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Integrated - Block 1 Exam 2 > BCH - Immunoglobulins > Flashcards

BCH - Immunoglobulins Flashcards

1
Q

How are Immunoglobulins/Antibodies proteins made

A

by B lymphocytes of the adaptive immune system

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2
Q

How do immunoglobulins bind ligands?

A

with a high affinity and high degree of specificity

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3
Q

Immunoglobulins are heterotetramers comprised of?

A

2 identical light chains and 2 identical heavy chains

(2 dissimilar units)

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4
Q

How are immunoglobulin chains held together

A

through non-covalent bonding forces (hydrogen bonds, hydrophobic interactions) and covalent disulfide bonds

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5
Q

Each immunoglobulin chain has regions of ?

A

constant sequence and variable sequence

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6
Q

What does constant sequence mean

A

different from one immunoglobulin class to another

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7
Q

where are the regions of variable sequence found

A

the amino-terminal domains of each chain

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8
Q

what do the variable regions of immunoglobulins cooperate to form

A

antigen-binding sites

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9
Q

Why are immunoglobulins referred to as being bivalent

A

there are 2 antigen-binding sites per immunoglobulin molecule

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10
Q

Immunoglobulins assume a what shaped structure with the antigen-binding sites and where?

A

a Y-shaped structure ; at the tips of the two upper domains

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11
Q

What is the stem/base of the Y-shaped structure formed by

A

constant regions of the heavy chains

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12
Q

Do imminoglobulins exhibit elements of quaternary structure?

A

NO, the polypeptide chains are COVALENTLY joined to one another through DISULFIDE bonds –> quaternary structures focuses on the non-covalent interactions between the polypeptide chains and involve weaker forces (hydrogen bonds, ionic interactions, hydrophobic)

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12
Q

What is a paratope

A

the specific part of the immunoglobulin that binds epitopes

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13
Q

What is a ligand

A

any molecule that binds specifically and reversibly to a protein (or other molecule)

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13
Q

What is an antigen

A

any substance recognized by the adaptive immune system that triggers an immune response (for B lymphocytes that includes substances recognized by immunoglobulins)

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14
Q

What is an epitope

A

the specific part of an antigen recognized by an immunoglobulin

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15
Q

Antigens bind to immunoglobulins via ?

A

complementary surfaces (think of a lock and key relationship)

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16
Q

the regions of extreme sequence variation are known as

A

hypervariable regions

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17
Q

How many hyper variable regions are there in each variable region of a heavy chain and a light chain

A

Three regions

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18
Q

What do the hypervariable regions form

A

the binding regions for the epitopes in antigens recognized by antibodies

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19
Q

what are hyper variable regions aka

A

complementary determining regions

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20
Q

what gives immunoglobulins their remarkable ability to recognize and bind an amazing array of different molecules

A

the sequence variation within the complementary determining regions

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21
Q

Developing B lymphocytes initially express what? what are they referred to as

A

Membrane-bound immunoglobulins

  • referred to as B cell receptors
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21
Q

B lymphocytes are white blood cells derived from

A

hematopoietic stem cells found in bone marrow

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22
Q

What does each B lymphocyte progenitor express

A

a unique immunoglobulin that is found in thousands of copies on the cell surface

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23
Q

How does the immunoglobulin expressed in a particular B cells differ from immunoglobulins synthesized in other B cells?

A

the unique amino acid sequences found within its variable domains

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24
Q

The binding of an antigen to a B cell receptor activates the B cell expressing this receptor, stimulating its proliferation and differentiation into?

A

Effector/plasma cells

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25
Q

What do effector/plasma cells do

A

produce large amounts of soluble immunoglobulins capable of recognizing the antigen and eliciting a response

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26
Q

what is a role of the constant regions of membrane-bound immunoglobulins

A

to anchor the immunoglobulin to the plasma membrane

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27
Q

Antigens bind to the ____ regions of immunoglobulins

A

variable

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28
Q

What are the 5 major classes of the immunoglobulins

A

IgA, IgD, IgE, IgG, IgM

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29
Q

What plays a major role in giving the different immunoglobulin classes their defining characteristics

A

the heavy chains

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30
Q

Which immunoglobulins perform the role of B cell receptors on the surface of B cells

A

IgM and Ig

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31
Q

Where do the immunoglobulins go from the ER

A

they transit through the Golgi and then to the cell surface

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31
Q

Protein trafficking - for immunoglobulins to reach the cell surface they must first be

A

directed to the ER

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32
Q

Where does the signal sequence exit? As the protein is doing what?

A

the ribosome tunnel as the protein is being synthesized and is recognized by the SRP

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33
Q

how do proteins transiting through the secretory pathway do so

A

by being packaged in lipid vesicles

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33
Q

what does the SRP do

A

binds the signal sequence and brings the nascent (early stage) protein and its associated ribosome to a tunnel within the ER membrane

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33
Q

Regarding signal peptides - for a protein to enter the secretory pathway it must contain

A

a signal sequence at its extreme amino terminus

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34
Q

What will happen if a protein only contains a signal sequence for its target information and this signal is cleaved/removed?

A

the resulting protein will be localized initially to the lumen of the Er and in lipid vesicles for transit through the secretory pathway to the cell surface

When the lipid vesicles fuse with the plasma membrane, the protein is released from the cell and secreted into the extracellular milieu (environment)

REMOVING/CLEAVING does NOT prevent the protein from proceeding through the secretory pathway

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35
Q

Secretory vesicles are essential for transporting ?

A

the protein from the Golgi apparatus to the plasma membrane, where the protein is then secreted into the extracellular milieu (environment)

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36
Q

What immunoglobulin proteins are located on the cell surface and what do they contain

A

IgM and IgD, they contain targeting information in addition to the signal sequence

STOP-TRANSFER SQUENCES

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36
Q

What are stop transfer sequences?

A

hydrophobic stretches of amino acids that stop the polypeptide chain from being translocated across the ER membrane

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37
Q

Explain IgM and IgD and their stop-transfer sequences

A

they disengage from the translocation channel allowing the protein to cross into the ER membrane with the result that the protein is now embedded within the ER membrane

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38
Q

Prior to fusion of transport vesicles, the carboxyl terminus of an immunoglobulin is oriented toward the

A

cytosol

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38
Q

As the IgM/IgD transit through the secretory pathway, it will remain ?

A

within the membrane of the lipid vesicles

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38
Q

Prior to fusion of transport vesicles, the amino terminus of an immunoglobulin is oriented toward the

A

Lumen of the ER

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39
Q

When the lipid vesicles fuse with the plasma membrane the protein is retained on the _______ ? in an orientation ______ of that in which it was first inserted into the ER membrane

A

plasma membrane ; opposite

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40
Q

When localized to the plasma membrane, which terminus of the protein in the figure above will be found on the outside of the cell?

A

the Amino terminus

Remember, when the vesicles fuse with the plasma membrane the protein is retained on the plasma membrane in an orientation OPPOSITE of that in which it was first inserted into the ER membrane

This can be simplified by: membrane vesicles invert their orientation upon fusion with the plasma membrane

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41
Q

Membrane vesicles ______ their orientation upon fusion with the plasma membrane

A

invert!!

a protein oriented with its amino terminus toward the LUMEN of the ER will have its amino terminus oriented to the OUTSIDE of the cell upon fusion of transport vesicles with the plasma membrane

42
Q

each immuboglobulin chain is synthesized _____ and contains a

A

independently ; signal peptide directing it to the ER

43
Q

heavy chains may contain ______ , meaning ?

A

both signal peptides and stop-transfer sequences

meaning they can become embedded in the ER membrane with their amino-termini localized to the luminal side of the membrane and their carboxyl-termini localized to the cytoplasmic surface

43
Q

Light chains only contain

A

signal peptides and pass through to the lumen of the ER

44
Q

Within the ER, light chains assemble with heavy chains to do what?

A

form the characteristic heterotetrameric structure

45
Q

Secreted forms of IgM generally have

A

lower affinities for their antigens than IgG antibodies

45
Q

B1 lymphocytes are a subclass of B cells, what do they synthesize/produce

A

secreted form of IgM –> “natural IgM antibodies”

45
Q

Which immunoglobulin is the first class of immunoglobulins expressed on immature B cells in the bone marrow

A

IgM

45
Q

As vesicles containing the assembled immunoglobulins fuse with the plasma membrane, what happens to certain immunoglobulins ?

A

they remain bound to the plasma membrane via the stop-transfer sequence, which serves as a membrane anchoring domain

45
Q

Which 2 classes of immunoglobulins are found embedded in the plasma membranes of the B cells in which they are made

A

IgM and IgD

45
Q

As B cells transit from the bone marrow into the peripheral blood they begin to express ____ and are called ?

A

IgD immunoglobulins ; mature naive B cells

45
Q

Secreted forms of IgM assemble into multimers of _____ IgM units with an associated joining (J) chain

A

5

45
Q

the lower affinities of secreted forms of IgM generally are compensated for by

A

higher avidities (overall strength) due to the multiple antigen binding sites present in multimers

45
Q

Which domain must be left out of IgM for it to be secreted from cells rather than being localized to the plasma membrane?

A

stop transfer sequence

45
Q

What is different about natural IgM antibodies

A

They are spontaneously produced without prior immunization

They are produced by unique “unmutated” variable gene segments and are directed initially against self and non-self antigens

They’re important when discussing the ABO blood system

46
Q

Stop transfer sequences play a role in

A

anchoring proteins to the plasma membrane

47
Q

We know that forms of IgM lacking stop transfer sequences do not disengage from the transfer channel and embed in the ER membrane during synthesis, so what happens instead?

A

Instead, an IgM lacking a stop transfer sequence completely transits the ER membrane to the lumen of the ER.

The lumenal IgM transits in vesicles from the ER through the Golgi to the plasma membrane where fusion of the vesicle with the plasma mebrane releases the soluble lumenal contents into the extracellular environment

48
Q

What is the most abundant immunoglobulin found in the serum

A

IgG

49
Q

How many subclasses of IgG containing slightly different heavy chains are there

A

4: γ1, γ2, γ3, and γ4

50
Q

IgGs are secreted immunoglobulins so they lack

A

stop-transfer sequences in their heavy chains

51
Q

Once naïve B cells are activated and become effector B cells (plasma cells), IgG are ?

A

produced in large amounts

52
Q

What is the primary role of plasma cells

A

the synthesis of secreted immunoglobulin molecules

53
Q

The majority of therapeutic antibodies are of what class

A

IgG

54
Q

Immunoglobulins can be cleaved into Fc and Fab fragments by ?

A

digestion with the proteolytic enzyme papain

55
Q

Pathogens are recognized by immunoglobulins through sequences in their

A

variable regions (Fab fragments)

56
Q

Pathogens can be targeted for destruction by macrophages and neutrophils through sequences in their

A

Fc fragments

57
Q

Tail regions on IgE molecules bind to _________ promoting _______ attracting _______?

A

Fc receptors on mast cells

cytokine and histamine release

other components of the immune system

58
Q

What immunoglobulin is found in the saliva and the surface of mucous membranes, including those of the oral cavity

A

IgA

59
Q

What antibody is the first line of defense against inhaled and ingested pathogens

A

IgA

60
Q

Why are IgA unusual

A

they are synthesized by mature plasma cells lying beneath epithelial cell surfaces

61
Q

IgA dimers synthesized by these B cells are recognized by ____________, and then are ________ , and are released from the

A

receptors on the basolateral surface of epithelial cells (pIgR)

then they are trafficked/transcytosed through the endothelial cells

released from the apical suface

62
Q

Release of IgA from the epithelial cells involves ?

A

proteolytic cleavage of the IgA receptor

62
Q

What are are found in the Ig domain proximal to the amino termini of light and heavy chains

A

Variable regions of immunoglobulins

63
Q

A portion of the IgA receptor remains associated with the

A

secreted IgA and is referred to as the secretory component

63
Q

Variable domains are regions where amino acid sequences

A

differ between one immunoglobulin of a given class and another

63
Q

Immunoglobulins are made up of repeating structural motifs called ______

Light chains contains ______ of these structural motifs, whereas heavy chains contain _______

A

Ig domains

2, 4

64
Q

Only a small number of residues within the hypervariable regions contribute to

A

the antigen-binding site

64
Q

In what element of secondary structure are the hypervariable loop regions of immunoglobulins found

A

random structure

their size and structural contains would not allow for the high degree of variability needed for reverse turns

64
Q

Hypervariable sequences are found in loops at the ends of

A

the variable domains where they form antigen-binding sites

64
Q

Naïve B cells form approximately 10^12 different immunoglobulin sequence variants referred to as the

A

primary Ig repertoire

64
Q

The primary repertoire of IgM and IgD molecules produce immunoglobulins capable of

A

recognizing a tremendous number of different types of antigens, but with relatively low affinities

65
Q

What is an example of class switching

A

B lymphocytes switching from IgM and IgD to IgG

66
Q

As B lymphocytes switch from IgM and IgD to IgG (class switching) during activation, affinities for antigens increase through _________ , this is known as ______ ?

A

continued amino acid sequence variation in variable regions

secondary Ig repertoire

67
Q

Effector helper T lymphocytes play an important role _____ , particularly during

A

in B cell activation

during class switching

68
Q

NA Rearrangements During B Cell Development Produce

A

Immunoglobulin Diversity

69
Q

Immunoglobulin light and heavy chains are encoded ______ on different _____

A

separately ; chromosomes

70
Q

Example using light chains as regarding how pieces of a gene come together to create immunoglobulins of diverse sequence

A

Each expressed light chain is derived from three distinct segments of DNA: V (variable), J (joining), and C (constant)

The κ light chain locus has approximately 35 segments to choose from in creating the V domain, 5 J region segments, and 1 constant region

Thus, there are approximately 175 potential sequence permutations of κ light chains

71
Q

The heavy chain locus contains ___ V (variable) segments, ___ D (diversity) segments, and ___ J (joining) segments for ____ different sequence permutations

** If you wanted to include the fact that there are 120 sequence permutations of λ light chains, what does this change?

A

40 V, 23 D, 6 J for

40 x 23 x 6 = 5520

** by recombination alone there are 295 x 5520 > 1.5 million different combinations of heavy and light chains

72
Q

Not to be answered as a question –> this is the full breakdown of using light chains as an example of how pieces of a gene come together to create immunoglobulins of diverse sequence

A

Each expressed light chain is derived from three distinct segments of DNA: V (variable), J (joining), and C (constant)

The κ light chain locus has approximately 35 segments to choose from in creating the V domain, 5 J region segments, and 1 constant region

Thus, there are approximately 175 potential sequence permutations of κ light chains

The heavy chain locus contains 40 V (variable) segments, 23 D (diversity) segments, and 6 J (joining) segments for 5520 different sequence permutations

By including the fact that there are 120 (30 V x 4 J) sequence permutations of λ light chains

By recombination alone there are (120 + 175 =) 295 x 5520 > 1.5 million different combinations of heavy and light chains

73
Q

The joining of V, (D), and J regions occurs via ______ and is catalyzed by an enzyme known as the ______ recombinase

A

recombination ; V(D)J

74
Q

The V(D)J enzyme randomly selects a ______ V site and links it to one of the

A

downstream, J segments (for light chains)

75
Q

What happens to any upstream V regions

A

excluded by transcription

76
Q

Any downstream J segments arising via the recombination process are

A

removed by RNA splicing

77
Q

What happens when V and J segments in making a light chain (reading frames) are joined

A

mistakes occur leading to a further increase in sequence diversity

78
Q

When V and J segments join in making a light chain, mistakes are made –> what is one of these mistakes involving amino acids?

A

Some of these mistakes simply change the amino acid that is coded for and that leads to immunoglobulin diversity

79
Q

When V and J segments join in making a light chain, mistakes are made –> what is one of these mistakes involving functional proteins?

A

these mistakes prevent a functional protein from being expressed

If this occurs, the B cell that made such a mistake dies in the bone marrow

This process is known as clonal deletion

80
Q

What is clonal deletion

A

V and J segments join = mistake –> functional protein is not expressed –> B cell that makes the mistake dies in the bone marrow

81
Q

When and why is expression of the V(D)J recombinase shut off

A

Once a B cell begins producing a functional immunoglobulin formed by the joining of heavy and light chains

to assure that only a single immunoglobulin is made by any individual B cell

82
Q

When and why would the V(D)J recombinase remain active?

A

If the immunoglobulin produced recognizes a self antigen in the bone marrow

it remains active to give the B cell a chance to make an immunoglobulin that does not recognize a self antigen

83
Q

What happens if B cells that recognizes a self antigen in the bone marrow escape the process of V(D)J remaining active?

A

it will produce self-antigens and can cause autoimmune diseases

84
Q

Somatic hyper-mutation further enhances the affinity of

A

immunoglobulins for antigens

85
Q

Once B cells are activated by antigen and begin making a unique immunoglobulin, cells producing this immunoglobulin enter into a

A

enter into a hyper-mutable state

86
Q

Explain the hyper-mutable state from B cells making a unique immunoglobulin

A

This state occurs to actively transcribed genes, and since the immunoglobulin expressed in a particular B cell is the major protein being produced, its gene is subjected to an ENHANCED rate of mutation

These mutations tend to be directed to the VARIABLE part of the immunoglobulin genes

87
Q

This hyper-mutable state occurs though the induction of ____ and what does this change create?

A

an activation-induced deaminase enzyme that converts cytosines to uracils on single-stranded DNA in the act of being transcribed

This change creates G-U mismatches, and repair of these mismatches can produce various types of mutations

88
Q

B cell clones with higher affinities for antigens are preferentially

A

activated leading to their survival and enhanced proliferation allowing them to dominate as the amount of antigen declines

89
Q

B cell clones with increased affinity are selected from

A

the initial population of B cell clones providing enhanced protection against pathogens

90
Q

What is final change that occurs to immunoglobulin genes upon antigen activation

A

the switching between different immunoglobulin classes

91
Q

Class switching is promoted by the

A

same activation-induced deaminase enzyme involved in hypermutation of the immunoglobulin variable region

91
Q

What is the major change that occurs as a consequence of class switching

A

exchanging one heavy chain constant region for another and the subsequent production of secreted rather than membrane bound immunoglobulins

92
Q

Deamination events cause

A

double-stranded breaks in switch sequences between heavy chain constant regions

93
Q

Recombination between Cμ and other C regions

A

allows class switching to occur

94
Q

Recombination is mediated by a

A

recombinase distinct from V(D)J recombinase

95
Q

Class switching is irreversible as the circular DNA released by the recombinase process is

A

degraded

96
Q

In this way (class switching) a B cell goes from making IgM and IgD immunoglobulins to making

A

IgG, IgA, and IgE

97
Q

High affinity forms of secreted immunoglobulins are the types of immunoglobulins used

A

therapeutically

Integrated - Block 1 Exam 2 (3 decks)

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