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065. My HDM Exam 2 > 3. Humoral Immune Responses > Flashcards

3. Humoral Immune Responses Flashcards

1
Q

IgM and IgD are expressed equally on a naive B cell. A single B cell can produce 5000 Ab cells per week. How many antibodies are produced daily?

A

10^12 antibodies

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2
Q

Which Ig is the most powerful complement pathway stimulator?

A

IgM

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3
Q

After a B cell is activated by Ag and costimulation, what are the four things the activated B cell can do?

A

Secrete IgM (way more expressed than naive)
Isotype switch depending on cytokines released
Affinity maturation - become high affinity IgG by mutations
High affinity Ig expressing B cells can become memory

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4
Q

Primary response is to nonprotein Ags (carbs/lipids/proteins), while secondary response is all protein antigens.. Why?

A

Memory cells are generated against a specific Ag protein, this cannot be made again carbs/lipids

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5
Q

During primary response, IgM is greater than IgG. Secondary is stimulated when the SAME protein Ag stimulates memory B cells, causing more IgG than?

A

IgM, response is more rapid, larger amounts of B cells, isotype switching and affinity maturation (high affinity)

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6
Q

Follicular B cells respond to protein Ags and intiate T -dependent Ab responses (long lived, high aff, IgG/A/E). Marginal Zone B cells respond to multivalent Ags and are T independent (short lived plasma cells, mainly IgM) B1 cells….?

A

are located in mucosal sites (peritoneum) and respond to multivalen and are T independent, mainly IgM

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7
Q

B1: From fetus (8th week), in mucosal sites, low receptor diversity, No memory, targets carbohydrates, IgM>IgD, Doesn’t isotype switch, does not require T cell help, can self renew in periphery.
B2: ?

A

Made in bone marrow, located widespread, high receptor diversity d/t junctional diversity (presence of TdT), has memory, target is proteins (Ag), IgD>IgM, isotype switch, Always need T cell help, replace by bone marrow

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8
Q

Most naive B cells are follicular B cells (B2/recirculating), go from spleen to LN to other 2o lymphoid tissues. Follicular B cells migrate to the B cell zone in lymphoid tissues and are called?

A

Follicles

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9
Q

Follicular DCs (FDC), which are DCs that are STUCK in secondary lymphoid tissue and do not come from the tissue release _______ which guides the movement of B cells into follicles.

A

CXCL13 chemokine (*remember FDCs function differently than other DCs in the fact that they trap a Ag on its surface and that is how it presents to the B cell instead of phagocytosis)

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10
Q

Ag brought to lymphoid tissue by afferent lymphatics and drain into subcapsular sinus. Small Ags are deliverd to follicles via conduits, Large Ags are delivered by subscapular sinus Mø or by DCs in the _____?

A

Medulla (most Ags presented to B cells are in native conformation)

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11
Q

FDCs do not express class II MHC and do not phagocytose and process exogenous Ags for class I MHC. FDCs secrete CXCL13 which organize intra-follicular migration of B cells and _______

A

Tfh cells (follicular T helper cells)

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12
Q

FDCs can retain immune Ag-Ab complexes on their surface for a long time. These complexes are retained by FcyRIIb (Fc receptors), CR1 or CR2(CD21) complement receptors. The immune complexes are key role in germinal center reaction because they provide….?

A

They provide the antigenic substrate that drives antibody affinity maturation

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13
Q

In the marginal zone there are mainly marginal zone (MZ) mø and marginal B cells whic lymphocytes and DCs passing through. The framework of __________ forms the basis of the marginal zone

A

reticular fibroblasts

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14
Q

Maginal Zone B cells in spleed bind to immune complexes which contain Ag coated in complement fragments using complement receptors (CR2). MzB will shuttle complex to FDCs which express high levels of CRs and bind to Ag, releasing it from MzB cells. What then happens?

A

Marginal zone B cells free of Ag complexes migrate back to the marginal zone to do the same thing

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15
Q

Polysaccharide Ags are captured by MZ mø and sent to Mz B cells, as well as blood borne pathogens captured by plasmacytoid DCs is sent to the spleen and delivered to?

A

MZ B cells

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16
Q

Ag induced cross-linking of BCRs and signaling induces many responses. (Agdependent B cell activation)

1) production of proteins that promote survival and proliferation, expression of cosimulators (B7) and cytokine receptors that promote interactions/responsivness to T helper cells.
2) ?

A

Expression of CCr7 induces migration of the B cell towards the T cell zone from follicule

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17
Q

BCR: Igalpha and Igbeta signaling complex are linked together by disulfide bonds and are non-covalently associated with the BCR… What do they contain on their cytoplasmic tails and what do those do?

A

Contain immunoreceptor tyrosine-based activation motifs (ITAM), which mediates signaling functions

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18
Q

Along with the signaling complex of BCRs, there are also coreceptors, including CD19, CD21, and CD32, which enhances or inhibits the signaling by BCR/Igab. How are the coreceptors and BCR linked?

A

Ag complement or Ag-Ab complex

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19
Q

CD19 is the dominant signaling component of B cells
CD21 is complement receptor 2 (CR2)
Together, they do what?

A

positively regulates B cell activation and Serves to lower the Ag threshold for B cell activation

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20
Q

What is the main negative regulatory coreceptor for the BCR complex?

A

CD32 (FcyRIIB), which contains a ITIM (inhibitor receptor)

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21
Q

Steps for the Signaling by the BCR complex?

  1. Ag with multiple epitopes binds chains (2) and crosslinks activation
  2. LCK/FYN/BLK (Src kinases) phosphorylate ITAMs on IgA/B to activated SH2 domain of Syk tyrosine kinase
  3. Syk phosphorylates BTK, which activates PLCy
  4. ?
  5. ?
  6. ?
A

(*JUST LIKE TCR)
4. PLCy cleaves PIP2 to form DAG and IP3
5. DAG activates PKC
IP3 combines with Ca2+ activates calcineurin
6. PKC phosphorylates IkB and NFkB migrates to the nucleus.
Calcineurin activates NFAT (leading to gene activation)
Ras is also activated which signals Ras-MAP kinase pathway
PLC pathway and PKC-B pathway

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22
Q

B cells express complex of CR2 (CD21) complement receptor and CD19 (w CD81 always needed) which contains ITAMs. Microbial Ags opsinzed by C3d can engage both CR2 and BCR. What does this enhance?

A

The signaling cascades from both the BCR complex and the CR2 complex great enhance (100 fold) B cell activation as compare to Ag without C3d attached

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23
Q

C3d, opsinizer, is derived from C3b when C3b is further degraded, which remains bound to Ag or Ag-Ab complex. C3d’s receptor, CR2 along with CD19 and CD81 is called the B cell coreceptor complex because?

A

CR2 binds C3d at the same time the BCR binds the antigen

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24
Q

When CR2 binds C3d, it brings CD19 close in to BCR-kinases, CD19 tail becomes tyrosine phosphorylated after the efficient recruitment of what?

A

CD19 ITAMs are phosphorylated after Lyn kinase(SRC kinase) phosphorylates the IgA/B ITAMs, which activates Syk which will phosphorylate CD19 (which amplifies BCR signaling)

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25
Q

PAMP recognition and TLR signaling can contribute to B cell activation (B cells only! no other APCs), which means that play an essential role in what?

A

Bridging innate and adaptive immunity

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26
Q

TLRs engage PAMPs and activate NFkB signaling. These pamps can be expressed while the Ag is bound to the BCR, activating the TLRs which will do what?

A

Stimulate B cells leading to B cell proliferation and differentiation into plasma cells.
TLR SIGNALING in B cells account for Adujuvant effect in any vaccine!

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27
Q

Again, what occurs when B cells are activated by Antigens? (5)

A
  1. Expression proteins that promote survival/proliferation
  2. Increase B7 expression = interaction with T cells
  3. Increased cytokine receptors= inc repsonse to cytokine
  4. Expression of CCR7= migration to T cell zone
  5. Generation of Plasma cells to secrete IgM
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28
Q

Protein Ags recognized by membrane Igs and endocytosed and presented with class II MHC, CD4 T cells recognize and bind, stimulating B cell reponse. How is this process different to hapten carrier conjugates?

A

The hapten (B cell epitope) is recognized by a specific B cell and endocytosed and peptides from the carrier (T cell eptiopes) are presented to T helper cell

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29
Q

When T helper cells are activated by B cells presenting Ags, the express CD40L which will bind to CD40 on B cells and stimulate?

A

B cell proliferation and differentiation in germinal center. Cytokines produces by the T cell will also help

30
Q

B cells and CD4 T cells recognize Ags, and once activated they migrate toward eachother and interact stimulating B cell proliferation and differentiation. B-T interaction leads to short lived plasma cells producing IgM. B cells will then migrate to where and do what?

A

Migrate the the germinal centers and undergo a) somatic mutation b) affinity maturation c) isotype switching , and generation of memory B cells and long lived plasma cells producing specific Igs

31
Q

To generate Tfh, T cells need to be activated by DCs and then (4-7 days later) activated by B cells, which then allows the Tfh cell to migrate into GCs where they help activate B cells. What is secreted by Tfh cells in the germinal center?

A

IL21: required for GC development and generation of plasma cells
IFNy or IL4: controls isotype Th1/Th2 switching

32
Q

Tfh cells are distinct from Th1/2/17/reg effeector T cells. They play a critical role in GC formation and function, B cell activation and differentiation, and express ICOS (inducible costimulator), PD1 (programmed death 1), IL21 and transcription repressor Bcl-6. What is IL21 important for?

A

IL21 is important for generation of B cell response in GCs resulting in development of B cells, isotype switching, affinity maturation, and antibody production

33
Q

B cells proliferate in the dark zone of GC where they undergo extensive isotype switching and somatic hypermation of Ig V(variable) genes, B cells migrate into the light zone where they encounter follicular DCs displaying Ag and Tfh cells. B cells with the highest affinity Ig receptors are selected to survive and do what?

A

They differentiate into Ab-secreting cells (plasma) and memory cells.

Ab-secreting cells reside in bone marrow as long lived plasma cells while memory B cells enter recirculating lymphocyte pool

34
Q

Dark zone of germincal center contains proliferating B cells and the light zone contains _________?

A

Follicular DCs, mantle zone has tightly packed small B cells of primary follicles (inactivated?)

35
Q

Tfh cells activate B cells with CD40L and cytokines, allowing switching to a different isotypes. IFNy will produce IgG which opsonizes, phagocytoses, complement activation
IL4 secreted by Tfh cells direct b cells to produce IgE, which helps against parasties and hypersensititivity
TGFB,BAFF,APRIL makes IgA, muscosal immunity
and IgM b cells makes?

A

IgM for complement activation (no cyotkines = IgM produced)

36
Q

Intracellular pathogens activate Th1 like -Tfh cells (IFN-y+Tfh cells), which produce IFNY (Th1) induces IgG switching and IL4(Th2) (IL4+Tfhcells) induces IgE switching.

A

What do IgG and IgE both function in?
G: intracellular pathogen response, block entry of microbes into hosts, activate comlement, promote phagocytosis
E: eosinophil and mast cell mediated elimination of helminths

37
Q

Activation-induced deaminase (AID) is needed for isotype switching and affinity maturation. When Cd40L binds to CD40, it induces AID. Without CD40/CD40L/AID, what would happen?

A

The Ab response to protein Ag is dominated by IgM Abs, whereas there is limited switching to other isotypes

38
Q

Class-switch recombination (CSR)…First, mature B cells produce IgM. The rearranged VDJ sequences are positioned next to other C genes (constant = different isotypes). every C gene is preceeded by?

A

By switching sequence (S) that controls the rearrangment process

39
Q

CSR takes place in activated (mature) B cells and changes Cu(m) to other Ch(e,g,a) genes. before CSR, germline transcripts are expressed which are initiated from intronic promoters. Germline transcription opens the chromatin structure of a specific S region, doing what?

A

Making it accessible to the putative recombinase

40
Q

CSR takes place between two switch sequences (S) comprising of palindrome-rich motifs and results in looped out deletion of intervening DNA. This process is regulated by cytokines. CSR switches Ig isotype from IgM to?

A

IgG, IgA, IgE with similar Ag specificity but with different biological properties

41
Q

Affinity maturation is the process that leads to increased affinity of Abs for a particular Ag, observed only in Ab response to TD Ags. Tfh and CD40/Cd40L are require fore?

A

somatic hypermutation of Ig V genes to be initiated

42
Q

In the GC, mutations occur during division, all cells are trying to have multiple mutations to have a high affinity. What are the 3 outcomes division has completed?

A
  1. No mutations occured, B cell goes to apoptosis
  2. Mutations leading to reduced affinity = apoptosis
  3. Mutations leading to high affinity, binding to APC FDC cell in light zone of GC and survives
43
Q

Affin maturation occurs in dark zone of GC, where Ig V genes of proliferating B cells undergo point mutations at a very high rate. 1 in 10^3 (1000) there is a mutation. These mutations in Ig V are called __________ for this reason

A

Somatic hypermutation

44
Q

How many mutations per cell division occur in proliferating B cells in the dark zone of the GC?

A

about 1 mutation per cell division, the more mutations (10) the higher affinity of the Ab for the Ag that induce the response

45
Q

It is estimated that, since IgV mutations continue to occur in the progeny of individual B cells, the nuecleotide sequence of IgG Abs derived from one clone of B cells has as much as what?

A

5% germline sequence mutated (much more than IgM)

46
Q

B cells proliferate and divided 10 times to bind an Ag. Why is this signification if it takes place in the Germincal center of a lymph node?

A

This causes swelling of the LN!

47
Q

Rememer***

A

B Cells with the highest affinity (usually meaning they have the most mutated Ig V genes) are able to bind to the FDC and antigen and present it to Tfh cells. B cells with less affinity will be outcompeted and under apoptosis

48
Q

As less and less Ag is present in GC, only the B cells with the MOST affinity can bind, resulting in affinity maturation. B cells that are selected to survive in GC produce Ig with?

A

increase affinity for the Ag, otherwise TREMENDOUS apoptosis at germinal center

49
Q

After B cell somatic mutation, they migrate into FDC rich light zone of GC. High affinity receptors on certain B cells survivie because of what 4 mechanisms?

A
  1. Ag recognition by itself induces expression of Bcl-2, an anti-apoptotic protein
  2. High aff B cells will present Ag for Tfh cells in GC which signal via CD40L to promote survival
  3. High aff B cells activate endogeneous inhibitors of FAS when BCRs recognize Ag, being protected from death
  4. Tfh cells express FasL, which recognize Fas and apoptose it
50
Q

B cell lymphomas develop from B cells in the germinal center, causing chromosomal translocation of oncogenes into Ig gene loci. DNA breaks associated with somatic hypermutation and isotype switching do what?

A

facilitate incorporation of oncogenes

51
Q

Germinal centers may also contribute to autoimmunity. What might somatic mutation produce?

A

A self-reactive B cell clone in the GC

52
Q

Memory cells are generated in BCs for T-dependent protein Ags. They acquire ability to survive a long time without Ag stimulation. Memory B cells express high levels of what?

A

Anti-apoptotic protein Bcl-2

53
Q

Memory B cells express high affinity BCRs and Ig molecules of switched isotypes. Quickly activated and produce Abs. Some stay in lymphoid organ where they were generated and others?

A

exit germinal centers and recirculate between the blood and lymphoid organs

54
Q

Antibodies that are produce in the absence of Th cells are generally…?

A

lower affinity and mainly consist of IgM, with limited Ig switching to IgG and IgA

55
Q

A majority of TI Ags are multivalent, being composed of repeated identical Ag epitopes. These are able to induce maximal crosslinking of the BCR complex on specific B cells, leading to?

A

Activation without a requirement of T cell help

56
Q

TI ab responses can be intiated in spleen, BM, peritoneal cavity, and mucosal sites. Marginal zone and B1 cells being most important for Ab response to TI ags. MZ B Cells are a distinct population of B cells in the spleen that mainly respond to?

A

polysaccharides

57
Q

After activation by polsaccharides, the MZB cells differentiate into short-lived plasma cells that secrete IgM. B1 cells respond to TI ags in a similar manner where?

A

peritoneum and mucosal sites

58
Q

The most important TI Ags are polysaccharides, glycolipids, and nucleic acids which cannot be processed and presented with MHC molecules and therefore cannot be recognized by?

A

CD4 T helper cells

59
Q

Polysaccharides activate the complement system by the alternative pathway, generating C3b which binds to the Ag and then is processed into C3d which is recognized by CR2 on the B cell. What another way TI responses can be facilitated?

A

by signals from microbial products that activate TLRs on B cells

60
Q

SOME TI ags can induce isotype switching such as pneumococcal capsular polysaccharide which switches to?

A

IgG2

61
Q

Cytokines produce by non-T cells may also stimulate isotype switching in TI responses. TGFB that helps mediate IgA switch are secreted by many non-lymphoid cells at mucosal sites. BAFF produce by DCs and Mø can induce what?

A

the synthesis of AID in Ag-activated B cells, which is further facilitated by the activation of TLRs on these B cells

62
Q

Humoral immunity is major defense against encapsulated bacteria. So people with immunodeficiencies of humoral immunity are susceptible to?

A

Pneumococcus, meningococcus, and haemophilus (nonencapsulated)

63
Q

TI Ags contribute to the generation of natural antibodies. These are low affinity anti-carbohydrate Abs, produced by PERITONEAL B1 CELLS stimulated by bacteria that colonize the GI tract and by what?

A

MZ B cells in the spleen

64
Q

Effective vaccines must induce affinity maturation and memory B cell formation. This ‘concept’ has been applied when designing vaccines for capsular polysaccharides, which are ?

A

incapable of stimulating T cells

65
Q

In this case, polysaccharide is covalently linked to a foreign protein to form the equivalent of a HAPTEN-carrier conjugate. These vaccines are called conjugate vaccines and do what?

A

More readily induce high-affinity Abs and memory cells

66
Q

Polysaccharide vaccines such as pneumococcal vaccine induce a long lived protective immunity. What may occur on secondary exporsure to the carbohydrate Ags?

A

Rapid and large secondary response typical of memory cells (but without much isotype switching or affinity maturation)

67
Q

The activation of B cells is tightly controlled to limit responses against microbe to avoid collarteral damage to host tissues. Inhibition signaling is used to prevent?

A

Uncontrolled inflammation and lymphoproliferation

68
Q

Generally how do inhibitory receptors work?

A

They recruit and activate phosphatases that counter signaling events induced by Ag receptors

69
Q

Inhibitory receptors are key in NK cells, T cells, and B cells, they have an ligand binding domain and a cytosolic ITIM motif. When a ligand binds, results in?

A

Phosphorylation of the ITIM tyrosine by a Src kinase. The P-ITMs recruit a SH2 domain containing tyrosine phosphatase that can inhibit immune receptor signaling

70
Q

Ag-Ab comlexes can simultaneously bind to the BCR and the FcyRIIB receptor (inhibitor) through the Fc portion of the antibody. This leads to?

A

Phosphatases associated with the cytoplasmic tail of the of the FcYRIIB inhibit signaling by BCR complex and block B cell activation.. SHIP converts PIP3 to PIP2, blocking downstream signaling

71
Q

FcR-mediated Abs secrete Abs to block Ab production as a control over the humoral immune system. What was seen in KO FcyRIIB mice?

A

Uncontrolled Ab production, also seen as a polymorphism defect which is linked to Autoimmune disorder systemic lupus erythematosus

72
Q

FcyRIIB (CD31) is key inhibitory receptor, also important attenuator of signaling in activated DCs and Mø. ITIMS of FcyRIIB can be phosphorylated by Src kinases which recruit what?

A

SH2 domain contrain tyrosine phosphatases such as SHP (Sh2 domain containing phosphatase) and SHIP (SH2 domain containing inositol phosphatase) which remove phosphates from PIP3 and inhibits PI3 kinase activity in lymphocytes, NK cells, and innate immune cells

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