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Immunology test III > Lecture 16 - B Cell Activation and Antibody Production (part II) > Flashcards

Lecture 16 - B Cell Activation and Antibody Production (part II) Flashcards

1
Q

Alternating processing of a primary RNA transcript resutls in what?

A

The formation of mRNA for the membrane or secreted form of μ heavy chain

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2
Q

What does B cell differentiation results in an increasing fraction of what?

A

The μ protein produced as the secreted form

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3
Q

What are four exons of the Cμ gene?

A

Cμ1, Cμ2, Cμ3, Cμ4

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4
Q

In T-dependent responses, some of the progeny of activated IgM and IgD expressing B cells under what?

A

Heavy chaing isotype (class) switching and produce Abs with heavy chains of different classes

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5
Q

Where does isotype switching primarily occur? What are they driven by?

A

In the germinal centers

Driven by Tfh cells

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6
Q

What is another place were some isotype switching may occur? What are they driven by?

A

In B cells in extrafollicular foci, driven by extrafollicular Th cells

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7
Q

The capacity of B cells to produce different Ab isotypes provides what?

A

A remarkable plasticity in humoral immune responses

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8
Q

Abs of various classes perform distinct effector function and are involved in defense against:

A

Different types of pathogens

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9
Q

Class-switching occurs in response to changing what?

A

The constant regions of the heavy chains

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10
Q

What is the specificity of the Abs determined by ?

A

The variable regions

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11
Q

In class-switching, what remains unaltered?

A

The specificity of the Abs

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12
Q

Isotype switching in response to different types of microbes is regulated by what?

A

Cytokines produced by the Th cells that are activated by these microbes

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13
Q

What induces B cell switching to IgG?

A

IFN-γ produced by Th1

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14
Q

What induces B cell switching to IgE?

A

IL-4 produced by Th2

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15
Q

What does the response to viruses and intracellular bacteria involve? why?

A

IgG abs, because they block the entry of microbes into host cells and also promote phagocytosis by Mo

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16
Q

Intracellular pathogens activate what Th cells?

A

T helper cells of the Th1 subset to produce IFN-γ and IFN-γ+ Tfh cells to make more IFN-γ

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17
Q

The response to helminths is mainly driven by what Abs?

A

IgE, it particiipates in eosinophil and mast cell-mediated elimination of the helminths

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18
Q

What do helminths likely influence Tfh cells to differentiate into?

A

IL-4+ Tfh cells which produce Th2-type cytokines during the germinal center reaction

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19
Q

B cells in different anatomic sites switch to different ______.

A

isotypes

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20
Q

B cell in different anatomic sites switching to different isotypes is controlled by what?

A

The cytokines produced at these sites

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21
Q

What do B cells in mucosal tissues switch to ?

A

IgA

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22
Q

What antibody is most efficiently transported through epithelia into mucosal secretions, where it defends against microbes that try to enter through the epithelia?

A

IgA

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23
Q

What is the switching to IgA stimulated by?

A

TFG-β, which is produced by many cell types including Treg and Th cells
Also BAFF, a cytokine of the TNF family

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24
Q

CD40 signals work together with what to induce isotype switching?

A

Cytokines

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25
Q

What does CD40 engagement induce?

A

The enzyme activation-induced deaminase (AID)

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26
Q

What is AID crucial for?

A

Both isotype switching and affinity maturation

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27
Q

In immunodeficiencies related to the CD40-CD40L axis, what occurs?

A

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

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28
Q

What do mature B cells first produce?

A

IgM immunoglobulins

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29
Q

What is every C gene preceded by?

A

A switching (s) sequence that controls the rearrangement process

VDJ—-SCμ

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30
Q

What is CSR?

A

Is a “switch” of the immunoglobulin isotype from IgM/IgD to IgG, IgA, or IgE with similar Ag specificity but with different biological properties

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31
Q

Where does CSR take place?

A

In activated B cells between two switch regions (S) comprising repetitive sequences of palindrome-rich motifs

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32
Q

What changes occur in the Ch gene during CSR?

A

Expression of the Cμ region to one of the other Ch genes

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33
Q

What does CSR result in?

A

A looped-out deletion of the intervening DNA segments

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34
Q

What is CSR preceded by?

A

The expression of germline transcripts initiated from intronic promoters and regulated by specifically by various cytokines

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35
Q

What does the germline transcription open?

A

The chromatin structure of a specific S region and renders it accessible to the putative recombinase

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36
Q

What is a key enzyme required for isotype switching and affinity maturation?

A

AID

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37
Q

What is AID expression activated mainly by?

A

CD40 signals from Tfh cells

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38
Q

What does AID deaminates?

A

Cytosines in single-stranded DNA templates, converting C residues to uracil residues

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39
Q

What does Uracil N-glycosylase do?

A

UNG removes U residues to generate abasic sites where the APE1 endonuclease creates nicks that lead to a double-stranded break

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40
Q

What is affinity maturation?

A

The process that leads to increased affinity of Abs for a particular Ag

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41
Q

Affinity maturation is observed only in Ab responses to what?

A

T-dependent protein Ags

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42
Q

What is required for somatic mutation to be initiated?

A

CD40:CD40L interactions

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43
Q

During the germinal center reaction, what results in the production of Abs with high affinity for Ag?

A

Somatic hypermutations of Ig V genes and selection of B cells with high-affinity Ag receptors

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44
Q

In proliferating GC B cells in the dark zone, what do Ig V genes undergo?

A

Point mutations at an extremely high rate

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45
Q

What is the rate of point mutations in the Ig V regions of B cells in the dark zone?

A

1 in 10^3 base pairs per cell division in V gene, which is about a 1000x higher rate than spontaneous rate mutation in other genes

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46
Q

Mutations in Ig V genes are also called what?

A

somatic hypermutation

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47
Q

The Vh and Vl genes of expressed heavy and light chains in each B cells contains how many nucleotides?

A

about 700

*this implies that mutations will accumulate in expressed V regions at an average rate of almost one per cell division

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48
Q

Ig V gene mutations continue to occur in the progeny of what?

A

individual B cells

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49
Q

Any B cell clone can accumulate what?

A

more and more mutations during its life int he germinal center

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50
Q

It is estimated that as a consequence of somatic mutations, the nucleotide sequences of IgG Abs derived from one clone of B cells can have how much of the germline sequence mutated?

A

5%

Usually translates up to 10 aa substitutions

51
Q

Where are the mutations clustered in?

A

V regions, mostly in the Ag-binding complementarity-determining regions CDR

52
Q

There are more mutations in IgM or IgG?

A

IgG

53
Q

What does the presence of mutations correlate with?

A

Increasing affinities of the Abs for the Ag that induced the response

54
Q

Mutations in V genes increase with time after what?

A

immunization and w repeated immunizations

55
Q

The affinities of the Abs produced also tend to increase with what?

A

more mutations

56
Q

somatic mutation of V genes generates Abs with what?

A

different affinities

57
Q

What is necessary to rescue the B cells from apoptosis?

A

Binding to Ag displayed on follicular DCs or present Ag to germinal center Tfh cells

58
Q

As the amount of available Ag decreases during an immune responses, what has a selective advantage? What does this lead to?

A

B cells with the highest affinity

This leads to an average increase in the affinity of Abs for Ag as the humoral immune response progresses

59
Q

Because somatic mutation also generates many B cells that do not express high-affinity receptors for Ag and cannot be selected to survive, what are germinal centers sites for?

A

Tremendous apoptosis

60
Q

B cells that have undergone somatic mutation migrate tow hat?

A

Into the FDC-rich ligh zone of the germinal center

61
Q

B cells with high -affinity receptors for the Ag are best ablew to bind to Ag when it is present in what levels?

A

low concentrations by follicular DCs

62
Q

What does Ag recognition by itself induce?

A

Expression of anti-apoptotic proteins of the Bcl-2 family

63
Q

High-affinity B cells will preferentially endocytose and present the Ag for Tfh cells in the Gc which signal via what?

A

CD40L to promote the survival of the B cells

64
Q

What do Tfh recognize on B cells to induce apoptosis?

A

Fas on B cells that are recognized by FasL on Tfh cells

65
Q

How do B cells protect themselves from death involving Fas?

A

High-affinity B cells may activate endogenous inhibitors of Fas when their BCRs recognize Ag and thus protect themselves from death, while low affinity B cells are killed

66
Q

Many tubors of B cells, B cell lymphomas, develop from what?

A

Germinal center B cells

67
Q

What are B cell lymphomas caused by?

A

Chromosomal translocations of various oncogenes into Ig gene loci

68
Q

DNA breaks associated with what facilitate incorporation of oncogenes?

A

With somatic hypermutation and isotpye swithcing

69
Q

How can germinal centers also contribute to the pathogenesis of autoimmunity?

A

Somatic mutations may produce a self-reactive B cell clone in the germinal center

70
Q

What are plasma B cells?

A

They are morphologically distinct, terminally differentiated B cells committed to abundant antibody production

71
Q

How are Plasma B cells generated?

A

After the activation of B cells through signals from the BCR, CD40, TLRs, and other receptors including cytokine receptors

72
Q

Short-lived plasma cells are generated during what?

A

T-independent responses

May as well be generated early during T-dependent responses in extrafollicular B cell foci

73
Q

Where are short-lived plasma cells generally found in?

A

Secondary lymphoid organs and in peripheral non-lymphoid tissues

74
Q

Long-lived plasma cells are generated where?

A

In T-dependent germinal center responses to protein Ag

75
Q

What signals generate long-lived plasma cells?

A

Signals from BCR and IL-21 via a stage of their precursors called plasmablasts

76
Q

Plasmablasts generated in germinal centers enter the circulation and home to what?

A

The bone marrow where they differentiate into long-lived plasma cells

77
Q

Typically 2 to 3 weeks after immunization with a T cell-dependent Ag, the bone marrow becomes a major site of what?

A

Ab production

78
Q

Long-lived plasma cells in the bone marrow are maintained by what?

A

BAFF allowing the cells to survive for long periods, often as long as the life span of the host

79
Q

Long lived plasma cells may continue to secrete Abs for how long after the Ag is no longer present?

A

months or even years

80
Q

Abs that are continually secreted for months are years after Ag is no longer present provide what?

A

Immediate protection if the Ag is encountered later

81
Q

It is estimated that almost how much of the Ab in the blood of a healthy adult is produced by long-lived plasma cells and is specific for Ags that were encountered in the past?

A

50%

82
Q

Memory B cells are generated mainly in what?

A

Germinal centers for T-dependent protein Ags

83
Q

Memory B cells acquire the ability to do what without continuing Ag stimulation?

A

Survive for long periods of times

84
Q

Memory B cells express high levels of what?

A

Anti-apoptotic protein Bcl-2

85
Q

What do memory B cells typically express?

A

High-affinity(mutated) Ag receptors and Ig molecules of switched isotypes

86
Q

Abs production is greatly accelerated after secondary exposure to Ags, and this can be attributed to what?

A

Activation of memory cells in germinal centers

87
Q

Some memory B cells may remain in the lymphoid organ where they were generated, whereas others exit germinal centers and do what?

A

recirculate between the blood and lymphoid organs

88
Q

Effective vaccines against microbes and microbial toxins must induce what? When will this only occur?

A

Both affinity maturation and memory B cell formation

It will occur only if the vaccines are able to activate helper T cells

89
Q

The concept of vaccines activating helper T cells has been applied to the design of what type of vaccine?

A

Vaccines for capsular polysaccharides, which is incapable of stimulating T cells.
Polysaccharide acts as a carrier for the foreign protein, they are covalently linked to form hapten-carrier conjugate
Such vaccines, called conjugate vaccines, more readily induce high-affinity Abs and memory cells

90
Q

What Ags are termed thymus independent or T independent?

A

Many non-protein Ags, such as polysaccharides and lipids that stimulate Ab production in the absence of Th cells

91
Q

The Abs produced in the absence of Th cells have what general characteristics?

A

Low affinity and consists mainly of IgM, with limited isotype switching to some IgG subtypes and also to IgA

92
Q

Most T-independent Ags are composed of repeated identical Ag epitopes termed:

A

multivalent

93
Q

Multivalent Ags may induce what that leads to activation without a requirement for cognate T cell help?

A

Induce maximal cross-linking of the BCR complex on specific B cells

94
Q

TI Ab responses may be initiated where?

A

In the spleen, bone marrow, peritoneal cavity, and mucosal sites

95
Q

What B cell subsets are especially important for Ab responses to TI antigens?

A

Marginal zone and B-1 subsets of B cells

96
Q

What are a distinct population of B cells that mainly respond to polysaccharides?

A

Marginal zone B cells

97
Q

After activation of marginal zone B cells, what do the cells differentiate into?

A

short-lived plasma cells that produce mainly IgM

98
Q

Where may TI Ags persist for prolonged periods where they are recognized by specific B cells?

A

On the surfaces of marginal zone Mo in the spleen

99
Q

What lineage of B cells respond readily to TI Ags mainly in the peritoneum and in the mucosal sites?

A

B-1 cells

100
Q

What are the most important TI Ags?

A

polysaccharides, glycolipids, and nucleic acids

101
Q

TI Ags cannot be processed and presented with what?

A

MHC molecules- therefore they cant be recognized by CD4 helper cells

102
Q

Many TI Ags of polysaccharide nature activate the complement system by which pathway?

A

The alternatThe alternativew pathway, generating C3d, which binds to the Ag and is recognized by CR2 on B cells

103
Q

TI responses may also be facilitated by additional signals derived from microbial products that activate what on B cells?

A

TLRs

104
Q

Some TI non-protein Ags can induce Ig isotypes other than IgM. In humans, the dominant Ab class induced by pneumococcal capsular polysaccharide is what?

A

IgG2

105
Q

Cytokines produced by non-T cells may stimulate ______ in TI responses

A

Isotype switching

106
Q

BAFF produced by DCs and Mo can induce the synthesis of what? This may be also be further facilitated by the activation of TLRs on these B cells

A

AID in Ag-activated B cells

107
Q

What is secreted by many non-lymphoid cells at mucosal sites that help mediate the IgA switch?

A

TGF-β

108
Q

Many bacterial polysaccharides of encapsulated bacteria belong to what Ags?

A

TI

109
Q

What is the major mechanism of host defense against infections by encapsulated bacteria?

A

Humoral immunity

110
Q

Individuals with immunodeficiencies of humoral immunity are especially susceptible to life-threatening infection by what pathogens?

A

Pneumoccocus, menigococcus, and Haemphilus

111
Q

TI Ags also contribute to the generation of natural antibodies, which are present in the circulation of normal individuals and are apparently produced without what?

A

overt exposure to pathogens

112
Q

What are most natural Abs? What are they postulated to be produced by?

A

Low-affinity anti-carbohydrate Abs
Produced by peritoneal B-1 cells stimulated by bacteria that colonize the gastrointestinal tract and by marginal zone B cells in the spleen

113
Q

Many polysaccharide vaccines, such as the penumoccocal vaccine, induce what type of protective immunity?

A

long-lived

114
Q

Rapid and large secondary responses typical of memory (but without much isotype switching or affinity maturation) may also occur one secondary exposure to what Ags?

A

polysaccharide (carbohydrate) Ags

115
Q

What are natural Abs that recognize certain glycolipids (blood group Ags) expressed on the surface of many cell types, including blood cells?

A

Anti-ABO Abs

116
Q

Blood group Ags and Abs are not important for host defense but for what instead?

A

For blood transfusions and transplantation

117
Q

Ag-Ab complexes can simultaneously bind to what receptors on B cells?

A

Membrane Ig (through Ag) and the FCγRIIB receptor through the Fc portion of the antibody

118
Q

Ag-Ab complexes binding to membrane Ig and FcγRIIB simultaneously causes what?

A

phosphatases associated with the cytoplasmic tail of the FcγRIIB inhibit signaling by the BCR complex and block B cell activation

119
Q

FcR-mediated Ab feedback is what type of mechanism in humoral immune responses?

A

Physiologic control mechanism

120
Q

FcR-mediated Ab feedback is triggered by what?

A

Secreted Ab and blocks further Ab production as apposing the activation via CR2

121
Q

It is not clear under which circumstances secreted Abs provide complement mediated amplification or what?

A

Fc receptor - mediated inhibition

122
Q

A likely scenaria is that iGm which activates complement but does not bind to the FcγR are involved in ________. Whereas increasing production of IgG leads to _________,

A

Amplification

Feedback inhibition

123
Q

A ________ in the FcγRIBB gene has been linked to susceptibility to the autoimmune disease systemic lupus erythematosus in humans.

A

polymorphism

Immunology test III (7 decks)

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