B Cells And Humoral Immunity

Question 1

Progenitor B cell characteristics (Pro-B cells)

Answer 1

• 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)

Question 2

Precursor B cell

Answer 2

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

Question 3

Immature B cells

Answer 3

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*

Question 4

Bruton X-linked recessive agammagloulinemia

Answer 4

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

Question 5

Membrane bound vs secreted antibodies

Answer 5

Differ in processing of the RNA that produces an anchor for the membrane bound and no anchor for the free antibodies

Question 6

Recombinantion of BCR and antibody chains

Answer 6

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

Question 7

What is unique to B cells as it pertains to rearrangement

Answer 7

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*

Question 8

Self reactive B cells

Answer 8

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

Question 9

Anergy

Answer 9

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*

Question 10

Clonal ignorance

Answer 10

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*

Question 11

Immature -> mature B cells

Answer 11

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

Question 12

Positive selection of B cells

Answer 12

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

Question 13

Marginal zone B cells

Answer 13

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

Question 14

Actions of mature B cells

Answer 14

Antibody secretion

Isotope switching based on cytokines in the area

Affinity maturation

Turn into a memory B cells

Question 15

B cell activation

Answer 15

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

Question 16

Signals required for B cell activation

Answer 16

First signal: antigen to BCRs (at least 2)

Second signal: helper T cell CD40:CD40L signaling

Question 17

Signal 1 (cross-linking)

Answer 17

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

Question 18

Signal 2 (T-dependent antigen)

Answer 18

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*

Question 19

Signal 2 (T-independent antigen)

Answer 19

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

Question 20

B-1 cells

Answer 20

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

Question 21

B-2 cells

Answer 21

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

Question 22

Marginal zone B cells

Answer 22

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

Question 23

Transient hypogammagloulinemia of infancy

Answer 23

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.

Question 24

Germinal centers

Answer 24

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

Question 25

4 postulates of clonal selection

Answer 25

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

Question 26

Affinity maturation

Answer 26

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*

Question 27

Isotope class switching

Answer 27

Always starts as IgM and then based on the environment, genetic manipulation will occur causing switching of the heavy chains. - light chains dont switch

Question 28

Cytokines regards for each type of class switching

Answer 28

IFN-y, TGF-B and IL-4 = IgG IL-4 only = IgE TGF-B, BAFF and mucosal cytokines = IgA

Question 29

B cell memory

Answer 29

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.

Question 30

Selective IgA deficiency

Answer 30

*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)

Question 31

X-linked hyper IgM syndrome

Answer 31

``` 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

Question 32

Common variable immunodeficiency

Answer 32

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*

Question 33

Tolerance vs autoimmunity

Answer 33

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

Question 34

Two main types of tolerance

Answer 34

Central: deletion via maturation in thymus of bone marrow Peripheral: usually results in anergy or suppression via Treg

Question 35

Loss of self-tolerance

Answer 35

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

Question 36

AIRE

Answer 36

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.

Question 37

Immune privilege

Answer 37

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

Question 38

Causes of failure to tolerance

Answer 38

Genetics: - mutations in immune genes and MHC alleles Chronic Infection and inflammation - leads to molecular mimicry in microbes and poor regulation of T cells

Question 39

Molecular mimicry

Answer 39

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

Question 40

Two most common infections that produce molecular mimicry

Answer 40

GAS infections Rheumatic fever

Question 41

Peripheral tolerance

Answer 41

Mechanism used by B-cells that eliminates lymphocytes and clones that become self-reactive over time

Question 42

5 consequences of cross linking signal 1 for Bcells

Answer 42

Increased survival Increases stimulation of CD 4 T cells Increases responsiveness to cytokines Migrates from follicle to T cell zone Secreted antibodies