lec 10- B cells and antibodies

Question 1

what are the 4 steps to B cell activation via an antigen?

Answer 1

1. crosslinking of monomeric IgM with antigen, associated with Ig-a and Ig-B which both contain ITAMS
2. ITAMS are phosphorylated by a member of the Src tyrosine kinase family: Blk, Fyn, or Lyn
3. Syk binds to the doubly phosphorlyated Ig-B and transphosphorylates each other
4. signal trasnduction is initiated which leads to changes in gene expression

Question 2

what are the 2 first events to B cell activation?

Answer 2

1. cross linking of membrane Ig by antigen
2. Tyrosine phosphorylation events

Question 3

B cell activation requires signals from what?

Answer 3

the B cell co-receptor complex

Question 4

what is the B cell co-receptor complex composed of?

Answer 4

-CR2 (CD21): complement receptor for C3d on pathogen surface (can also bind iC3b)
-CD19: the signaling component (has long cytoplasmic tail)
-CD81: binds to CD19 and brings it to the cell surface

Question 5

what does CR1 on B cells do?

Answer 5

binds to C3b and makes it susceptible to cleavage by factor I into iC3b and C3d

Question 6

how is B cell activation done with the help of the B cell co-receptor complex?

Answer 6

-binding of CR1 to C3b makes it susceptible to cleavage via factor I
-factor I cleaves C3b into iC3b
-iC3b is cleaved by factor I into C3d
-the CR2 component of the B cell co receptor complex then attaches to C3d (on pathogen) which allows a signal transduction to occur

Question 7

do the B cell receptor and co receptor cooperate in activating the B cell?

Answer 7

yes

Question 8

what is CR2 of the B cell co-receptor made of?

Answer 8

it is made up of many CCP modules

Question 9

what does CCP module stand for?

Answer 9

complement control protein module

Question 10

are DAF and MCP complement control proteins?

Answer 10

yes

Question 11

is the CCP module flexible, allowing it to bind soluble antigen coated with C3d?

Answer 11

yes

Question 12

do signals from BCR and co-receptor combine to activate the B cell in response to surface and soluble antigens?

Answer 12

yes

Question 13

how does crosslinking of the BCR lead to signals from the BCR and the co-receptor to combine?

Answer 13

-after BCR crosslinks, a Src family kinase phosphorylates the ITAMS on the a or B-chains of the BCR as well as the cytoplasmic tail of CD19 on the co-receptor
-the phosphorylated CD19 recruits Syk to initiate signal transduction
-synergistic signals from BCR and the co-receptor are generated from the phosphorylation of the cytoplasmic tail of CD19
-the synergistic signal increases B cell signaling singnificantly and absence of CD19 or 81 leads to low antibody levels, no isotype switching and poor B cell response

Question 14

are most B cells thymus dependent because they need CD4 Tfh cells to help them generate and secrete antibodies?

Answer 14

yes

Question 15

how do CD4 T cells get activated and how do the CD4 T cells help B cells generate and secret antibodies?

Answer 15

-dendritic cells present antigen to T cells to activate them
-the T cell is activated into a CD4 Tfh cell (follicular helper)
-the BCR recognizes the same antigen as the dendritic cell and undergoes the same antigen processing and presentation pathway and then present the antigen to the CD4 Tfh cell in the context of MHC class II
-the TCR on the Tfh cell recognizes the antigen and a signal transduction pathway is initiated and the B cell secretes IgM

Question 16

what is intact antigen?

Answer 16

antigen that has not been processed (by phagocytosis) and are still displaying surface antigen

Question 17

do circulating intact antigen have pieces of complement component C3d attached on them?

Answer 17

yes

Question 18

where do B cells encounter antigen during primary response?

Answer 18

in the blood or lymph

Question 19

what are the 2 types of macrophages in the lymph node and what do they do?

Answer 19

-subcapsular sinus macrophages: do not phagocytose, use CR2 and CR1 to catch intact antigens and hold them at the cell surface where a B-cell can screen the antigen
-medulary macrophages: capture, phagocytose and destroy pathogens so that they cannot escape the lymph node

Question 20

what do follicular dendritic cells do in a lymph node?

Answer 20

-store intact antigens and display them to B cells

Question 21

do follicular dendritic cells have any relation to the other 2 dendritic cells? are they hematopoietic cells?

Answer 21

no relation to antigen presenting dendritic cells or plasmacytoid dendritic cells
-no

Question 22

how do antigens attach to follicular dendritic cells? how long does the antigen stay?

Answer 22

-the extensive surface area of their dendrites allow large quantities of antigen to attach to them via complement receptors
-due to no phagocytosis, the antigen can stay attached for months or years

Question 23

if a B cell recognizes an antigen on a FDC, what does the B cell do?

Answer 23

-it engulphs it and then presents it to a Tfh cell

Question 24

can B cells that already met with a FDC encounter them again after somatic hypermutation and affinity maturation?

Answer 24

yes

Question 25

after a B cell engulphs pathogen, does it move to the boundary area where it can form an immune synapse with a Tfh cell?

Answer 25

yes

Question 26

what is linked recognition?

Answer 26

when B cells and T cells recognize the same antigen but different epitopes

Question 27

does linked recognition result in the formation of a cognate pair? what is a cognate pair?

Answer 27

-yes -two interacting cells, one of which is a lymphocyte

Question 28

after a Tfh cell forms a cognate pair with an activated B cell and recognizes the antigen, how does the Tfh cell activate antibody secretion in B cells?

Answer 28

-Tfh cells express C40 ligand, which binds to C40 on B cells -this activates the NFkB pathway and cytokine secretion to initiate IgM antibody production

Question 29

do some cognate pairs return to the primary follicles of the B cell area where they proliferate to form germinal centers?

Answer 29

yes

Question 30

explain the steps of how a cognate pair of an activated B and Tfh cell leads to the B cells turning into plasma cells of some and the formation of the germinal center in others?

Answer 30

-cognate pairs cells in the boundary area proliferate for days and form clones of identical cognate pairs which then move to the medullary chords -some of the B cells in the cognate pairs differentiate into IgM secreting plasmablasts (they still continue dividing) -IgM enters the blood stream -other cognate pairs move into the B cell area and form germinal center where the B and T cells from the original cognate pair proliferate and somatic hypermutation and affinity maturation occurs

Question 31

what do B cells from a cognate pair in a germinal center differentiate into? after the new cell undergoes somatic hypermutation, affinity maturation, and isotype switching, what does the cell differentiate into?

Answer 31

-centroblasts -plasma or memory cells

Question 32

what are centroblasts?

Answer 32

activated B cells that are rapdily proliferating in the germinal center

Question 33

what are centrocytes?

Answer 33

derived from a centroblast and has undergone somatic hypermutation and does not proliferate

Question 34

what is single nucleotide substitutions in centroblasts driven by?

Answer 34

-activation induced cytidine deaminase (AID) produced by B cells

Question 35

do high affinity B cells need to engulf pathogen to present to new Tfh cells that help them to isotype switch?

Answer 35

yes

Question 36

do high affinity B cells form a cognate pair with new Tfh cells?

Answer 36

yes

Question 37

what determines which class of Ig the IgM BCR switches to?

Answer 37

cytokines produced by the Tfh cell

Question 38

does isotype switching also depend on nature and location of the infection?

Answer 38

yes

Question 39

do individuals with deficiency of CD40 ligand on Tfh cells lack the ability to class switch resulting in high amounts of IgM?

Answer 39

yes

Question 40

what occurs before differentiation into plasma or memory cells?

Answer 40

class switching

Question 41

do centrocytes differentiate under the influence of Tfh cells secreting IL-21 and IL-10?

Answer 41

yes

Question 42

between memory cells and plasma cells, what is needed first during an infection and what is needed second?

Answer 42

-first need antibody secreting plasma cells then the same cytokines direct the formation of memory cells

Question 43

what are the two locations plasma cells stay or go to?

Answer 43

-some plasma cells remain in the lymph node to produce antibodies that bind antigens arriving from infected tissue (short lived) -some plasma cells migrate to the bone marrow to provide a systemic source of antibody circulating between blood and lymph (long lived)

Question 44

have naive B cells ever seen antigen?

Answer 44

no

Question 45

do plasma cells divide?

Answer 45

no

Question 46

do high affinity neutralizing antibodies prevent viruses and bacteria from infecting cells?

Answer 46

yes

Question 47

are many diseases caused by bacterial toxins at mucosal surfaces?

Answer 47

yes

Question 48

how does IgM and IgG cause classical pathway of complement?

Answer 48

-one IgM or two IgG bind to pathogen surface allowing C1 to bind -C1s cleaves C4 into C4a and b and C4b attaches to the pathogen surface -C1s cleaves C2 into C2a and b and C2a binds to C4b -C4bC2a is a C3 convertase that cleaves C3 into C3a and C3b -C3b attaches to pathogen surface coating for opsonization, membrane attack complex and more

Question 49

how does erythrocyte CR1 help clear immune complexes from circulation?

Answer 49

-small antigen-antibody complex forms in circulation and activates complement -immune complex is coated with covalently bound C3b -CR1 on an erythrocyte surface binds to C3b-tagged immune complex -erythrocyte carries immune complex to the liver or spleen, where it is detached and transferred to CR1 of a macrophage and degraded

Question 50

are there different types of Fc receptors specific for classes and subclasses of antibodies?

Answer 50

yes

Question 51

is FcRI high affinity for IgG and FcyRII and FcyRIII low affinity for IgG?

Answer 51

yes

Question 52

what is antibody-dependent cell-mediated cytotoxicity (ADCC)?

Answer 52

when anti-CD20 antibodies (mainly IgG) bind to CD20 on a tumor cell (B-cell lymphoma cell), which lets the Fc receptors on NK cells to recognize the antibody and signal the NK cell to kill the tumor cell via apoptosis