of bone marrow
Peripheral: usually results in anergy or suppression via Treg
Loss of self-tolerance
Failure of central tolerance in primary lymphoid tissues
- specifically, negative selection
Failure of peripheral tolerance in secondary lymphoid tissues
- specifically inability to turn on anergy or suppression
AIRE
Autoimmun regulator protein that promotes self antigens in the thymus
- not just thymus antigens, promotes antigen presentation fo all organs from the body in the thymus to present to developing T cells.
Immune privilege
Sites where lymphocytes are kept out of since immune responses will cause irreversible damage
- sites also have reduces MHC expression on the cells and massive amounts of T regulatory cells
Locations:
- brain
- eye
- uterus
- testis
Causes of failure to tolerance
Genetics:
- mutations in immune genes and MHC alleles
Chronic Infection and inflammation
- leads to molecular mimicry in microbes and poor regulation of T cells
Molecular mimicry
Microbial epitopes that are similar to self-antigens can then activate T and B cells against the self
- produces cross-reactive T cells and antibodies against both the microbe and self-antigens
Two most common infections that produce molecular mimicry
GAS infections
Rheumatic fever
Peripheral tolerance
Mechanism used by B-cells that eliminates lymphocytes and clones that become self-reactive over time
5 consequences of cross linking signal 1 for Bcells
Increased survival
Increases stimulation of CD 4 T cells
Increases responsiveness to cytokines
Migrates from follicle to T cell zone
Secreted antibodies
